Cure Cancer Naturally

50 Things About 50 Cancers

This ebook from medical practitioner and family doctor Dr. Parajuli gives you all of the signs and symptoms that you need to know in order to catch cancer in the very early stages and protect yourself from it. You don't have to worry about if you have cancer anymore, and better yet you don't have to spend thousands of dollars to make sure of that either! All it takes is a bit of knowledge and you are on your way! This book also teaches about other aspects of cancer patients, such as how to live with different kinds of cancer, how to prepare yourself mentally to accept this reality if it IS a reality for you, and how to deal with doctors and insurance companies. This book is easy to read and in PDF format, so you don't have to worry at all about reading it. Make it easy on yourself! Read more...

Do I Have Cancer Overview

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Gastrointestinal Cancer

Department of Gastrointestinal Medicine and Nutrition The University of Texas M. D. Anderson Cancer Center Houston, TX 77030-4009 USA Oncology The University of Texas M. D. Anderson Cancer Center Houston, TX 77030-4009 USA Oncology The University of Texas M. D. Anderson Cancer Center Houston, TX 77030-4009 USA Oncology The University of Texas M. D. Anderson Cancer Center Houston, TX 77030-4009 USA M. D. Anderson Cancer Center Houston, TX 77030-4009 USA Gastronomical i.e. gastrointestinal cancer edited by Jaffer A. Ajani et al. . p. cm. (M.D. Anderson cancer care series) ISBN 0-387-22090-9 (sc alk. paper) 1. Digestive organs Cancer. I. Title Gastronomical cancer. II. Title Gastrointestinal cancer. III. Ajani, Jaffer A. IV. Series.

Cancer Drug Discovery and Development

Proteasome Inhibitors in Cancer Therapy, edited by Julian Adams, 2004 Nucleic Acid Theapeutics in Cancer, edited by Alan M. Gewirtz, 2004 Cancer Chemoprevention, Volume 1 Promising Cancer Chemopreventive Agents, edited by Gary J. Kelloff, Ernest T. Hawk, and Caroline C. Sigman, 2004 DNA Repair in Cancer Therapy, edited by Lawrence C. Panasci and Moulay A. Alaoui-Jamali, 2004 edited by George Morstyn, MaryAnn Foote, and Graham J. Lieschke, 2004 Handbook of Anticancer Pharmacokinetics and Pharmacodynamics, edited by William D. Figg and Howard L. McLeod, 2004 Anticancer Drug Development Guide Preclinical Screening, Clinical Trials, and Approval, Second Edition, edited by Beverly A. Teicher and Paul A. Andrews, 2004 Handbook of Cancer Vaccines, edited by Michael A. Morse, Timothy M. Clay, and Kim H. Lyerly, 2004 Drug Delivery Systems in Cancer Therapy, edited by Dennis M. Brown, 2003 Oncogene-Directed Therapies, edited by Janusz Rak, 2003 Cell Cycle Inhibitors in Cancer Therapy Current...

Hormonal Carcinogenesis

It was Furth9 who first tentatively suggested that hormones might be directly carcinogenic not by a genotoxic mechanism per se but by influencing the rate of cell division and thereby increasing the potential for spontaneous mutations. Drawing partially on the work of others, he suggested that while DNA molecules replicate, some copying mistakes might go unrepaired. In fact, the chromosomal instability at mitosis, could produce cells carrying new karyotypes, which are potential ancestors of novel clones liable to become malignant tumors.9 Furth9 went on to describe five lines of evidence to support the hypothesis of carcinogenesis without an extrinsic, genotoxic carcinogen. This evidence drew heavily on his own experience with thyroid carcinogenesis in the rat. During the early 1970s, MacMahon and col-leagues10 published a series of papers suggesting that estrogens, generally, and estradiol, specifically, could be involved in human breast cancer carcinogenesis. At the same time, there...

Genetic Basis Of Hormonal Carcinogenesis

The identification and genetic characterization of families at high risk of breast cancer is the most striking example of the potential importance of inherited traits in breast cancer causation. The localization and sequencing of BRCA1 and BRCA2 has provided two important genes contributing to familial breast and ovarian can-cer.24,25 Somewhat surprisingly, mutations in these genes, which appear to be classic tumor-suppressor genes, seem to contribute little, if at all, to the causative pathway of sporadic breast cancer. Likewise, mutations in two other tumor-suppressor genes, TP53 and AT, contribute to breast cancer risk in certain families but, again, not generally to the risk of sporadic breast can-cer.26 The focus of much current breast cancer research is on susceptibility and progression, until the hormone-independent stage, by endogenous hormone stimulation (Fig. 1.2). Under the majority of circumstances, we assume that a breast epithelial cell does not contain a germline...

Current Trends In Hormonerelated Cancers

While we propose that genetic variation influences cancer risk in hormone-responsive tissue by programming endogenous hormone production, transport, and response, other lifestyle, diagnostic, and treatment factors appear to explain short-term trends in incidence and mortality. For example, trends in hormone-related cancers, such as breast, ovarian, prostate, and uterine cancers, show that incidence and mortality rates are influenced by several factors, including changing patterns of hormone-replacement therapy, oral contraceptive use, disease-screening practices, reproductive characteristics, and other lifestyle factors that vary over time and by racial ethnic group. During the past two decades, efforts to diagnose early stage cancer through screening have resulted in artificial increases in breast and prostate cancer incidence. The impact of changing reproductive factors and screening efforts on the incidence and mortality of each of these hormone-associated cancers is discussed...

Anticarcinogenic Effects

Both in vitro and animal studies indicate that astragalus may have a role as adjunctive therapy in the treatment of some cancers. In vivo studies have shown that astragalus extract exerts anticarcinogenic effects in carcinogen-treated mice, mediated through activation of cytotoxic activity and the production of cytokines (Kurashige et al 1999). An extract of the root (90 and 180 mg kg) prevented the development of preneoplastic lesions and delayed hepatic cancer in chemically-induced hepatocarcinogenesis in a rat model (Cui et al 2003). The saponin, astragaloside IV, can increase the fibrinolytic potential of cultured human umbilical vein endothelial cells by downregulating the expression of plasminogen activator inhibitor type 1 (Zhang et al 1997). Another constituent (astragalan) increased the secretion of TNF-alpha and TNF-beta (Zhao and Kong 1993).

Genomics In Cancer Drug Discovery And Development

Perhaps the single-most important driver of current oncology drug discovery is our knowledge of the cancer genome, particularly at the level of expression of encoded genes, proteins, and regulatory elements. The coalescence of genome sequencing with laboratory automation and miniaturization now enables a truly global view of the state of a cancer cell's genes and their expression. The translation of this vast genomic resource into useful insights and tools for the detection and treatment of cancer is the context in which the current volume of Advances in Cancer Research was conceived.

Chapters 16 Discovery Of Cancer Diagnostics And New Therapeutic Targets

By examining the signatures of gene or protein expression, cancer cells can now be readily differentiated from their normal counterparts at a molecular level, thus enabling the possibility of cancer diagnostics (Chapters 1 and 2). Expression analysis has also found significant use in aiding the selection of patients who may respond to therapy as well as delineating new therapeutic strategies for specific subtypes of cancer (Chapter 3). With improved diagnosis comes the need for new points of therapeutic intervention. Fuchs and Borkhardt (Chapter 4) and Li et al. (Chapter 5) illustrate how the use of small interfering RNA and ribozyme libraries, which now cover a majority of human genes, can identify those that encode proteins crucial to cell survival. These strategies provide the starting points for small molecule screening campaigns against the encoded proteins and the identification of drug leads for preclinical development. Chapter 6, by Caldwell, focuses on how the information...

Screening for cervical cancer

Pap smears should be performed at least every 1 to 3 years. Testing is usually discontinued after age 65 in women who have had regular normal screening tests. Women who have had a hysterectomy, including removal of the cervix for reasons other than cervical cancer or its precursors, do not require Pap testing.

The Molecular Pathogenesis of Human Prostate Cancer

Prostate cancer (PCA) has become the most commonly diagnosed cancer among men in the USA, with an estimated 189,000 cases diagnosed in 2002 (1). Encouragingly, over the past several years, increased use of serum prostate-specific antigen (PSA) screening has increased the fraction of men diagnosed with PCA confined to the prostate gland, leading to more effective use of surgery and radiation therapy for treatment, and to a decline in PCA mortality (2, 3). Despite these improvements, some 30,200 men will likely died of progressive metastatic cancer in 2002 (1). Furthermore, even though men with early PCA can be cured using surgery or radiation therapy, the side effects of treatment frequently include erectile dysfunction, urinary incontinence, or rectal irritation (4-6). New insights into the etiology of PCA are needed so that new strategies for its prevention can be developed. Recent studies of the earliest molecular steps in the development of human PCA have generated new evidence...

The Role Of Leukemia Inhibitory Factor In Cancer And Cancer Metastasis

Department of Bioimmunotherapy, The University of Texas, M. D. Anderson Cancer Center, Houston, Texas, U.S.A Key words Leukemia inhibitory factor (LIF), Cancer, Metastasis Abstract Leukemia inhibitory factor (LIF) is a cytokine that exerts pleiotropic activities. LIF is a member of the interleukin-6 family of cytokines which share a similar receptor complex and signal through the gp 130 receptor subunit. Several neoplastic cells originating from various tissues express either LIF, its receptor, or both and respond to this cytokine. Data accumulated thus far provide a complex picture of LIF activities with LIF being stimulatory, inhibitory or having no effect, depending on the system in which it is studied. LIF appears to play an important role in stimulating the growth of certain tumours, and in affecting the surrounding tissue and the target organ of tumour metastases, particularly bone and skeletal tissue. Overproduction of LIF is likely to have significant constitutional effects....

Factors Affecting Efficacy Of Ad As An Anticancer Agent

Initial attempts to utilize Ads as anticancer therapeutics were undertaken shortly after their discovery in early 1950s (4). Administration of wild-type Ads into patients with cervical carcinomas did not demonstrate significant efficacy. As a result, further development of Ad-based anticancer therapeutics was essentially abandoned for four decades. By the mid-1990s, accumulated data on the virus genome organization and protein expression coupled with significant insights into mechanisms governing Ad-host cell interactions revived the idea of using Ad for the therapy of cancer in humans resulting primarily from the following three remarkable features of the virus (1) its great efficiency in killing infected cells during virus replication, (2) it's ability to infect a variety of primary human cells in vitro, and (3) it's relative safety and ease of propagation and large-scale production in the laboratory. A number of academic research teams and companies worldwide have focused their...

Anticarcinogenic Activity

Observational epidemiological studies have consistently shown a relationship between dietary beta-carotene intake and low risk of various cancers (Cooper et al 1999b, Pryor et al 2000). In animal studies beta-carotene has been found to be chemoprotective, with inhibition of spontaneous mammary tumours (Fujii et al 1993, Nagasawa et al 1991), as well as prevention of skin carcinoma formation (Ponnamperuma et al 2000), UV-induced carcinogenesis in mice (Epstein 1977, Mathews-Roth 1982) and oral cancer in laboratory and animal models (Garewal 1995). Studies in ferrets suggest that the beta-carotene molecule becomes unstable in smoke-exposed lungs and that when given with alpha-tocopherol and ascorbic acid to stabilise the beta-carotene molecule, there is a protective effect against smoke-induced lung squamous metaplasia (Russell 2002). A review of carotenoid research by the International Agency for Research on Cancer suggests there is sufficient evidence that beta-carotene has...

The Role of Progesterone in the Etiology of Breast Cancer

While E's role in the etiology of BC has been extensively studied, and E has been shown to play multiple roles in BC pathways, less is known about the relationship between P and BC etiology. Initially, P was thought to protect the breast from cancer based on its anti-proliferative effects on the endometrium. However, several recent studies suggest that P is involved in multiple pathways associated with BC. In 1994, Shi, et al. (39) summarized evidence documenting the role of P in the initiation and promotion of BC, including how P 1. Stimulates growth in the normal human breast (in contrast to its effect on the endometrium). 2. Has mitogenic effects on BC cell lines. 3. Promotes mammary tumor growth in rodents. 4. Induces mitogenic growth factors and their receptors in hormone receptor positive BC cells. 5. Regulates receptors for adhesion molecules involved in metastases. 6. Tumorigenesis is inhibited by anti-progestins. Details regarding this evidence and more recent work...

Th1 vs Th2Type Response in Cancer

In animal models of cancer and cancer patients, the tumor microenvironment can swing the Th1 Th2 balance to a predominantly Th2 response. Such predominance has been demonstrated in the peripheral blood of patients with advanced-stage cancer (85,86). The measurement of intracellular levels of cytokines in renal cell carcinoma patients by flow cytometry demonstrated a significant shift from a Th1 to a Th2 response with an increasing stage of the disease (87). A Th2 bias and barely or undetectable IFN-y expression by CD4+ T-cell population in cancer might create an environment that would not support the development of tumor antigen-specific CD4+ T cells. Although factors causing a shift to Th2 responses in cancer patients are not well defined, animal studies suggest that both TGF-P and IL-10 are involved in this process. TGF-P may skew T cell responses to Th2 via IL-10 as an intermediate and or inhibit Th1-type responses directly in certain animal models (88,89). IL-10 downregulates the...

Abnormal Dendritic Cell Differentiation and Accumulation of Immature Myeloid Cells in Cancer

The induction of an effective antitumor immune response requires antigen presentation by host APCs (94). DCs are the most potent APCs. DCs, macrophages, and granu-locytes are differentiated from common myeloid progenitors. Only mature DCs can efficiently prime CD8+ CTL precursors (95). Impaired differentiation of the myeloid lineage may result in the accumulation of cells able to inhibit CD8+ T cells (96). Tumors severely affect differentiation of myeloid cells, which results in the decreased production of mature DCs resulting in low DC numbers in peripheral blood and lymph nodes of cancer patients as well as tumor-bearing mice. A direct correlation between DC infiltra tion of tumor and outcome of the disesase has been established. A decreased DC production in cancer is associated with the accumulation of immature myeloid cells. These cells express class I MHC molecules and inhibit antigen-specific responses of CD8+ T cells but not CD4+ T cells (97) via direct cell-to-cell contact...

Applications Of Retroviral Gene Transfer For Cancer Therapy

The use of hematopoietic stem cells (HSC) in bone marrow transplantation approaches have convincingly demonstrated the potential of this approach to repopu-late the different hematologic lineages in mice and in humans, and has found application not only in the treatment of hereditary diseases but also in myelo-reconstitution after high-dose chemotherapy and in controlling graft vs host disease. Because it was shown that HSC can be persistently transduced ex vivo with retroviral vectors (22), these vectors have been extensively used in gene replacement or augmentation and anticancer strategies involving the hematopoietic system. More recently, however, it has become evident that lentiviral vectors are more efficient at transducing quiescent HSC than murine retroviral vectors. Thus, some of the specific applications of hematopoietic gene transfer with implications for cancer gene therapy using retroviral vectors are presented below, with emphasis on lentiviral vectors. 3.1.3. Approaches...

Neoadjuvant And Adjuvant Treatment For Gastric Cancer

Surgical resection remains the primary curative treatment option in gastric cancer, with five-year survival rates of 58 to 78 and 34 reported for stage I and II disease, respectively (35). Despite this, the overall five-year survival rate for all patients remains poor and ranges between 15 and 38 . Recurrences are frequent after surgery. Recurrence rate and subsequent survival is dependent on the stage at diagnosis. Prospective randomized trials have evaluated the role of D1 or D2 resection in the management of gastric cancer and they did not show any advantage in terms of overall survival in favor of D2 lymphadenectomy (10,11,36). In an expert consensus report, it has been agreed that at least a D1 resection should be performed and that it is mandatory that at least 15 lymph nodes are removed and recovered (12). Local or regional recurrence in the gastric or tumor bed, anastomosis, or the regional lymph nodes occurs in 40 to 65 of patients after gastric resection with curative intent...

Molecular Mechanisms of DC Dysfunction in Cancer

Tumor cell-conditioned media and VEGF inhibited the activation of NF-kB in hematopoietic progenitor cells in vitro (127). This inhibition was seen as early as 2 h after the treatment with tumor cell supernatants or VEGF. Similar results were obtained in vivo. NF-kB activation was blocked in bone marrow cells as early as 7 d after the start of VEGF infusion. This well preceded any morphological changes observed in bone marrow of these mice (113). The same inhibitory effect was detected in tumor-bearing mice (113). These data indicate that inhibition of NF-kB could be a mechanism responsible for a defective DC differentiation in cancer. Currently, autologous DCs represent an optimal vehicle for the delivery of tumor vaccines to the immune system of the cancer patient. The potential therapeutic benefit of this intervention, however, may be limited because of the significant proportion of immunosuppressive immature myeloid cells present in the tumor-bearing host. One approach to correct...

Use of Human Breast Cancer Cell Lines to Detect Specific Receptor Induced Proteins

Before the development of DNA micro-array and SAGE approaches, the use of labelling of proteins synthesized in cell culture, before and after hormone stimulation, allowed us detection of several steroid hormone specific induced proteins, as defined by their molecular weight in SDS-PAGE, which could then be identified and studied in tumour samples to specify their significance in human carcinogenesis (16). Regarding progestins, using dose response curves and anti-hormones, we could not discriminate between MPA and R5020 (promegestone) with respect to the induction of specific PR responses, such as the secreted 48 kD protein (16-17) and the cellular 250 kD protein, which were both inhibited by the anti-progestin RU486, but not by the anti-androgen flutamide (18 and D.Chalbos et unpublished).

Natural killer cell defects in cancer

Tumor progression is associated with the impairment in cell number or function of NK cells (144,145). Metastases in head and neck cancer patients were also found to be dependent on NK-cell activity (146). The NK-cell defects related to cancer involve a decrease of both activity and numbers of CD56+ and CD56dim NK cells (147,148), impaired perforin-dependent mechanism of cytotoxicity (metastatic melanomas) (149), and immunosuppression associated with impaired granulysin expression (150). Patients with advanced lung, breast, gastrointestinal, hepatobiliary, pancreatic, urinary tract, uterine, and ovarian cancers had significantly fewer granulysin-positive NK cells than healthy individuals. The expression of perforin determined in this study was not significantly impaired (150). In some cases, the defective function of NK cells was associated with low level of spontaneous IFN-y secretion (151). The mechanisms of NK-cell defects in cancer patients can also be linked to abnormally high...

What Is Hereditary Breast Cancer

It is worth stating at the outset that the term hereditary breast cancer, while in widespread usage, is somewhat problematic. Hereditary implies that the propensity to disease in that individual has been inherited. Thus, the implication is that breast cancer can be dichotomized into those cases where susceptibility is inherited and those where it is not. This concept arose from consideration of cancers with a simpler genetic basis such as retinoblastoma and Wilm's tumor, which can be usefully categorized in this way (2,3). As we shall see, the situation is much more complex for breast cancer. There are many different susceptibility genes for breast cancer, and a substantial fraction (in fact the majority) of breast cancer cases occur in women who are predisposed in some way. It is also worth emphasizing here that there is no known pathologically distinct type of breast cancer that is hereditary (although certain pathological features are more common in BRCA1 carriers), so it is not...

Clinical and Molecular Prognostic Markers for Ovarian Cancer

Several clinical features have been shown to have significant impact on ovarian cancer patient survival. As discussed in Section I.A, patients with early stage diseases have significantly better survival rate than those with late-stage diseases. Optimally debulking of patient surgically (ability to remove residual tumor nodules which are greater than 2 cm) is associated with improved outcomes. In addition, patients with poorly differentiated tumors and clear cell lesions have a poorer prognosis than those with low-grade tumors or BOTs, or mucinous ovarian cancer, respectively. Finally, other clinical features, such as a large volume of ascites and age at the time of diagnosis (> 65 years), have also been shown to be associated with poorer clinical outcomes (Cannistra, 1993). Recent molecular studies have identified multiple markers, which have prognostic values. Both epidermal growth factor receptor (EGFR) and HER-2 neu overexpression have been shown to be associated with poor...

Epidemiological Studies Of Familial Breast Cancer

Much of the impetus for breast cancer genetics has come from observations of families with extraordinary numbers of cases of the disease (5). These families have often been critical to the identification of the high-risk susceptibility genes. They are, however, less useful for evaluating the risks associated with a family history of breast cancer or with any particular gene, because they are not collected in a systematic fashion. To provide useful information for genetic counseling, risk estimates from epidemiological studies are required. Fortunately, many such studies have been conducted. Most are case-control studies that compare the family history of breast cancer in cases with the family history in controls. Other studies are cohort studies of relatives of breast cancer patients. These latter studies include those based on record linkage with national records, notably those done in Sweden, Iceland, and Utah, and they provide estimates that are free from any potential recall bias...

What is the Significance of FAS Overexpression in Cancer Cells

Is FAS over-expression a marker only associated with aggressive solid tumours or is it actively engaged in mammary carcinogenesis FAS activity and endogenous fatty acid synthesis are required for normal embryonic development since FAS gene knock-out is lethal in mice (43). In normal adult cells, except in lactating mammary glands (30), FAS activity is low since fatty acids are mostly provided by food and imported from local vascularization (47). We hypothesize that in solid tumours the bio-availability of fatty acids from the circulation is weak because their vascularization is generally poor, as also indicated by the lower extra-cellular pH. BC cells overexpressing FAS may have a growth advantage compared to normal peripheral cells in these solid tumours. Cancer cells require nutrients to grow, and not only mitogens. In addition to proteins, they also need fatty acids as precursors for synthesis of membranes, lipid mediators and lipid anchors and they may use FAS for endogenous...

Twin Studies and Bilateral Breast Cancer

In principle, the familial aggregation of breast cancer may be due either to genetic factors or to lifestyle or environmental factors that are shared among relatives. The latter possibility is unlikely in that no lifestyle risk factors that are sufficiently strong to materially affect familial aggregation of the disease have been identified. More formal evidence that familial aggregation has a genetic basis comes from twin studies. Based on an analysis of population-based twin registers from the Nordic studies, Lichtenstein et al. (23) found that the risk of breast cancer in the monozygotic (MZ) twins of cases was about twice as great as the risk in the dizygotic (DZ) twins. Using a particular multifactorial model, this study estimated that about 27 of the variation in breast cancer risk was genetic. This particular estimate should be viewed cautiously since it does depend on the model used and on how one defines the variation in breast cancer risk, but it does point to a substantial...

Prevention Of Colorectal Cancer

High dietary intake of calcium has demonstrated a reasonably consistent risk reduction of between 15 and 40 for colorectal cancer. Clear parameters for dosing are not yet available, with some studies showing no further benefit above Calcium 155 A 2005 Cochrane review examining the effect of supplementary calcium on the incidence of colorectal cancer and the incidence or recurrence of adenomatous polyps included two double-blind, placebo-controlled trials with a pooled population of 1346 subjects. The doses of supplementary elemental calcium used were 1200-2000 mg day for 3-4 years. The reviewers concluded that while the evidence to date appears promising and suggests a moderate degree of prevention against colorectal adenomatous polyps, more research with similar findings is required before this can be translated into any preventative protocol (Weingarten et al 2005).

Genetic Alterations of Colorectal Cancer

The molecular genetic alterations in colorectal carcinoma are among the best understood in human cancer and involve abnormalities in multiple dominant-acting oncogenes and tumor-suppressor genes (Kinzler and Vogelstein, 1996 Fearon and Dang, 1999). Various pathways of colorectal carcinogenesis are evident in sporadic, familial, and inflammatory bowel disease-associated neoplasms. The somatic alterations in sporadic colo-

Breast Cancer Susceptibility And Other Risk Factors

An important and largely unresolved question is the relationship between genetic and lifestyle risk factors for breast cancer. The combined analysis by the Collaborative Group examined the effect of several important risk factors on the familial risk of breast cancer, including parity, age at first full-term pregnancy, and ages at menarche and menopause. In each case, they found that the relative risks conferred by these risk factors were similar in women with and without a family history (1). These results imply that such risk factors can be assumed to multiply the familial risks of breast cancer (an assumption made in the Tyrer et al. and Gail models). It also suggests that such risk factors are largely independent of genotype. Whether this is true for specific susceptibility genes, in particular BRCA1 and BRCA2, is less clear however. Several studies have examined the effects of these risk factors in BRCA1 2 carriers but many of the results are contradictory, perhaps reflecting...

Models Of Breast Cancer Susceptibility

Several models have been developed to derive estimates of risk to women with a family history of breast cancer or to estimate the probability of carrying a mutation in the BRCA1 or BRCA2 gene. These models can be broadly categorized as empirical models and genetic models. Empirical models are based summarily on measures of family history, such as the number of affected relatives and other risk factors. Perhaps the most widely used model of this kind is the Gail model, which incorporates a variety of breast cancer risk factors in addition to the number of affected relatives (31). Such a model is useful in the general population context, for example, in selecting women for prevention trials but is less useful in high-risk families where the nuances of the family history cannot be captured well. Genetic models seek to model the familial aggregation of the disease in terms of the effects of specific genes or other familial risk factors. These models are developed from population-based...

Brain Tumor Models for Cancer Therapy

The most frequently used preclinical in vivo models of brain tumors include the rat carcinogen-induced syngeneic models and human tumor xenografts. Both types of tumors are routinely implanted subcuta-neously or intracranially in host animals including conventional and nude rats or nude or SCID mice. These models have been used to explore the efficacy of diverse therapeutic strategies.

ProgesteronePR Signaling in Mammary Carcinogenesis

In normal mammary epithelial cells, the initial impact of progesterone signaling through PR results in an increase in proliferation. Therefore, in its capacity as a mammary gland mitogen, progesterone has the potential to trigger carcinogenesis. An excellent example of this P action is the animal model developed by Lanari et al. in which the progestin, medroxyprogesterone induces mammary tumors (21). Another example is the p53-null mutant mammary epithelium in which progesterone alone strongly enhances mammary tumorigenesis (22). Studies from our laboratory (as reviewed here) showed that a deregulation in progesterone action (as in PR-A transgenics) can alter the growth potential of epithelial cells, at least, in part, at the level of cell cycle, leading to transformation. Recent population based studies also demonstrated that, in uninterrupted combined hormone (estrogen + progestin) replacement therapy (CHRT), progesterone is the contributing factor for the increased risk for mammary...

Association of 16aHydroxylated Estrogens with Breast Cancer Risk

Mation of 16a-hydroxylated estrogen metabolites might be associated with increased risk of developing breast cancer. Their initial studies showed that 2- and 16-hydroxylation of estradiol was minimally affected by age and did not differ between premenopausal and post-menopausal women.129 However, when these enzymatic activities were compared between breast cancer patients (n 33) and matched controls (n 10), 16-hydroxylation was associated with increased risk of breast cancer, whereas the competing 2-hydroxylation pathway was either neutral or associated with decreased risk.135 The investigators suggested that the breast cancer patients had an increased extent of 16a-hydroxylation prior to the onset of the disease, unless the increase was a consequence of the cancer itself. In a subsequent study, using a murine mammary tumor model, Bradlow and associates136 reported a close correlation between the extent of tumor incidence and 16a-hydroxylation, but not 2-hydroxylation, of estra-diol....

Vaccinia As A Cancer Vaccine

The experience with vaccinia in the eradication of smallpox led to research into its use as an antitumor vaccine. Vaccinia was engineered to express tumor antigens and serve as a cancer vaccine. The size of the potential transgene that can be put into the vaccinia vector allows for flexibility in engineering, such that immune enhancing genes and antigenetic genes can be recombined into the genome. The immunostimulatory effects and efficient transcriptional machinery of the virus were utilized to create various cancer vaccine vectors (Table 2). Recently, a phase I clinical trial of vaccinia expressing prostate specific antigen (PSA) in prostate cancer patients was published. In this trial the Wyeth strain virus was delivered intradermally every 4 wk for three doses without producing significant systemic toxicities. A cutaneous reaction, consistent with viral replication was seen in all patients treated with the virus at a dose of 2.65 x 107 pfu. Several patients developed T-cell immune...

Risks of Other Cancers in BRCA1BRCA2 Carriers

In addition to the marked excess of breast and ovarian cancer in BRCA1 and BRCA2 carriers, there is also evidence of more moderate risks of other cancer types. The largest study of cancer risks in BRCA1 carriers, based on 699 carrier families, found an overall cancer risk in male carriers very close to that in the general population, but the risk of cancers other than breast or ovarian in female carriers was increased by approximately twofold (44). Specifically, significant excesses were seen for cancers of the corpus uteri, the cervix, the fallopian tubes, and the peritoneum. There was also some evidence of a twofold relative risk of pancreatic cancer in carriers of both sexes and prostate cancer below age 65. In a parallel study based on 173 BRCA2 families, the risk of other cancers was approximately twofold in both male and female carriers (42). The largest excess risk was for prostate cancer, with an estimated 4.7-fold relative risk, increasing to sevenfold in men below age 65. A...

Other Breast Cancer Genes High Risk Breast Cancer Genes

Breast cancer is involved in two other hereditary syndromes, for which causative genes have been identified. The Li-Fraumeni syndrome is characterized by childhood sarcoma and early-onset breast cancer, brain tumors, and a variety of other cancers. Most families with Li-Fraumeni syndrome appear to be due to germline mutations in the TP53 gene. TP53 mutations confer a very high risk of breast cancer (approaching 100 by age 50) but are much rarer than BRCA1 or BRCA2 mutations (45,46). Cowden's syndrome is a rare syndrome characterized by hamartomas, multiple hamartomas, thyroid cancer, and mucocutaneous lesions and is due to germline mutations in PTEN (61). The risk of breast cancer associated with Cowden's syndrome has not been well estimated, but it is of the order of 30 to 50 lifetime (47).

The Effectiveness Of Genetic Toxicity Tests For Identifying Carcinogens And Noncarcinogens

The use of in vitro and in vivo genetic toxicity tests for identifying carcinogens and noncarcinogens are based on several premises (a) tests for both gene mutations and chromosome aberrations are needed (b) mammalian cell tests are more relevant than microbial or other nonmammalian tests, and (c) in vivo mammalian tests are more relevant than in vitro tests. These premises guide most genetic tox-icity testing requirements, whether from government regulatory agencies or industrial chemical or drug development scientists. The premises have recently been re-examined using the databases of chemicals tested by the U.S.-NTP for rodent carcinogenicity and genetic toxicity. The U.S.-NTP databases of carcinogenicity and genetic toxicity test results were used for the evaluation. These studies are characterized by defined, standardized test protocols and evaluation criteria and the availability of the peer-reviewed test data and summary conclusions (47-49). Other, unpublished genetic toxicity...

Low Risk Breast Cancer Genes

A growing list of genes is associated with more moderate risks of breast cancer. The first such gene to be identified was ATM. Mutations in this gene cause the recessive condition Ataxia-Telangiectasia (A-T) (62). Studies dating back over 30 years have suggested that relatives of A-T patients were at increased risk of breast (and perhaps other) cancer (63). This was long regarded as controversial because the studies were small. However, more recent national cohort studies, and direct studies of ATM mutations in breast cancer families and controls, have confirmed that ATM mutations confer an approximately twofold risk of breast cancer (with perhaps a higher relative risk at young ages) (64-67). Another important low-risk susceptibility gene is CHEK2, another DNA repair gene that acts downstream of ATM. Mutations in this gene were first identified in patients with a family history reminiscent of Li-Fraumeni syndrome, and it was therefore suspected that this was another high-risk...

Patients With Cancer Can Be Immunized With Class I Peptide Based Vaccines

Clinical trials performed vaccinating cancer patients with class I binding peptides derived from a variety of tumor antigens have demonstrated that patients can be immunized to boost immunity to self-tumor antigens. Peptide-based vaccines offer an excellent model for assessing the ability to immunize by measuring immunity generated with assays that can specifically measure class I T-cell responses. Lee et al. (13) used MHC tetramer flow cytometry to evaluate in vivo response to vaccination with gp100209_217 and tyrosinase368-376 peptides in 44 HLA-A2 patients with advanced-stage melanoma. Tetramer assays performed before, during, and following the period of vaccination demonstrated appearance of gp100-specific T cells as early as 4 wk, i.e., after two vaccinations. At 18 wk at least 20 of CD8+ T cells were specific for gp100209-217 in four of six

Mechanisms of Cyclin E Deregulation in Cancer

The first report of cyclin E gene amplification as tumor-linked mechanism for elevation of cyclin E expression was based on a breast cancer (BC) derived cell line (15). Subsequently cyclin E gene amplification has been reported at varying frequencies in a variety of different tumor types, particularly gastrointestinal and ovarian cancer (16-18). In BC, however, cyclin E gene amplification is rare (16). We therefore sought to determine if deregulation of cyclin E could be mediated by defects in the cyclin E degradation pathway. First, we analyzed tumor-derived DNA for mutations in cyclin E itself that might impair phosphorylation-dependent ubiquitination. Single stranded conformational polymorphism (SSCP) analysis of DNA from more than 100 tumors yielded no mutations that could account for cyclin E stabilization. Therefore, we turned to analysis of the cyclin E ubiquitation machinery. SCF protein-ubiquitin ligases are characterized by specificity factors, known as F-box proteins that...

Contribution Of Known Genes To Breast Cancer Incidence

The frequency of BRCA1 and BRCA2 mutations in breast cancer cases has been estimated by a number of studies. By pooling data from a number of population-based studies, Thompson and Easton (78) estimated that the prevalences of BRCA1 and BRCA2 mutations among breast cancer patients diagnosed below their mid-30s were approximately 4.6 and 3.5 , respectively. In contrast, the Anglian Breast Cancer Study (the largest population-based study to date) found the prevalences among cases diagnosed between 45 and 54 years of age to be just 0.3 and 1.0 , respectively (79). These studies underestimate the true prevalence of mutations because studies use methods that are not fully sensitive. Indeed, the fraction of mutations that are detected by such studies is somewhat uncertain because some variants in BRCA1 and BRCA2 are of uncertain significance and may or may not be associated with risk. Nevertheless, overall fraction of breast cancer patients in outbred populations carrying BRCA1 and BRCA2...

Patterns Of Recurrence In Gastric Cancer

Early sites of recurrent gastric cancer are difficult to identify, even with current advances in imaging techniques. Most recurrent disease goes undetected until it is fairly advanced (14-16). Historical autopsy series outline late patterns of recurrence in gastric cancer, but typically demonstrate large volumes of disease obscuring the initial site of treatment failure (17). A valuable addition to our understanding of recurrence patterns was provided by studies from Wangensteen et al. at the University of Minnesota, where they routinely performed second-look laparotomies. In 1982, they reported on this reoperative series, finding that locoregional recurrence was at least one component of treatment failure in 88 of patients with relapse and the only component in 29 (18). Of those patients with recurrence, 55 recurred in the gastric bed, 27 at the anastomosis, and 43 in locoregional lymph nodes. In studies from Japan, 67 of a total of 107 patients had evidence of a locoregional...

Mass Spectrometry Uncovering the Cancer Proteome for Diagnostics

Early Detection C. Mass Spectrometry as a Cancer Diagnostic Tool VI. Current Limitations of Diagnostic Mass Spectrometry Despite impressive scientific achievements over the past few decades, cancer is still a leading cause of death. One of the major reasons is that most cancer patients are diagnosed with advanced disease. This is clearly illustrated with ovarian cancer in which the overall 5-year survival rates are only 20-30 . Conversely, when ovarian cancer is detected early (stage 1), the 5-year survival rate increases to 95 . Biomarkers, as tools for preclinical detection of cancer, have the potential to revolutionize the field of clinical diagnostics. The emerging field of clinical proteomics has found applications across a wide spectrum of cancer research. This chapter will focus on mass spectrometry as a proteomic technology implemented in three areas of cancer diagnostics, tissue imaging, and biomarker discovery. Despite its power, it is also...

Clinical Patterns In Head And Neck Cancer

What factors determine the TNM stage of a patient's tumor when they present with their head and neck cancers Certainly time can be implicated in accounting for such differences. Patient delay in seeking treatment and their differences in tolerance thresholds for noxious symptoms are clearly important in this respect. Moreover, certain primary sites, such as the endolarynx, tend to be detected earlier due to their anatomy and the subsequent early disruption of function, whereas tumors such as pyriform sinus, supraglottic larynx, and base of tongue tend to present at a later stage. Time alone, however, does not adequately account for the spectrum of TNM stages observed at presentation. The inexperienced clinician is often skeptical when confronted with a patient who claims that their N3 neck mass was not present a few Head and Neck Cancer

Current Cancer Biomarkers

1 Abbreviations NACB, National Academy of Clinical Biochemistry EGTM, European Group on Tumor Makers SEER, Surveillance, epidemiology, and end results WHO, World Health Organization EDRN, Early Detection Research Network ELISA, Enzyme-linked immunosorbent assay CGAP, Cancer Genome Anatomy Project SAGE, Serial analysis of gene expression EST, Expressed sequence tag SELDI-TOF, Surface-enhanced laser desorption ionization-time-of-flight MUDPIT, Multidimentsional protein identification technology HPLC, High-performance liquid chromatography ESI, Electrospray ionization MALDI, Matrixassisted laser desorption FT-ICR MS, Fourier transform ion cyclotron ionization resonance mass spectrometer CID, Collisional-induced dissociation SILAC, Stable-isotope labeling with amino acids in cell culture ICAT, Isotope-coded affinity tag LCM, Laser capture microdissection IMAC, Immobiliszed metal affinity capture NCI, National Cancer Institute.

Centrosome Amplification in Cancer

Recent studies implicate centrosome abnormalities in the pathogenesis of cancer (4, 10-14). The term centrosome amplification refers to centrosomes that appear larger than normal, centrosomes that contain more than four centrioles, and or when more than two centrosomes are present within a cell. In addition to these structural abnormalities, amplified centrosomes also show protein hyperphosphorylation and altered functional properties such as an increased microtubule nucleating capacity (4, 8, 15-17). Electron microscope studies revealed supernumerary centrioles in centrosomes of humans and animal model tumors, including leiomyosarcoma, neuroblastoma, glioma, and thymic carcinoid tumors (18-23). Systematic analyses of centrosomes in human breast carcinomas and a mouse model for prostate cancer revealed a range of abnormalities in centrosome structure including excess number of centrioles, increased pericentriolar material, abnormal centriole orientation, and inverted polarity of...

Computer Applications in Pancreatic Cancer Imaging

There is limited development of automatic approaches for the detection and or diagnosis of pancreatic cancer either from CT or other imaging modalities. This is certainly an area worthy of further investigation and an area identified as in great need of technological advances by the NCI Review Group 2 . Imaging priorities set by the Group have been summarized earlier in this chapter. One of the most interesting recommendation was for a collaborative research and training approach that will link molecular biology, pathology, and imaging as well as for a well documented source of images to support computer applications and image processing 2 .

Hyperplastic and Premalignant Lesions Precursors and Markers of Increased Risk of Breast Cancer

The ductal carcinomas in-situ (DCIS) are well accepted as precursors lesions. They probably have a magnitude of risk in the range of 50 over a ten year period with some variation in both size at time of diagnosis and risk differing between the low and high grade varieties. Presentation of DCIS raises the very important consideration not frequently discussed, the nature of the subsequently developing invasive lesion. The majority ofthe invasive carcinomas developing at least in the short period of several years after initial identification ofan inadequately removed low grade DCIS are low grade invasive cancers, and many ofthese lesions may have prolonged periods without invasion (16, 17). General distribution of cancer risk, in each breast, Cancer in same breast as ALH 70 of the time, and possibly favoring same region in same breast. RR 4.0 x, decreasing with menopause.

Translational Or Correlative Cancer Research

The terms translational or correlative research are meant to represent that area of cancer research that brings together clinical observations, laboratory research, and the application of the product of this interaction for the treatment of patients with cancer 54 . This process also implies the potential to individualize treatment strategies that are tailored to the patient's tumor biology 55 . However, where is the optimum point, if any, to initiate this process While important and valid molecular-genetic observations are often made at cellular and subcellular levels in the laboratory, how such observations become properly integrated into the extraordinary complex panorama of human cancer is often problematic. Guidelines for research that have evolved over the centuries have culminated in an agreed upon format generally referred to as the scientific This is basically a unidirectional system and one that works best when not begun in the middle or run backward The observational step...

Antiid antibodies and human cancer

Carcinoembryonic Antigen (CEA) A number of anti-Id antibodies (Table 1) have been generated that mimic CEA (1523). CEA is one of the first TAAs to be identified and is one of the most widely investigated human TAAs. CEA is a 180 kD glycoprotein and was originally detected in colonic carcinoma and fetal gut. However, it has since been detected at high density in 95 of colorectal carcinoma, 70 of lung adenocarcinoma, and 50 of breast cancer. In order to generate the most highly specific and the least cross-reactive Ab1' antibodies, a suitable anti-CEA monoclonal antibody should be chosen. A number of anti-CEA monoclonal antibodies have been raised, some of which react with the carbohydrate moiety of the molecule, whereas others recognize the peptide part, which may, however, be present in CEA-related antigens. Such CEA-related antigens include the normal cross-reacting antigens (NCAs), NCA2, normal fecal antigen (NFA-2), and biliary glycoprotein (BGP), all...

Tyrercuzick International Breast Cancer Intervention Study

This is the most recently developed of the breast cancer risk assessment models (32). It was developed using published data regarding BRCA1 and BRCA2 mutation carrier frequencies from a study of mother-daughter pairs (33) and penetrance estimates from the Breast Cancer Linkage Consortium (34) rather than one specific dataset. There are two parts to the model's calculations a genetic part and a personal risk factors part. Like the BRCAPRO model, International Breast Cancer Intervention Study (IBIS) uses Bayesian calculations as a basis for the genetic part of the model. The Bayesian variables used are BRCA1 mutation, BRCA2 mutation, and other genetic risk factor, an as yet unknown low-penetrance gene that is assumed to follow an autosomal-dominant inheritance pattern. Like BOADICEA, IBIS can incorporate exact family relationships and is not restricted to a certain number of first- and second-degree relatives in order to make its assessment. It is also capable of dealing with bilateral...

Iigenetic Changes In Cancer Cells

Based on the somatic cell mutation theory of carcinogenesis proposed in the 1920s (3), gene mutation has long been considered as the primary mechanism of chemical carcinogenesis. The most convincing evidence of this theory comes from studies of inheritable cancers (4, 5) and various tumors that are known to associate with specific genes in humans (2). These findings confirmed the presence of human cancer genes and that they are chromosomally located. Mutations of these genes could result in neoplasm, although allelic mutations alone are not considered sufficient to acquire malignancy (6). Human cancer genes are often tumor suppressor genes, proto-oncogenes, and DNA repair genes. There are about 15 tumor suppressor genes, and more than 100 proto-oncogenes (7). All human and rodent tumor cells contain mutations and chromosome aberrations (8, 9), with multiple, and sometimes specific, DNA sequence changes (10, 11). Studies of neoplastic transformation in cultured cells (12, 13) and in...

Iiigenetic And Epigenetic Mechanisms Of Carcinogenesis

In practice, the genotoxicity of a carcinogen is determined by a battery of genetic toxicology tests. A battery typically consists of three to four mutagenicity tests considered reliable for the detection of mutagens. They are a bacterial mutagen-icity test (such as the Ames test), an in vitro cytogenetic assay in mammalian cells (chromosome aberration), an in vivo cytogenetic assay in rodents (such as micronucleus, chromosome aberration), and sometimes a mammalian cell gene mutation assay (such as mouse lymphoma, Chinese hamster ovary cells) (15). The test procedures and specific requirement of these tests are well established and have been extensively described in two recent international guidelines (16-18). If positive or equivocal findings are observed, additional tests may need to be conducted (such as unscheduled DNA synthesis, DNA adduct), and final decisions are often made by weight of evidence and sound scientific judgment. Based on the results of these tests, a carcinogen is...

Sex Steroid Hormone Receptors and Cancer

Because of their involvement in the regulation of growth control and differentiation during development of the reproductive system, ER, PR, and AR activities are targets of therapeutic intervention in cancers associated with these tissues. Both ER and PR are expressed in breast and uterine cancers, and activation of AR has been implicated in prostatic cancer.306,307 Onco-genes such as c-myc, c-fos, and c-jun are both direct and indirect transcriptional targets for these receptors in these tissues and it is likely that these and other cell cycle regulators are influenced by steroid action.308-310 Clinical use of antagonists and partial agonists of these receptors, such as 4-hydroxytamoxifen and RU486, results in reduction of tumor progression in patients whose tumors are characterized as hormone-responsive. Hormone responsiveness of these tumors often declines following treatment, probably due to second-site mutations that alter the ligand-binding capacity of the receptor.7...

Vsv As A Therapy Against Cancer

Our data, as well as that of others, also indicated that whereas normal cells treated with IFN were protected from VSV infection, transformed cells were much less protected (21,34). Even many types of IFN-treated tumor cells eventually succumbed to virus infection, speculatively inferring a common defect in innate immune responses (61,62). Given our above data, we naturally examined the status of PKR in VSV-susceptible tumor cells. For example, it was plausible that PKR could be defective in cells sensitive to VSV. However, our data indicated that PKR was functional in many cases and remained able to phosphorylate eIF2a (23). We subsequently noted that a key translation factor that recognized phosphorylated eIF2a and slowed protein synthesis, referred to as eIF2B, was frequently defective (23). The consequences of this were that phosphorylated eIF2a did not impede translation rates. This may assist viral translation and allow VSV to replicate faster than an antiviral state involving...

Aromatase Transgenic Mice are Susceptible to Carcinogens

To test the hypothesis that tissue E-induced preneoplastic changes induced may be susceptible to carcinogens like DMBA, and that exposure to these carcinogens may result in acceleration and or increase in the incidence of BC (21). Exposure to a single sub-threshold concentrations of DMBA (0.5 (ig mouse) resulted in development of MG tumors in 25-1 of the transgenic animals and non in wild type mice. All the DMBA-exposed transgenic females had microscopic evidence of tumor formation neoplastic progression. When the ARO transgenic female animals were exposed to a higher DMBA dose (1.0 Hg mouse week 4 weeks), more than 50 developed palpable MG tumors within 4.0 mo, while 100 show microscopic evidence of tumor formation Previous data (6, 13, 22) suggest that the ERa has a negative regulatory effect on EGFR expression and its ligands. These results are consistent with the clinical observations that loss of ERa in BC results in the upregulation of growth factors like TGFa, leading to a more...

Genetically Engineered VSV as a Gene Therapy Tool Against Cancer

Oncolytic studies indicated that wild type VSV exhibited considerable potential as an anticancer agent. However, the ability to modify VSV through genetic engineering obviously affords the prospect of creating new generations of custom-made VSV vectors that contain immunomodulatory and or suicide cassettes designed to increase their antitumor activity. In order to begin evaluating whether genetically engineered VSV carrying tumor-killing cassettes could be created and whether such viruses were more efficacious in tumor therapy than the wild-type VSV, we developed VSV vectors carrying, as models, the herpesvirus TK suicide cassette or the cytokine gene interleukin-4 (IL-4). The foreign genes were cloned as additional transcription units between the VSV G and L genes and all viruses were grown to exceptionally high titers (71,103). TK protein was synthesized to extremely high levels and was functional, being able to phosphorylate ganciclovirs (GCV). Recombinant viruses also retained...

Human Versus Rodent Carcinogenesis

Of the more than 400 rodent chemical carcinogens in the IARC carcinogen list (group 2), only about 50 human chemical carcinogens (group 1) have been identified so far (101). This large difference may be explained by the lack of sufficient epidemiological studies of rodent carcinogens, which are required for their evaluation as human carcinogens. However, it is also possible that there are inherent genetic and biochemical differences between humans' and rodents' response to chemical carcinogenesis. Evidence to support this proposition is discussed below. A very significant finding, but seldom discussed, is the unique resistance of human cells to chemical carcinogenesis in culture, as demonstrated in in vitro neoplastic transformation studies. Neoplastic transformation in vitro means the immortalization of a primary cell culture to become established cell lines and to acquire neoplastic phenotypes, including the ability to form a tumor in immuno-deficient mice. In these studies, rodent...

Adenovector Mediated Cancer Gene Therapy

Early-region (E1)-deleted, replication-defective adenovectors have been widely used in preclinical and clinical studies of cancer gene therapy. Recently, the use of conditional replicating or oncolytic adenovectors in cancer gene therapy or virotherapy has received much attention. Clinical trials with E1-deleted adenovectors and oncolytic adenovirus have shown that adenovector-mediated cancer gene therapy is well tolerated and can produce clinical responses in patients with advanced diseases. Moreover, numerous strategies to improve vector safety and therapeutic efficacy have been explored, including vector modification and the development of vector formulations to enhance transduction efficiency, to modulate tropism for vector targeting, to improve controlled or tissue-specific transgene expression, and to reduce vector-related toxicity. Yet, much has to be improved in this type of vector system to ensure its future success in clinical applications.

Peroxisome Proliferatoractivated Receptors And Cancer

The ability of PPARy to promote and establish differentiated phenotypes in at least two cell types (i.e., adipose and macrophage) suggests that PPARy activators may also be useful to block proliferation in malignant cells that express this receptor. In fact, preliminary studies demonstrate that in breast cancer and liposar-coma cell lines PPARy and or RXR ligands are capable of limiting cell growth by promoting dif-ferentiation.407,408 This differentiation therapy is similar in concept to RA treatment in APL, where activation of the NR interferes with or su-percedes proliferative growth signals by unknown mechanisms. The ability of PPARy to promote differentiation, however, is likely tissue- and context-dependent. For example, activation of PPARy in the colon of the adenoma-tous polyposis coli (APC)-deficient Min mouse (a model of familial adenomatous polyposis) results in an increase in colon polyp number.397,409 However, studies in colon cancer cell lines found that...

Mass Spectrometry as a Cancer Diagnostic Tool

Mass spectrometry of endogenous human serum peptides using the Ciphergen Biosystems TOF in the MALDI or SELDI mode (Weinberger et al., 2000) as a diagnostic tool and their identification by MALDI-Qq-TOF was successfully demonstrated by Jackowski and coworkers (Takahashi et al., 2001). Later Petricoin and coworkers proposed using only the SELDI pattern of the unidentified peaks as a diagnostic tool (Petricoin et al., 2002a). Biovision (BioVisioN AG, Hannover, Germany) proposed the examination of the MALDI profile of endogenous peptides prepared by reversed phase chro-matography against a previously established library of analytes. Their approach is based on identifying patterns of differentially expressed proteins analyzed by computer algorithms, between samples from diseased and nondiseased subjects, without requiring knowledge of the identity of the individual discriminating molecules (Tammen et al., 2003). Since then, many papers have been published on using protein pattern...

Surgery for Testicular Cancer Radical Orchiectomy

Testicular cancer remains the most curable solid tumor in men. Careful histologic diagnosis and prompt evaluation for metastatic disease are essential for the selection of appropriate treatment. The first surgical step in the management of testicular cancer is inguinal orchiectomy. In the past, before the advent of good techniques for testicular imaging, inguinal exploration with open biopsy of the testis was the primary method of making a definitive diagnosis of testicular cancer. Now, scrotal ultrasonography is nearly 100 accurate in identifying a tumor in the testis, and it is rarely necessary to perform a truly exploratory surgery.1,2

Hormonal Prevention of Breast Cancer Mimicking the Protective Effect of Pregnancy

Hormonal prevention strategies have used exogenous hormonal treatment to mimic the protective effect of pregnancy against BC. Huggins, et al. (29) reported that high levels of E2 and P given for 30 days beginning 15 days after DMBA administration inhibited MC in SD rats. They proposed that treatment with high levels of these hormones destroyed the potential cancer cells. Grubbs, et al. (30, 31) and McCormick and Moon (32) demonstrated that treatment of SD rats with high levels of and P, or alone following treatment with MNU, a direct acting chemical carcinogen, was as effective as ovariectomy in preventing MC. Grubbs (31) suggested that the primary action of the hormones was to cause differentiation of the pre-neoplastic cells. Recent studies have reported on persistently altered expression of genes in the mammary glands ofparous rats (33). They reported that certain genes involved in growth promotion are persistently down regulated in mammary glands. They also reported that TGF-P3...

Presentation Of Testicular Cancer

The clinical presentation of testicular cancer is usually quite obvious. The typical patient is a man aged 17 to 45 years who notices a growing and relatively painless mass in the scrotum and seeks medical attention. However, as many as 10 of patients present with atypical complaints, such as sudden pain in the scrotum, a new-onset hydrocele, or recent trauma. Some patients are misdiagnosed as having epididymitis, causing an unnecessary delay in diagnosis. A high index of suspicion is required when evaluating any man in this age group with testicular complaints, and the possibility of testicular cancer must be in the differential diagnosis. Patients diagnosed with presumed epididymitis should be observed until the testicular examination result returns to normal, which might take several months. Any patient with nonspecific orchialgia who is completely normal on examination should probably have at least one follow-up examination in 3 to 6 months to ensure that a small tumor was not...

History Of Parvovirus And Cancer

Since the discovery of parvoviruses, there has been significant advance on the relationship between parvoviruses and cancer. Epidemiological surveys in humans have revealed a correlation between serological evidence of parvoviral infection and lower incidence of certain human cancers (7,8). In vivo studies have demonstrated that animals infected with parvoviruses exhibited increased protection against chemical carcinogen- and virus-induced tumorigenesis (9). Several in vitro studies have also reported inhibition of cellular transformation by parvoviruses and interestingly, preferential killing of established tumor cell lines by parvovirus infection compared with normal cells (9). Results of these studies have led to the belief of possible interference with the induction of malignant transformation as well as survival and proliferation of tumor cells. Subsequent studies have provided molecular evidence on the role of NS proteins of parvoviruses in oncosuppression (10-12). More...

Preimplantation And Prenatal Testing For Hereditary Breast Cancer

Another emerging issue concerns the use of preimplantation genetic diagnosis (PGD) (89) and prenatal diagnosis for hereditary cancer syndromes. A recent review of this issue cited 55 reports of testing for these purposes (90). Both technologies have been utilized in families with Li-Fraumeni syndrome, and PGD has been used by parents at risk for having a child with a BRCA1 2 mutation (90). The ethical issues raised by these procedures share some similarities but also have some unique features. The option of prenatal diagnosis raises the question of appropriate use of this technology. In most developed countries, the offer of prenatal diagnosis and selective termination is generally considered acceptable when the condition is a childhood onset disorder with significant morbidity and premature mortality. In contrast, the application of prenatal diagnosis to a disorder such as hereditary breast ovarian cancer syndrome is controversial. In the case of PGD, the strongest argument in favor...

Causative Factors for Refractoriness of Parous Rats to Mammary Carcinogenesis

Parous Rats Treated with MNU Have a High Incidence of Latent Mammary Cancers. In collaboration with Dr. Airo Tsubura, the role ofparity before and after MNU treatment was studied (24). Pregnancy and lactation before (22 ) or after (25 ) MNU treatment reduced the incidence of frank MCs compared to age- matched nulliparous females (72 ) and (94 ), respectively. At termination, rats that underwent pregnancy prior to MNU (67 ) or after MNU (50 ) both had high incidences of microscopic latent mammary cancers. These findings suggest that MCs are initiated at a fairly high incidence in parous rats, but many ofthese cancers do not progress to frank MCs during the 12 mo after MNU treatment. Thus, these studies indicate that the MEC are highly susceptible to initiation of carcinogenesis and are not completely refractory to the carcinogenic process. Refractoriness to Frank Mammary Carcinogenesis in Parous Rats can be Overcome by Hormone Treatment. In a separate study, MNU was given to parous...

Laparoscopicminimally Invasive Vs Openconventional Surgical Resection For Colon Cancer

In recent years, extensive discussions have been made of minimally invasive or laparoscopic techniques in addressing colon cancers. Initial concerns surrounded such issues as the appropriateness of the surgical margins, number of harvested lymph nodes, and port site recurrences, that is, tumor recurrence at the site of laparoscopic trocar insertion areas or specimen removal sites. Several large studies have addressed these concerns. A prospective but nonrandomized study reported by Franklin et al. (3) compared 191 patients undergoing laparoscopic resection versus 224 patients with open techniques. They found that the laparoscopic method was able to accomplish equal or greater lymph node retrieval, length of resection and distal margins than the open method. Benefits to the laparoscopic method included shorter hospital stay (5.7 vs. 9.7 days), less blood loss, fewer wound complications and a quicker return to bowel function, and in addition there were no trochar implants in the...

The Promotional Environment for Mammary Carcinogenesis is Decreased in the Parous Rats Compared to that of Nulliparous

Nulliparous Rats Mammogenic Hormones and Mammary Epithelial Cells. Administration of MNU to 50-60-day old nulliparous rats, 120-day-old nulliparous rats, and 120-day-old parous rats, resulted in a high incidence of mammary cancers in the nulliparous rats (97 in 50-60 day old rats 75 in 120 day old rats), no MCs developed in the parous rats (26). The concentrations in the serum of mammotropic hormones were measured at the time of MNU treatment. GH concentration was reduced in parous rats (16.1 ng ml) compared to young nulliparous (59.3 ng ml), and age matched nulliparous (38.6 ng ml). PRL levels were 14.6 ng ml in parous, 25.7 ng ml in young nulliparous, and 25.5 ng ml in age-matched nulliparous. Levels of E2, P, corticosterone, and thyroxine were not different in the three groups. The concentrations of ERa and EGFR were decreased in the mammary glands of parous rats (3.5 fmol mg protein, 3,500 cpm mg) compared to young nulliparous (12.1 fmol mg, 5000 cpm mg), and...

Identifying Epidemiologic and Genetic Risk Factors for Colorectal Cancer

Absolute risk is the most easily interpreted risk measure and is often specified in terms of risk per time unit per individual. Using the definitions in Table 6-1, the absolute risk among exposed individuals (e.g., individuals exposed to an environmental carcinogen or with a disease-causing genotype) per unit time is a (a + c). The relative risk is the risk for disease among individuals who have been exposed to a risk factor divided by the risk for disease among individuals who have not been exposed to that risk factor a (a + c) b (b + d) . Finally, the odds ratio is the ratio of the exposed individuals among the diseased to the exposed individuals among the nondiseased, divided by the ratio of the nonexposed individuals among the diseased to the nonexposed individuals among the

Adenoassociated Virus For Cancer Gene Therapy

Similar to the APV, wild-type AAV has also been identified to possess antioncogenic properties (62,63). Although rAAV vectors are relatively less studied in cancer gene therapy, those reported so far indicate their future potential. In addition, whereas most of the cancer gene therapy strategies target tumor cells directly for increasing therapeutic benefit, targeting normal cells that regulate key events conducive for tumor growth is becoming a promising alternative for cancer therapy. For direct targeting of tumor cells, although long-term expression is not required, this may be beneficial in strategies aimed at targeting normal cells, such as tumor endothelium, that exert a sustained control over tumor growth. In this regard, AAV remains a promising vector for cancer gene therapy. The last few years have also seen increased application of AAV serotypes other than the widely used serotype 2-based vectors (64-68). Variations in the amino acid sequences of capsid protein between...

Development of Short Term Hormone Treatments for Prevention of MNUinduced Mammary Carcinogenesis in Rats

Inhibitor) for 3 weeks beginning at 9 weeks of age (10). Both of these treatments caused late pregnancy-like lobule development in mammary glands. 90 of the control rats, 73 ofthe PPZ-treated, and only 9 ofthe rats treated with sustained exposure to E2 + P in silastic capsules developed mammary cancer during the 9 mo-period of observation following MNU treatment. The E2 + P-treated rats developed 93 fewer MCs compared to controls not receiving hormonal treatment. Both PPZ and treatments induced, similar to pregnancy, lobular growth, secretory differentiation, and involution after cessation oftreatment ofthe mammary gland. Assays of blood levels of E2 and P indicate that after PPZ treatment, only the P levels (P 101.5 ng ml, E2 16.6 pg ml,) were increased to pregnancy levels. There was no increase in circulating E2 levels compared to untreated control virgin rats (E2 18.3 pg ml, P 12.7 ng ml). Treatmentwith E2 + P resulted in pregnancy levels of E2 (168.8 pg ml), and lower than...

Procedure For Obstructed Leftsided Colon Cancer

The operation of choice is not clear with an obstructing left-sided colon cancer. There are several options, including resection with colostomy, also known as the Hartman's procedure, subtotal colectomy with or without an anastomosis, resection with on-table lavage, and followed by an anastomosis. Several studies have addressed each.

Followup After Surgical Resection For Colon Cancer

A number of recent studies have investigated the follow-up of colorectal cancer patients after surgery (17-20). Among the studies on the subject, there is a great variation between procedures, duration, intensity, and types of follow-up testing as a result, there is no consistent pattern of follow-up that seems to impact overall and cancer-related survival and no recommendations have been made. One Norwegian study looked into detection of asymptomatic curable recurrence, compliance, and cost of follow-up as compared between two groups, one following a standard follow-up program and the other receiving no follow-up care (17). Although patients in this trial were not randomized into the follow-up or no follow-up group (patients were placed based on guidelines by the Norwegian Gastro-Intestinal Cancer Group, NGICC), there were significant differences in survival crude survival rate was higher in the follow-up group (73 ) than in the no follow-up group (52 ), P < 0.0001. Cancer-specific...

Adenoassociated Virusmediated Longterm Expression For Cancer Therapy

A recent study on the potential use of rAAV encoding sFlt1 in ovarian cancer reported that transduction of a human ovarian cancer cell line RMG-1 with AAV-sFlt1 in vitro followed by intraperitoneal administration in nude mice resulted in a decrease in proliferative and metastatic indices suggesting the feasibility of localized AAV-sFlt1 antiangiogenic gene therapy (101). However, a major limitation of intratumoral delivery of rAAV is the inefficient rate of transduction and limited dispersion of the vector in tumor cells. Also, unlike genetic metabolic diseases, which require only partial amounts of the deficient protein enzyme for phenotypic correction of the disease, tumor therapy requires inhibition of the tumor growth in toto. Antiangiogenic therapy, in particular, requires a constant level of the inhibitory factor(s) for sustained therapeutic effect. Recent studies with rAAV encoding antiangiogenic factors angiostatin and endostatin have also shown in vivo antitumor efficacy...

Neoadjuvant Therapy In Rectal Cancer

The goals for surgical approaches to rectal cancer should be to develop improved local control and overall survival, while maintaining quality of life and preserving sphincter, genitourinary, and sexual function. Much has been made of neoadjuvant therapy and its application for mid- to lower-lying rectal tumors. The effects of downstaging possibly enhance the rate of curative surgery and may increase sphincter preservation. The Swedish rectal trial reported its five-year follow-up data on a randomized, prospective trial looking at the role of preoperative radiation in resectable rectal cancer (21,22). The study randomly assigned 1168 patients younger than 80 years of age who had resectable rectal cancer to undergo preoperative irradiation 25 Gray (Gy) delivered in five fractions in one week followed by surgery within one week or to have surgery alone. No chemotherapy was given either pre- or postoperatively. Irradiation did not increase postoperative mortality. After five years of...

Recombinant Aavmediated Cancer Gene Therapy As Adjuvant Therapy

Based on several studies over the last decade, it is becoming increasingly clear that gene therapy includes a repertoire of cancer treatment paradigms. At the same time, limitations in both target definition and vector efficacy need to be overcome to utilize this as an exclusive therapeutic modality. However, important to this discussion is the realization that gene therapy can be combined with other traditional treatments as an adjuvant therapy. For many of the solid tumors, surgery, chemotherapy, radiation therapy, and hormonal therapy constitute the major therapeutic measures. Despite advances in early detection and successful initial control, many tumors recur yielding a much more ominous prognosis. In these situations, it may be more appropriate to advance our ability to effectively utilize gene therapy to prevent such recurrences. These adjunct therapies may well be targeted toward secondary cellular events such as antiangiogenesis or toward elicitation of host immunity for a...

Hypermethylation and Colorectal Cancer

Tumor suppressor genes, such as p 6 and hMLHl, are inactivated in colorectal cancers by mutation, deletion, or methylation (Kane et al, 1997). Abnormal patterns of DNA methylation are common molecular changes in human neoplasms, including colorectal cancer. p16 methylation is closely associated with K-ras mutations (Guan et al, 1999). Also, aberrant methylation is associated with the microsatellite instability (MSI) pheno-type in colorectal cancer. Recent studies showed that hypermethylation of the MLHl promoter region is common in MSI-positive sporadic colorec-tal cancers (Cunningham et al, 1998). Hypermethylation of MLH1 is also associated with the absence of immunoreactive MLH1 protein (Miyakura et al, 2001). Most sporadic cancers with an MSI phenotype are hypermethylated in the promoter region of hMLH1, whereas mutations and allelic loss cause the MSI phenotype in most HNPCC cancers (Wheeler et al, 2000).

Basic Principles And Concepts Of Mechanismbased Sar In Predicting Carcinogenicity Of Chemicals

Basically, mechanism-based SAR analysis involves comparison of the chemical in question with structurally related compounds with known carcinogenic activity, identification of structural moiety(ies) or fragment(s) that may contribute to carcinogenic activity through a perceived or postulated mechanism, and evaluating the modifying role of the rest of the molecule to which the structural moiety fragment is attached. Since the pioneer work of the Millers (2), which conceptualized electrophiles as the ultimate carcinogen to interact with DNA to initiate carcinogenesis, considerable knowledge of the mechanisms of chemical carcino-genesis has accrued. For many carcinogen classes, the molecular basis of carcinogenic activity is now known in considerable detail, and the concept of electrophiles provides the most probable rationale for their carcinogenic action. The knowledge of molecular mechanisms and other factors that affect carcinogenesis by various types of chemical carcinogens has...

Aromatase Inhibitors and Treatment of Breast Cancer

Neoadjuvant protocols in which therapy is given with the primary cancer remaining within the breast allow tumor responses to be assessed in individual patients by monitoring changes in tumor volume during treatment. Impressive anti-tumor effects have been observed in selected groups of patients with estrogen receptor (ER)-a rich cancers. (19, 35) (Table 2). Marked reduction in tumor size provides clinical benefits, and many patients who initially required mastectomy or were inoperable can be treated by more conservative breast surgery (19, 35) (Table 3).

Estrogens Aromatase and Risk of Breast Cancer

These observations provide the rationale for the use of endocrine therapy as preventative measures against BC in women with high risk ofthe disease. Four trials using tamoxifen have been published (55-57), as has a fifth trial using raloxifene (58). Although there are differences among studies, a recent metaanalysis of the tamoxifen trials indicated that results were compatible with a 42 reduction in short term incidence of breast cancer with tamoxifen use (59).

Familial Clustering Of Hormoneresponsive Cancers

Our primary topic of discussion is the role of inherited variation in gene sequence and its impact on cancer risk in the general population. We begin by examining the evidence that genetics (inherited variation in genome sequence) actually plays a role in the risk of cancer. The strongest data involve familial aggregation, showing that rates of disease are higher in the families of cancer patients than in the population at large. Of course, families are characterized by shared environment as well as shared genes. These factors are typically disentangled by comparing rates of concordance in monozy-gotic (MZ) and dizygotic (DZ) twin pairs.7 Monozygotic twins are 100 identical in genome sequence, whereas DZ twins are identical (on average) across only 50 of their DNA the method relies on the assumption that both types of twins share environmental influences to a similar degree. To the greatest degree possible, comparison of MZ to DZ twins separates the effects of genes and the...

Role of Estrogens in the Development of Breast Cancer

The mechanism by which Es increase risk of overt BC is still the subject of debate (Figure 4). Es can stimulate the proliferation of breast epithelial cells, leading to genetic mistakes and a transformed cellular phenotype (72). Additionally, Es can accelerate the growth of occult cancers resulting in increased incidence of overt disease (73). These promotional properties of Es appear to be largely mediated through ER signaling system. Consequently, both SERMs and aromatase inhibitors should attenuate such promotion. Figure 4. Mechanisms whereby E may cause breast cancer (1) via the ER, (2) via metabolism of E. Note that anti-estrogens block only ER-mediated events, whereas aromatase inhibitors block both ER and metabolic pathways However, evidence is accumulating that E metabolites are genotoxic (74). In particular, metabolism of Es via catechols (2- 4-hydroxyestradiol or hydroxyestrone) may produce reactive quinones which can directly interact with and mutate DNA, initiating...

Intrachromosomal recombination in tumour suppressor genes in cancer

Genomic deletions occur in tumour suppressor genes and genes regulating cell proliferation and such mutations are encountered frequently in the pathogenesis and progression of cancer. As discussed elsewhere in this book (see Chapter 3), homologous and non-homologous intrachromosomal recombination or unequal exchanges and recombination between chromatids can bring about the duplication of genetic material, which is often visualised as HSRs or DMs. Drug resistant cell lines contain DMs and HSRs, which represent amplification of the multi-drug resistance gene. These DMs not only contain amplified DNA but they also harbour Alu repeats (Sognier et al., 1994), and one could tacitly assume that Alu might have played some part in the amplification process. The BRCA1 gene is associated with susceptibility to develop breast and ovarian cancer. It may be described as a classical suppressor gene, shows LOH in cancer families and somatic mutations may also occur in breast and ovarian cancers. The...

Aromatase Inhibitors and Prevention of Breast Cancer

Effects ofthird generation inhibitors make long-term monitoring of bone and lipid profiles mandatory. Ongoing adjuvant trials with aromatase inhibitors provide information on the incidence ofnew contralateral BCs and side-effect profiles. The large ATAC trial shows a significant reduction in contralateral cancer in the aromatase inhibitor (anastrozole) group compared with tamoxifen (35 vs 20, p

Microarrays to Identify New Therapeutic Strategies for Cancer

*Division of Hematology Oncology, Children's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115 IV. Microarrays to Direct the Use of Cancer Therapeutics B. Breast Cancer VI. Conclusions Over the past decade, microarrays have emerged as an important tool for the characterization of cancer cells. Numerous studies have demonstrated that cDNA arrays can help delineate biological subsets of disease that have prognostic relevance. Such studies provide hope that introduction of this information into clinical trials will lead to more biologically based stratification schemes such that appropriately tailored therapies can be developed. While the identification of unique subsets of cancer promises to improve our ability to predict which cancers are unlikely to have a significant response to therapy, new therapeutic approaches are needed in...

Strategies Using Nonviral Vectors In Cancer Gene Therapy

Various nonviral vector systems have been used to deliver DNA into cancer cells to induce an antitumor effect. Naked DNA encoding genes ranging from cytokine genes to tumor antigen genes have been delivered alone (63), by gene gun (64,65), or by electroporation (66,67), resulting in significantly induced cytokine levels or specific antigen expression. Electroporation has also been used to introduce plasmids that encode antisense RNA against E6 and E7 mRNA to human papilloma virus (HPV) expressing cancer cells, which resulted in a significant inhibition of tumor growth (68). Another approach involved gene gun-mediated delivery of heat-shock protein 70 (Hsp70) linked to the HPV16 E7 tumor antigen gene into antigen presenting cells (APCs). It led to an enhanced E7-specific immune response of lymphocytes after exposure to these transfected APCs (69). LPD also plays an increasingly important role in antitumor gene therapy. An interesting method is to deliver a plasmid containing an...

Breast Cancer Risk In Males

Familial clustering of female breast cancer was demonstrated as early as 1926 (81), and epidemiological studies have shown that although both men and women with breast cancer are more likely to have family histories in first-degree relatives than unaffected individuals, men with breast cancer were even more likely to have a first-degree relative with ovarian cancer than affected women (82,83). It is noteworthy that initial linkage studies of BRCA1 did not reveal an association with male breast cancer (14,84). Linkage studies for BRCA2, on the other hand, did contain male breast cancer cases (16). Germline analyses of 50 men affected with breast cancer unselected for family history revealed that 14 of these men carried a BRCA2 mutation (85). Easton et al. (52), in a study of two large kindreds linked to BRCA2, estimated the cumulative risk of breast cancer in male carriers to be 6.3 by the age of 70 years. In an analysis of 164 BRCA2 kindreds, a similar estimate for cumulative risk...

Roles Of Sar In Cancer Risk Assessment

In the absence of adequate epidemiologic data and based on the findings that virtually all known human carcinogens are also rodent carcinogens, data from lifetime exposure animal bioassays are primarily used for identifying chemical substances that may be associated with carcinogenic effects in humans. However, the high cost of testing, the large number of animals used in 2-year rodent bioassays, and the huge number of chemicals for which carcinogenicity data do not exist have made it impractical and inhibitory to test each of the thousands of existing chemicals for carcinogenicity. Meanwhile, government health regulatory agencies are under increasing mandate to screen large lists of existing chemicals in commerce and the environment for carcinogenic and other toxicologic effects. Structure-activity relationship is serving an increasingly important role in the risk assessment process as the first line approach in hazard identification, prioritizing chemicals for testing, designing...

Further Chemotherapy For Radically Resected Residual Cancer

The presence of viable cancer cells in completely resected residual masses carries the worst prognosis when compared with the presence of mature teratoma or necrosis alone (see also Chapter 16).26,33 Since the study by Einhorn and colleagues,37 which reported a dismal outcome for all 18 patients with residual cancer at postchemotherapy surgery who received no further therapy, many investigators have opted for the routine use of postoperative adjuvant chemotherapy.2,5,9,11,12,24,26,33 No compelling evidence has existed to confirm whether adjuvant chemotherapy for consolidation is justified in this setting. Thus, my colleagues and I recently challenged this approach as we found no difference in the 5-year survival in a retrospective study of 49 evaluable patients who were treated (24 patients) or not treated (25 patients) with adjuvant chemotherapy following complete resection of residual cancer after first-line (30 patients) or salvage (19 patients) chemotherapy.38,39 An international...

Modifiers Of Penetrance And Breast Cancer Genes Other Than Brca

Several studies have noted an increased penetrance for BRCA1 2 in more recent birth cohorts. The NYBCS (9) confirmed Narod's earlier observation of a significant increase in breast cancer risk by the age of 50 years in birth cohorts after 1940 (67 after 1940, 24 before 1940) (39). Ovarian cancer risk did not differ by birth cohort. This increase in incidence for BRCA1 2 mutation carriers parallels an increase in breast cancer in the general U.S. population over that period (37). Antoniou et al. (61) analyzed the results of 22 studies in which cases were unselected for family history. The RR for breast cancer among BRCA1 2 mutation carriers in the post-1960 birth cohorts was two to three times the RR in the preceding four decades. A study of Austrian BRCA1 mutation-positive women found that those from birth cohorts after 1958 had a significantly higher incidence of breast cancer by 40 years of age than those from earlier birth cohorts 46 versus 27 , respectively (89). Finally,...

Types Of Cancer Associated With Brca12 Mutations Ovarian Cancer

The most significant cancer, other than breast cancer, in individuals with BRCA1 2 mutations is ovarian cancer, as reflected in the nomenclature, hereditary breast ovarian cancer (HBOC) syndrome. As with breast cancer, early linkage studies probably overestimated the penetrance of ovarian cancer for BRCA1 2 mutation carriers with estimates by the age of 70 years of 44 for BRCA1 carriers (51) and 27 for BRCA2 carriers (97). In contrast, later studies, utilizing nonlinkage-based ascertainments, derived lower penetrances. Struewing et al. (28) estimated the penetrance for ovarian cancer in those who harbored one of the three Ashkenazi Jewish BRCA1 2 founder mutations to be 16 by the age of 70 years. The Anglian Breast Cancer Study Group (59) estimated the combined penetrance of BRCA1 2 for ovarian cancer by the age of 80 years at 22 . In 2002, Antoniou et al. (91) estimated the penetrance of BRCA1 for ovarian cancer by the age of 70 years to be 25.9 and the corresponding estimate for...

Chromosome Mutations and Cancer

Some types of tumors are consistently associated with specific chromosome mutations, suggesting that in these cases the specific chromosome mutation played a pivotal role in the development of the cancer. However, many cancers are not associated with specific types of chromosome abnormalities, and individual gene mutations are now known to contribute to many types of cancer. Nevertheless, chromosome instability is a general feature of cancer cells, causing them to accumulate chromosome mutations, which then affect individual genes that contribute to the cancer process. Thus, chromosome mutations appear to both cause and be a result of cancer. At least three types of chromosome rearrangements deletions, inversions, and translocations are associated with certain types of cancer. Deletions may result in the loss of one or more genes that normally hold cell division in check. When these so-called tumor-suppressor genes are lost, cell division is not regulated and cancer may result....

Molecular Mechanisms ofOncogenes in Carcinogenesis 241 Platelet Derived Growth Factor and Its Receptors

EGF receptors are commonly overexpressed in a number of epithelial malignancies and are often associated with an aggressive phenotype. They are overexpressed in over 50 of non-small-cell lung cancers (NSCLC), head and neck squamous cell carcinoma (HNSCC), and colon cancers, along with overexpression of one or more other EGFR family members (21,23,24). Karyotypic abnormalities, including the translocation, duplication deletion, and loss of chromosomes, have long been recognized. Most chromosomal abnormalities do not correlate with cancer types, suggesting that these abnormalities are likely secondary events and reflecting the inherent genetic instability of cancer cells. In contrast, some types of malignancies consistently undergo certain chromosomal changes. For example, a reciprocal translocation between chromosomes 9 and 22 occurs in the leukemia cells of more than 90 of patients with chronic myelogenous leukemia (CML) (28). As a result of this translocation, the abl proto-oncogene,...

Investigational Measures for Colorectal Cancer Screening

Two new methodologies, virtual colonoscopy (also known as computed tomography colonography) and stool-based testing for mutated DNA, are exciting and of considerable interest. Virtual colonoscopy entails the use of spiral computed tomography with very thin cuts (otherwise, small lesions would be missed) and new computer techniques for 3-dimensional reconstruction. Currently, standard bowel preparations are required and elimination of all effluent is important. Efforts are under way to develop oral contrast agents that mix with enteral contents so that they may be subtracted from images, eliminating the bowel preparation, which many patients find more noxious than the colonoscopy itself. Several singleinstitution trials have yielded virtual colonoscopy sensitivities of greater than 90 for the detection of adenomas larger than 1 cm. In one study (Pickhardt et al, 2003) of CT with 3-dimensional endoluminal display vs conventional colonoscopy in 1233 asymptomatic adults, CT colonography...

Interaction of Oncogenes and Tumor Suppressor Genes in Human Carcinogenesis

Humans are the highest class of organism on earth, likewise, human carcinogenesis is more complicated than carcinogenesis in any other organisms. For example, a single activated oncogene can cause neoplastic transformation in avians and rodents. In humans, however, expression of a single oncogene such as myc or ras in normal human cells induces only apoptosis or senescence (31). This has led to the widely accepted concept of multistep carcinogenesis involving the activation of multiple cellular onco-genes and the inactivation of tumor suppressor genes. Often, several tumor suppressor genes form pathways with other tumor suppressor genes or with oncogenes that govern cell growth, apoptosis, differentiation, and genome integrity (31). A good example is the Rb pathway. In its nonphosphorylated form, Rb inhibits the cell cycle by blocking DNA synthesis (S-phase). It does so by binding to proteins of the E2F family of transcriptional factors and inhibiting their functions as...

Colon Cancer Chemoprevention

Chemoprevention of colorectal cancer has come to imply the use of orally administered agents, whether dietary or strictly pharmacologic, to reduce the risk of developing adenocarcinoma. Epidemiologic data strongly point to geographic differences in colo-rectal cancer incidence. Rates have been highest in northwestern Europe, North America, Oceania, and Argentina and lowest in sub-Sahara Africa. As such differences were explored in greater detail, specific factors in the diet came to be implicated. Several studies have led to the conclusion that diets high in animal fat and total energy intake increased risk, while diets high in total fiber, whether fruit, vegetable, or bran, were associated with lower risk. Although well accepted as a key paradigm in carcinogenesis and taken for granted in many ways, the adenoma-to-carcinoma sequence is very important to our understanding of chemoprevention. Even though most adenomas do not progress to invasive adenocarcinoma, essentially all...

Protective Effects Against Cancer

A 2001 critical review of the epidemiological evidence suggests a preventive effect for garlic consumption in stomach and colorectal cancers, but not other cancers (Fleischauer & Arab 2001). In regard to gastric cancer protection, case-control studies suggested a protective effect for raw and or cooked garlic when eaten at least once a week whereas protective effects against colorectal cancer seem to require at least two servings of garlic per week. A similar view was reported in a 2003 review by Ernst, which stated that the weight of evidence to support the use of allium vegetables, such as garlic, in cancer is clearly positive. Intervention study in colorectal cancer A preliminary double-blind, randomised clinical trial in patients with colorectal adenomas-precancerous lesions of the large bowel produced promising results with the use of high-dose aged garlic extract (AGE 2.4 miyday) (Tanaka et al 2006). The study of 51 patients measured the number and size of adenomas at...

Microarrays To Direct The Use Of Cancer Therapeutics

Microarrays are being heavily utilized in cancer research and are proving to be useful in all aspects of study, including the classification of cancer, the study of biochemical pathways, and the identification of potential targets for novel therapeutics. Gene expression technologies are also being used to distinguish on-target versus off-target effects of cancer therapeutics, mechanisms of resistance to treatment, mechanisms of therapeutic function, and prediction of drug response. Resistance to chemotherapy drugs is a major barrier to the successful long-term treatment of cancer. In order to better understand the mechanisms involved, gene families were identified that appear to contribute to the evolution of drug resistance and may be regulated through a multiple pathway gene expression program. Microarray analysis of tumor samples will make feasible the identification of critical genes that are most relevant to clinical drug resistance, and the data can be used to develop strategies...

Establishment of Models for Studying Prostate Cancer Cell Progression

We believe that a better understanding of the process of PCA cell progression is very important for establishing better methods for PCA treatment. To investigate PCA progression, we established a model system (Figure 2) using a clone derived from the human PCA cell line, LNCaP, whose growth was dependent on the presence of nanomolar concentrations of testosterone, 5a-DHT or 17 P-hydroxy-17-methyl-estra-4,9,11 -trien-3 -one (R1881) (21-23). The original cancer cell (named LNCaP 104-S) population was cultured through weekly passages and after about 40-70 passages in A-depleted culture medium, these cells progressed to A-independent cancer cells that we named LNCaP 104-R1 cells. These cells can grow well in culture without A. After continuous culture of 104-R1 cells in A-depleted medium for 60-120 additional passages, these 104-R1 cells were transformed into faster-growing cells, named 104-R2 cells. This transition of A-dependent 104-S cells to A-independent 104-R1 and 104-R2 cells is...

10 Ways To Fight Off Cancer

10 Ways To Fight Off Cancer

Learning About 10 Ways Fight Off Cancer Can Have Amazing Benefits For Your Life The Best Tips On How To Keep This Killer At Bay Discovering that you or a loved one has cancer can be utterly terrifying. All the same, once you comprehend the causes of cancer and learn how to reverse those causes, you or your loved one may have more than a fighting chance of beating out cancer.

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