DEFINITION. A cancer is a malignant tumor growth that expands locally by invasion and systemically by metastasis.
ONCOGENES. Cancers arise from cells in which growth-regulating and repair genes (protooncogenes) have become ineffective as a result of random mutation or following viral infection or physical or chemical damage. When protooncogenes become altered or damaged, they are termed oncogenes and are capable of causing neoplastic growth. Examples of oncogenes and their actions include the following.
A. p53 gene. As a protooncogene, p53 encodes a nuclear phosphoprotein that inhibits cell division, thus suppressing tumor growth. Mutations in p53 result in uncontrolled growth.
B. ras. As a protooncogene, ras controls a guanosine triphosphate (GTP) binding-protein involved in signal transduction. Mutation results in failure of guanosine triphosphatase (GTPase) inactivation of ras and continuous ras activity.
C. c-myc. When this protooncogene is translocated onto a different chromosome (e.g., as in Burkitt's lymphoma), it becomes oncogenic, resulting in loss of regulation of B cell growth and a B cell lymphoma.
D. Bcl-2 gene. In normal concentrations, the cellular protein produced by this gene (Bcl-2) inhibits apoptosis; high concentrations of Bcl-2 in B cells promote cell expansion and follicular lymphoma.
E. bcr/abl gene fusion results in a protein with increased tyrosine kinase activity, and is involved in chronic myeloid leukemia.
A. Cancer antigens. Cancer cells arise from normal cells. In order for the immune system to attack cancer cells, the cancer cells need to be distinguished from self (i.e., they need to possess antigens).
1. Types. Two types of antigenic molecules have been found on cancer cells.
(1) Virus-induced TSA are cross-reactive (i.e., the genome of a particular virus synthesizes the same viral antigens in whatever cell that virus infects). Consequently, immunotherapy should be applicable to all individuals infected by the same virus.
(2) Carcinogen-induced TSA. Carcinogens induce random mutations in the genome of affected cells. Consequently, each mutated gene product (antigen) differs (depending on which gene has been affected by the carcinogen) and immunologic cross-protection is not feasible, b. Tumor-associated antigens (TAA) are not found exclusively on cancer cells; however, they are generally present in higher quantities in cancer patients, and aid in diagnosis.
(1) Carcinoembryonic antigen (CEA) reappears in the serum of most patients with colorectal cancer. (High concentrations of CEA on fetal gastrointestinal and liver cells disappear at birth.)
(2) p-Fetoprotein (AFP) attains high levels in patients with hepatomas and testicular teratocarcinomas. Levels are normally very low in adults (although high AFP levels are normal in fetal and maternal serum).
2. Immune response to cancer antigens a. Antigen-responsive T cells. Immunocompromised hosts with diminished T cell function have a higher incidence of lymphoproliferative cancers.
(1) CD4+ T cells secrete cytokines [e.g., interleukin-2 (IL-2), interferon-y (IFN-y)] that activate CD8+ cytotoxic T cells (Tc) and macrophages.
(2) CD8+ T cells lyse cancer cells through cytotoxic factors and perforins.
b. Macrophages are found frequently in the bed of regressing tumors. They must be activated by macrophage-activating factors (MAF), such as IFN-y, in order to eradicate tumor cells. Mechanisms of destruction may include the respiratory burst, nitric oxide release, neutral proteinases, tumor necrosis factor-a (TNF-a), and antibody-dependent cell-mediated cytotoxicity (ADCC).
C. Natural killer (NK) cells kill cancer cells through ADCC and lysis following contact. NK cell cytolytic activity is increased by IL-2, IL-12, and IFN-y and is not major histocompatibility complex (MHC)-restricted.
3. Cancer cell evasion of the immune system. Cancer cells can evade the immune system in multiple ways. Examples include the following.
a. The relatively weak immune response may be overwhelmed by rapid tumor growth.
b. Certain cancers may possess subliminal numbers of human leukocyte antigen (HLA) or costimultory signal molecules, rendering them unable to trigger a TSA T cell response.
C. Non-complement fixing antibodies that arise as a result of the cancer may actually enhance cancer growth by blocking the TSA from attack by cell-mediated immunity (CMI).
4. Certain cancers may elicit a dominant T cell suppressor (Ts) response or secrete immunosuppressive molecules [e.g., prostaglandins, transforming growth factor-(3 (TGF-P)].
5. Antigenic modulation can occur, causing the cancer cells to change or lose their TSA.
6. The cancer may arise in an immunologically privileged site [e.g., eye, central nervous system (CNS)].
A. Lymphokine-activated killer (LAK) cells are tumor-reactive lymphocytes that are isolated from the blood of the cancer patient, expanded in vitro with IL-2, and reinfused into the patient. Although heterogenous, they are thought to constitute a population with some specificity. Their lineage is unknown.
B. Tumor-infiltrating lymphocytes (TIL) are T cells isolated from the tumor bed (therefore, they should have higher specificity for the tumor antigens). TIL cells are expanded in vitro with IL-2 and reinfused into the patient.
C. Monoclonal antibodies specific for TSA can be infused into the patient, either directly or with a toxin, drug, or radioisotope conjugated to the antibody. The antibody directs the conjugate exclusively to the cancer cell.
D. Cytokine therapy—using various cytokines capable of elevating humoral immunity, CMI, or both—is the goal of current clinical trials. The multiple variables (e.g., dose, concentration, bolus or multiple injections, route, patient population, cytokine specificity, toxicity) have impeded research progress.
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