The Molecular Pathogenesis of Human Prostate Cancer

William G. Nelson, Angelo M. DeMarzo, Theodore L. DeWeese, and William B. Isaacs

Introduction

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 supporting causative roles for prostate inflammation and diet in prostatic carcinogenesis. These new findings have provided new clues as to how PCAs likely arise, and new insights into how the disease might be prevented. A new lesion, termed proliferative inflammatory atrophy (PIA), in which prostate epithelial cells undergo regenerative proliferation in response to inflammatory damage, appears to be a precursor to prostatic intraepithelial neoplasia (PIN) and to PCA (7). PIA lesion cells exhibit many signs of stress, including the induction of carcinogen-detoxification enzymes such as glutathione S-transferases GSTA1 and GSTP1 (7). Somatic inactivation of GSTP1, encoding the human GST, renders prostate epithelial cells vulnerable to suffer genome damage mediated by reactive chemical species generated by inflammatory cells, or ingested as part of the diet (8). By leading to more somatic genome alterations, loss of GSTP1 function leads to PIN or PCA.

Thus, GSTP1 likely acts as a "caretaker" gene in the prostate (9). When induced, as in PI A lesion cells, it affords protection against cell and genome damage; when its function is lost, genomic instability, driven by genome damage, ensues. New PCA prevention strategies can target this vulnerability to genome damaging, perhaps by attenuating prostatic inflammation, buttressing carcinogen defenses, or by both approaches.

PCA Epidemiology: Prostate Inflammation and Diet

PCA is a disease of Western lifestyle. PCA incidence and mortality are known to vary widely between different geographic regions, with high rates in the USA and Western Europe, and low rates in Asia (10). Asian immigrants to North America adopt higher PCA risks, especially after more than 25 years exposure to a Western lifestyle, and Asian men born in North America have high PCA risks (11-13).

Chronic (or recurrent) prostatitis is one etiological factor that is increasingly suspected to lead to PCA (14). Prostate inflammation is ubiquitously present in prostates removed by radical prostatectomy for PCA in the USA, however, the prevalence and age distribution of asymptomatic prostatitis, in the USA, or elsewhere, is not known. About 9% of men between 40 and 79 years of age report suffering of symptomatic prostatitis, with half of them having repeated episodes (15-17). Although many of these inflammations may be triggered by infections, the infectious cause is most often not identified. Since prostatitis is so common in the USA, often asymptomatic, and of uncertain etiology, causative associations between prostatitis and PCA have been difficult to assess in epidemiology studies. Despite these limitations, an increased PCA risk has been associated with sexually transmitted infections, independent of the specific pathogen, hinting that the inflammatory response to infection, rather than the infectious agent itself, may lead to PCA (18, 19). In addition, host responses to prostate infections may underlie some familial PCA clusters. Genetic studies of familial PCA have identified two candidate PCA susceptibility genes, 2'-5'-oligoadenylate-dependent ribonuclease L (RNASEL), and macrophage scavenger receptor 1 (MSR1). These genes are thought to encode proteins with critical functions in host responses to a wide variety of infectious agents (20-23). Finally, an inflammatory lesion in the human prostate, PIA, may be a precursor to PIN and to PCA (7).

A key feature of Western lifestyle that may promote PCA development is the diet. Several epidemiology studies have implicated various dietary components, such as animal fat and charred meat, rich in the Western diet, as high PCA risk factors; while vitamins, fruits, and vegetables, poor in the Western diet, as dietary factors that decrease PCA risk (24-31). However, whether the high PCA risk diet represents an error of commission (i.e., over-consumption of animal fats and charred meats), omission (i. e., under-consumption of fruits and vegetables), or both has not been proven. Nevertheless, there are carcinogens present in the Western diet. Male rats fed the heterocyclic aromatic amine 2-amino-l-methyl-6-phenylimidazo [4,5-0] pyridine (PhIP), an intermediate metabolite formed while preparing "charred" or "well-done" meat, develop DNA mutations in prostate cells that result in PCAs (32, 33).

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