Prostate Cancer

> Prostate cancer, called more precisely 'prostate adenocarcinoma', becomes clinically significant in up to 10% of all males in Western industrialized countries. It is rare in younger males, but its incidence increases continuously with age.

> The clinical course of prostate cancer is variable, ranging from clinically insignificant tumors which grow slowly over decades to aggressive cancers which spread locally and metastasize to bone and other organs, killing the patient within a few years.

^ The detection of prostate cancer has been improved by modern imaging methods and especially by use of the biochemical serum marker prostate specific antigen (PSA), a moderately specific and very sensitive serum marker. Molecular markers for the classification of prostate cancers are still urgently sought.

> Androgens and the androgen receptor (AR) have been central issues in prostate cancer research for many years and represent major targets for therapeutic intervention. Most prostate cancers respond to treatment by androgen depletion and receptor blockade, apparently by apoptosis of better differentiated tumor cells. Unfortunately, this therapy is palliative and only marginally prolongs survival, because the cancer is repleted from cells with altered responses to androgens that are refractory to anti-androgenic treatment. Several mechanisms contribute, including mutations and amplifications of the AR gene as well as changes in signaling pathways acting on the AR.

> The incidence of clinically significant prostate cancer is vastly different between North-Western Europe and South-East Asia. This difference can be partly ascribed to the aging of the population in industrialized countries and improved detection by PSA assays. A difference remains after adjustments for age and detection rate, and points to factors in the 'Western life-style' fostering prostate cancer. One candidate is a diet rich in saturated fat and relatively low in vitamins and micronutrients from fruit and vegetables.

^ Genes associated with familial prostate cancer do not behave as classical tumor suppressors. A large number of polymorphisms in genes related to hormone metabolism and action, nucleotide metabolism, and cell protection may modulate the risk for prostate cancer.

> Initial changes in prostate cancer are predominantly chromosome losses and other mechanisms leading to down-regulation of gene expression. In particular, silencing of several genes by promoter hypermethylation coincides with the onset of malignancy. Detection of tumor cells by hypermethylation assays therefore appears particularly promising in prostate cancer.

^ Tumor suppressors and oncogenes involved in other cancers such as TP53, PTEN, MYC, and ERBB1 seem to be predominantly important during the progression of prostate carcinoma. Initial changes in prostate cancer appear mainly to result in decreased apoptosis and altered interactions with stromal cells.

^ As potential tumor suppressors in familial cases, several tumor suppressor candidates in sporadic prostate cancers do not undergo genetic alterations in their second alleles. It is therefore possible that quantitative alterations by decreased gene dosage or epigenetic inactivation rather than qualitative alterations by mutation initiate prostate cancers. > Epithelial cells in the normal prostate interact tightly with the underlying mesenchyme which supplies growth factors, partly in response to androgens. Throughout much of their development, prostate cancers seem to retain a strong dependency on stromal cells, perhaps more so than other carcinomas. Intense epithelial-mesenchymal interactions are even maintained in bone metastases, where prostate cancer cells appear to find a suitable 'soil' for survival and growth. Here, a vicious cycle may be established, in which the cancer cells stimulate the maturation and activity of osteoblasts and osteoclasts which in turn produce growth factors that promote growth and survival of the cancer cells.

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