Info

activity

PCa risk

*PCa: prostate carcinoma

*PCa: prostate carcinoma epithelial cells, is induced by androgens, and is very likely necessary for the proper differentiation of prostate epithelium. Knockout mice engineered to lack the factor fail to develop a functional prostate and hemizygous mice display hyperproliferation of the prostate epithelium. In these respects, NKX3.1 is as good a tumor suppressor candidate as they come. The problem prohibiting its general acceptance as a tumor suppressor is that in most prostate cancers, including those with LOH or outright deletion of 8p, at least one allele of the gene remains functional and is often expressed at close to expected levels (i.e. 50% of normal). To accept NKX3.1 as a tumor suppressor, one would have to postulate that diminuation of its expression to half the normal level suffices to inactivate its function. Such 'haploinsufficiency' has also been postulated for other genes (^5.4, ^14.2), but is, of course, very difficult to prove in the context of a real human cancer. This is particularly so for prostate carcinoma, which is thought to be unusually heterogeneous and to always contain substantial amounts of stroma. Therefore, the suspicion lingers that the crucial changes in a gene might have escaped detection for technical reasons.

The same sort of problem concerns other established or novel tumor suppressors in prostate cancers. So, PTEN is clearly inactivated in some prostate carcinomas by loss of one allele and mutation of the second one; even homozygous deletions have

Prostate cancer

Figure 19.10 Genetic predisposition to prostate cancer Estimated proportions of cases contributed by mutations in the indicated genes. In prostate cancer (right) true mutations leading to high-risk alleles in HPC1 and HPC2 etc. may be extremely rare. However, polymorphisms in these and other genes may strongly modulate the risk conferred by environmental factors (e.g. diet or infections?). Note that the risk in 'sporadic' cases may also be modulated by genetic polymorphisms, albeit more weakly. The situation in breast cancer (left) is in so far different, as high risk alleles in BRCA1, BRCA2 and a number of other genes may account for a substantial proportion of all cases.

Figure 19.10 Genetic predisposition to prostate cancer Estimated proportions of cases contributed by mutations in the indicated genes. In prostate cancer (right) true mutations leading to high-risk alleles in HPC1 and HPC2 etc. may be extremely rare. However, polymorphisms in these and other genes may strongly modulate the risk conferred by environmental factors (e.g. diet or infections?). Note that the risk in 'sporadic' cases may also be modulated by genetic polymorphisms, albeit more weakly. The situation in breast cancer (left) is in so far different, as high risk alleles in BRCA1, BRCA2 and a number of other genes may account for a substantial proportion of all cases.

been observed. Nevertheless, in many prostate carcinomas, the gene is intact, but strongly down-regulated. It is possible that loss of one PTEN allele suffices to promote tumor progression in the prostate, while complete loss of function is a characteristic of very advanced cancers.

Similarly, RB1 is located at 13q14 telomeric to a region that undergoes LOH and net loss in many prostate cancers, but the remaining RB1 copy is intact, although its expression level is debated. So, perhaps, the 'classical' concept of tumor suppressors demanding inactivation of both alleles may not apply in prostate carcinomas. There are indeed 'heretical' concepts which attempt to explain cancer development by the overall changes in relative copy numbers, without an absolute requirement for mutational events. Perhaps they may be helpful to understand prostate cancer.

While these ideas are speculative, it is clear that epigenetic mechanisms (^8) are very important in prostate cancers and could account for some of the unexpected findings at the genetic level. Specifically, alterations of DNA methylation (^8.3) are unusually prevalent in prostate cancer. One of the most consistent alteration in prostate cancer is inactivation of the GSTP1 gene encoding an enzyme protective against electrophilic compounds from exogenous and endogenous sources (^3.5). Loss of expression occurs very early during cancer development and may help to sensitize the tumor cells to further genomic damage. Loss of GSTP1 is almost always caused by epigenetic mechanisms and usually accompanied by dense hypermethylation of the gene promoter (Figure 19.11). More than a dozen genes have now been reported to become hypermethylated in prostate cancer at significant frequencies. Several appear to become coordinately hypermethylated by a sort of 'epigenetic catastrophe' at around the stage of initiation of the carcinoma, perhaps even in advanced prostate intraepithelial neoplasia. Other genes, including those encoding cell adhesion molecules like E-Cadherin and CD44 (^9.2) become hypermethylated later, and still others, including PTEN, seem to be down-regulated by epigenetic mechanisms without becoming hypermethylated.

These observations carry interesting prospects for diagnostics and therapy of prostate cancer. Hypermethylation of CpG islands, as in the GSTP1 gene, can be comparatively easy detected with high sensitivity and specificity, since CpG islands are unmethylated in normal tissues (^8.3). So, detection of GSTP1 hypermethylation, and that of additional genes, is being developed to assay for the presence of prostate carcinoma (^21.3). Also, since epigenetic gene inactivation is, in principle, reversible, prostate cancer may be a particularly good target for inhibitors of histone deacetylases, histone methylases, and DNA methyltransferases currently under development. In cell and animal models of prostate cancer at least, such compounds are efficacious, usually by induction of apoptosis.

Figure 19.11 Hypermethylation of the GSTP1 promoter in prostate cancer cells (1) Structure of the GSTP1 gene; (2) Its CpG island, each line indicates a CpG site; (3) 66 CpG sites located within 757 nt around the transcriptional start site. The end of an ALU element and three transcription factor binding sites are indicated; (4) In a prostate carcinoma cell line (LNCaP), almost all of these sites are methylated, while in normal tissues all CpGs 3' of the ATAAA repeat remain unmethylated. Modified from Stirzaker et al, Cancer Res. 64, 3871ff, 2004

Figure 19.11 Hypermethylation of the GSTP1 promoter in prostate cancer cells (1) Structure of the GSTP1 gene; (2) Its CpG island, each line indicates a CpG site; (3) 66 CpG sites located within 757 nt around the transcriptional start site. The end of an ALU element and three transcription factor binding sites are indicated; (4) In a prostate carcinoma cell line (LNCaP), almost all of these sites are methylated, while in normal tissues all CpGs 3' of the ATAAA repeat remain unmethylated. Modified from Stirzaker et al, Cancer Res. 64, 3871ff, 2004

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.

Get My Free Ebook


Post a comment