ReviewMultidimensional approaches in dealing with prostate cancer
Introduction
In any given living system, cell division and cell death are well orchestrated processes to cope up with various physiological, biochemical and environmental challenges and to maintain homeostasis. Regulation of cell cycle at the highest possible stringency level is an integral part for successful survival of any living system. Deviation in any of these mechanisms to the slightest level may result in cancer (uncontrolled cell growth) or other malignancies. There are different genetic aspects involved in different types of cancer with the underlying principle being loss of control over cell division.
The prostate gland develops by the 9th week of embryonic life and is the modified wall of the proximal portion of the male urethra. Thereafter, the mesenchyme, urethra and Wolffian ducts condense to give rise to the adult prostate gland. Its main function is to store and secrete a clear, slightly alkaline fluid that constitutes up to 1/3rd volume of the seminal fluid. It also contains some smooth muscles that help expel semen during ejaculation. It needs androgens (male hormones) for its proper maintenance and function. The main male hormone, testosterone, is produced primarily by testicles and in small amounts by the adrenal glands. Owing to the important role of androgens in maintenance and functioning of prostate gland they are supposedly key players in PCa as well (Fig. 1).
Prostate cancer (PCa) or carcinoma of prostate (CaP) is one of the most prominent cancers affecting the human male population around the world. A man has a 1/5 chance of developing PCa during his lifetime (Feuer, 1997). Notable regional differences have been observed in the populations in the prevalence of PCa with its occurring frequency highest in the African Americans and lowest in the Asian populations (Whittemore, 1994). Studies on familial clustering of PCa have shown an increased risk of an individual with several affected first-degree relatives or with an affected brother who had an early age at onset and about 9% of cases are expected to occur in families with several affected family members (Carter et al., 1992). The role of environmental factors in PCa has also been studied which highlighted the importance of immigration (Dunn, 1975), lifestyle and dietary habits (Whittemore et al., 1995). Apart from these factors, age is also a primary risk factor in PCa occurrence with incidence per 100,000 increasing from 34 to 150 to 440 in American Caucasian men of age 60, 70 and 80 years, respectively (Kosary et al., 1995).
PCa is expected to be diagnosed in 15% of the men in the United States. Also, results of autopsy studies suggest that 30% of the men of age > 45 years may have prostate lesions that can be histologically identifiable as PCa (Kosary et al., 1995, Dhom, 1983). There is a good chance that these lesions remain latent for the person's lifetime but what actually triggers some of them to become biologically active metastatize and manifest as a potentially lethal disease remains a mystery till date though a genetic role is very strongly suggested. Different types of studies with variable but reasonable sample size have been done to understand the genetics of PCa. These include case-control, cohort and twin studies as well as segregation analyses. All the results point towards existence of prostate cancer-susceptibility genes in the population but there is difference in the suggested modes of inheritance. Three independent segregation analyses support an autosomal dominant mode of inheritance. Dominant alleles with a population frequency of 0.36%–1.67% are supposed to account for ~ 9% of all PCa cases at age ≤ 85 years and ~ 43% cases at age ≤ 55 years (Carter et al., 1992). In contrast to this data from two studies are most consistent with an X-linked or recessive model of inheritance (Monroe et al., 1995, Narod et al., 1995). Studies have indicated linkage of prostate susceptibility genes to multiple loci on chromosome 1 and single locus each on chromosomes 4, 8, 16, 17, 19, 20 and X chromosome.
Section snippets
1q24–25(HPC1)
There have been number of studies indicating evidence for linkage to regions that may contain disease susceptibility loci for PCa. Smith et al. (1996) proposed the first such locus on chromosome 1q24–25 termed hereditary prostate cancer 1 (HPC1) and was supposed to account for the disease in 34% families with PCa in a data set defined by families with three or more first-degree affected relatives, PCa in three or more generations or two affected siblings diagnosed at age ≤ 60 years. Another study
PCa and Y chromosome
The analysis of the Y chromosome in patients with PCa is crucial due to its occurrence in the human males and the indispensable role of male sex hormones in the maintenance of prostate gland. Complete absence of the Y chromosome in PCa samples has been reported and was found to occur at a higher frequency than in bladder cancer. However, the cancer was not the sole cause but was supposedly aided by chromosomal instability (Nadal et al., 2007). The human Y chromosome haplotypes around the world
The candidate genes
The studies on prostate have given us few candidate genes to focus on but the exact role and implication of these genes with reference to PCa remains elusive. Some of the candidate genes, their chromosomal localization and role in living system have been summarized in Table 2. The list though non-exhaustive gives a fair idea of where things are headed. One of the best studied genes in this regard is that of the androgen receptor (AR). The androgens function via AR which in turn needs steroid
Measure of PCa aggressiveness
A pathological measure of aggressiveness assigned to a prostate tumor is the Gleason score (Gleason, 1992). It reflects the patterns of tissue architecture observed by a pathologist in two prostate biopsy or surgery samples. Each pattern is given a whole number score between 1 and 5, so the total Gleason score range is 2–10. For tissue with heterogeneous scores the maximum two scores are added to obtain the total score. Low Gleason scores (i.e., 2–4) indicate well differentiated tumor cells and
Treatment and management of PCa
PCa can be regarded as one of the most potent and prevalent health challenge for the human male population. Our failure to combat PCa is supported by the steady deaths due to the disease with ~ 27,350 expected deaths due to this in US in 2006 (Jemal et al., 2006). The different approaches in treatment and management of the disease involve targeting the important hormones, radiation and gene therapy.
Conclusions
Our efforts in dealing with one of the greatest challenges of the human male population, PCa, have had limited success till date. The existing gaps in the understanding of PCa need to be filled up for more effective diagnostics and treatment. This would involve having a complete knowledge of AR dysfunctions, its network in PCa and specific actions of estrogen through its varying receptors, among others. There have been promising results with different approaches but none of them comes near to
Acknowledgments
This work was supported by a DBT grant no. BT/PR2752/ AAQ/01/113/2001 and DST grant no. SP/SO/DO3/99 to SA and a core grant from the Department of Biotechnology, Government of India, to the National Institute of Immunology, New Delhi.
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