Elsevier

Gene

Volume 410, Issue 1, 29 February 2008, Pages 1-8
Gene

Review
Multidimensional approaches in dealing with prostate cancer

https://doi.org/10.1016/j.gene.2007.11.020Get rights and content

Abstract

Prostate cancer is one of the most prevalent malignancies worldwide affecting the human male population. Different case-control, cohort or twin studies and segregation analyses point towards the presence of prostate cancer-susceptibility genes in the population. The studies have shown 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. However, differences right from the mode of inheritance (autosomal dominant or X-linked recessive) to the target genes exist. There have been reports supporting no or weak linkage to these loci as well. Also, region (environmental factors), age and dietary habits have implications in different aspects of the disease. The important targets for treating prostate cancer are androgens and estrogen (synthesized from androgens by the action of enzyme aromatase) owing to their involvement in development and progression of prostate cancer. Further, prostate gland needs androgens (male hormones) for its normal maintenance and functioning. Besides, radiation therapy and surgical methods have also been used. The emerging areas include identifying and preparing successful vaccines from candidate peptides and gene therapy in several forms. This review deals with the paradox of linkage analyses and the various approaches in practice for treatment and management of 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.

References (85)

  • HsiehC.

    A genome screen of families with multiple cases of prostate cancer: evidence of genetic heterogeneity

    Am. J. Hum. Genet.

    (2001)
  • KubanD.

    Hazards of dose escalation in prostate cancer radiotherapy

    Int. J. Radiat. Oncol. Biol. Phys.

    (2003)
  • KurhanewiczJ. et al.

    The prostate: MR imaging and spectroscopy. Present and future

    Radiol. Clin. North Am.

    (2000)
  • McIndoeR.A.

    Linkage analysis of 49 high-risk families does not support a common familial prostate cancer-susceptibility gene at 1q24–25

    Am. J. Hum. Genet.

    (1997)
  • PickettB.

    Time to metabolic atrophy after permanent prostate seed implantation based on magnetic resonance spectroscopic imaging

    Int. J. Radiat. Oncol. Biol. Phys.

    (2004)
  • PriceD.

    Toremifene for the prevention of prostate cancer in men with high grade prostatic intraepithelial neoplasia: results of a double-blind, placebo controlled, phase IIB clinical trial

    J. Urol.

    (2006)
  • SimonsJ.W. et al.

    Granulocyte-macrophage colony-stimulating factor transduced allogeneic cancer cellular immunotherapy: the GVAX vaccine for prostate cancer

    Urol. Oncol.

    (2006)
  • SuarezB.K.

    A genome screen of multiplex sibships with prostate cancer

    Am. J. Hum. Genet.

    (2000)
  • TakamiyaR. et al.

    A zero PSA slope in posttreatment prostate-specific antigen supports cure of patients with long-term follow-up after external beam radiotherapy for localized prostate cancer

    Int. J. Radiat. Oncol. Biol. Phys.

    (2003)
  • van der LindenR.

    Virus specific immune responses after human neoadjuvant adenovirus-mediated suicide gene therapy for prostate cancer

    Eur. Urol.

    (2005)
  • WitteJ.S.

    Genomewide scan for prostate cancer-aggressiveness loci

    Am. J. Hum. Genet.

    (2000)
  • XuJ.

    Combined analysis of hereditary prostate cancer linkage to 1q24–25: results from 772 hereditary prostate cancer families from the International Consortium for Prostate Cancer Genetics

    Am. J. Hum. Genet.

    (2000)
  • XuJ.

    Linkage and association studies of prostate cancer susceptibility: evidence for linkage at 8p22–23

    Am. J. Hum. Genet.

    (2001)
  • XuJ.

    Evaluation of linkage and association of HPC2/ELAC2 in patients with familial or sporadic prostate cancer

    Am. J. Hum. Genet.

    (2001)
  • YuenJ.

    Endorectal magnetic resonance imaging and spectroscopy for the detection of tumor foci in men with prior negative transrectal ultrasound prostate biopsy

    J. Urol.

    (2004)
  • AgoulnikI.U.

    Role of SRC-1 in the promotion of prostate cancer cell growth and tumor progression

    Cancer Res.

    (2005)
  • AkhtarM. et al.

    Mechanistic studies on C-19 demethylation in oestrogen biosynthesis

    Biochem. J.

    (1982)
  • BevanC.L. et al.

    The AF1 and AF2 domains of the androgen receptor interact with distinct regions of SRC1

    Mol. Cell Biol.

    (1999)
  • BochumS. et al.

    Confirmation of the prostate cancer susceptibility locus HPCX in a set of 104 German prostate cancer families

    Prostate

    (2002)
  • CarptenJ.

    Germline mutations in the ribonuclease L gene in families showing linkage with HPC1

    Nat. Genet.

    (2002)
  • CarterB.S. et al.

    Mendelian inheritance of familial prostate cancer

    Proc. Natl. Acad. Sci. U. S. A.

    (1992)
  • CooneyK.A.

    Prostate cancer susceptibility locus on chromosome 1q: a confirmatory study

    J. Natl. Cancer Inst.

    (1997)
  • DenisL.J.

    Maximal androgen blockade: final analysis of EORTC phase III trial 30853. EORTC Genito-Urinary Tract Cancer Cooperative Group and the EORTC Data Center

    Eur Urol

    (1998)
  • DenisL.J. et al.

    Overview of phase III trials on combined androgen treatment in patients with metastatic prostate cancer

    Cancer

    (1993)
  • DePrimoS.E.

    Transcriptional programs activated by exposure of human prostate cancer cells to androgen

    Genome Biology

    (2002)
  • DhomG.

    Epidemiologic aspects of latent and clinically manifest carcinoma of the prostate

    J. Cancer Res. Clin. Oncol.

    (1983)
  • DunnJ.E.

    Cancer epidemiology in populations of the United States–with emphasis of Hawaii and California–and Japan

    Cancer Res.

    (1975)
  • EllemS.J. et al.

    Local aromatase expression in human prostate is altered in malignancy

    J. Clin. Endocrinol. Metab.

    (2004)
  • EwisA.A.

    Prostate cancer incidence varies among males from different Y-chromosome lineages

    Prostate Cancer Prostatic Dis.

    (2006)
  • FeuerE.J.

    Lifetime probability of cancer

    J. Natl. Cancer Inst.

    (1997)
  • GopalkrishnanR.V. et al.

    Molecular characterization of prostate carcinoma tumor antigen-1, PCTA-1, a human Galectin-8 related gene

    Oncogene

    (2000)
  • LynD.

    A duplicated region is responsible for the poly(ADP-ribose) polymerase polymorphism, on chromosome 13, associated with a predisposition to cancer

    Am. J. Hum. Genet.

    (1993)
  • Cited by (5)

    • A literature review on the role of MIR-370 in disease

      2016, Gene Reports
      Citation Excerpt :

      The other recently researched function of miR-370 in the gynecologic setting was that of miR-370 in steroidogenic cells of ovary, which is likely to play a key role in posttranscriptional/posttranslational regulation of steroidogenesis (Hu et al., 2013). Prostate cancer is currently the second most common malignancy in males, with more than 110,000 new cases occurring globally each year (Diaw et al., 2007; Ali and Ali, 2008; G and K, 2011; Torre et al., 2015). Stegeman et al. (2015)investigated the association between 2169 miSNPs and prostate cancer risk in a large-scale study of 22,301 cases and 22,320 controls of European origin.

    • Molecular mechanisms of TRP regulation in tumor growth and metastasis

      2009, Biochimica et Biophysica Acta - Molecular Cell Research
    • TRP channels and cancer

      2011, TRP Channels in Health and Disease: Implications for Diagnosis and Therapy
    View full text