Skip to main page content
U.S. flag

An official website of the United States government

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2019 Jul 30;6(3):82.
doi: 10.3390/medicines6030082.

Cellular and Molecular Mechanisms Underlying Prostate Cancer Development: Therapeutic Implications

Ugo Testa  1 , Germana Castelli  2 , Elvira Pelosi  2
Affiliations
Review

Cellular and Molecular Mechanisms Underlying Prostate Cancer Development: Therapeutic Implications

Ugo Testa et al. Medicines (Basel). .

Abstract

Prostate cancer is the most frequent nonskin cancer and second most common cause of cancer-related deaths in man. Prostate cancer is a clinically heterogeneous disease with many patients exhibiting an aggressive disease with progression, metastasis, and other patients showing an indolent disease with low tendency to progression. Three stages of development of human prostate tumors have been identified: intraepithelial neoplasia, adenocarcinoma androgen-dependent, and adenocarcinoma androgen-independent or castration-resistant. Advances in molecular technologies have provided a very rapid progress in our understanding of the genomic events responsible for the initial development and progression of prostate cancer. These studies have shown that prostate cancer genome displays a relatively low mutation rate compared with other cancers and few chromosomal loss or gains. The ensemble of these molecular studies has led to suggest the existence of two main molecular groups of prostate cancers: one characterized by the presence of ERG rearrangements (~50% of prostate cancers harbor recurrent gene fusions involving ETS transcription factors, fusing the 5' untranslated region of the androgen-regulated gene TMPRSS2 to nearly the coding sequence of the ETS family transcription factor ERG) and features of chemoplexy (complex gene rearrangements developing from a coordinated and simultaneous molecular event), and a second one characterized by the absence of ERG rearrangements and by the frequent mutations in the E3 ubiquitin ligase adapter SPOP and/or deletion of CDH1, a chromatin remodeling factor, and interchromosomal rearrangements and SPOP mutations are early events during prostate cancer development. During disease progression, genomic and epigenomic abnormalities accrued and converged on prostate cancer pathways, leading to a highly heterogeneous transcriptomic landscape, characterized by a hyperactive androgen receptor signaling axis.

Keywords: cancer stem cells; gene expression profiling; gene sequencing; prostate cancer; tumor xenotrasplantation assay.

PubMed Disclaimer

Conflict of interest statement

The author declares no conflicts of interest.

Figures

Figure 1
Figure 1
(A) Comparison of the main genetic alterations (copy number alterations and mutations) observed in primary and metastatic prostate cancer. The data are reported in the study of the Cancer Genome Atlas Project (TCGA) [38]. (B) Comparison of the alterations in signaling and biochemical pathways observed in primary and metastatic prostate cancer. The data are reported in Armenia et al. [61]. (C) Common genomic alterations observed in prostate cancer (mostly primary cancers) patients subdivided according to the presence of ERG gene fusions into ETS+ and ETS-. The data are reported in Wedge et al. 2018 [65]. (D) Common genomic alterations observed in primary prostate cancer patients subdivided into ETS+ and ETS- groups according to the presence of ETS gene fusions. Data are reported in Xiao et al., 2018 [66].
Figure 2
Figure 2
(A) Most recurrent somatic and germline genetic alterations observed in metastatic CRPC through DNA and RNA sequencing of clinical biopsies. The data are reported by Robinson et al., 2015 [67]. (B) Recurrent somatic genetic alterations in metastatic lesions of CRPC patients through whole genome sequencing. The data are reported in Quigley et al., 2018 [68]. (C) Recurrent somatic molecular aberrations observed in metastatic lesions of CRPC patients analyzed by wide exome sequencing. The data are reported in Kumar et al. 2016 [73].
Figure 3
Figure 3
Gene and protein organization of AR and AR variants. (A) Human AR is encoded by a single gene located at Xq 11–12 and is normally organized into 8 exons, encoding a protein of 919 amino acids. The full-length AR protein (AR-FL) is divided into structural and functional domains: (i) a large amino terminal transactivation domain (NTD) containing activation function-1 (AF-1) and activation function-5 (AF-%); (ii) a DNA-binding domain (DBD); and (iii) a small hinge region, containing a nuclear localization signal (NLS), and a ligand-binding domain (LBD), containing activation function-2 (AF-2). It is important to note that cryptic exons (CE) are located either between exon2 and 3 (CE 2b/CE4) or between exon 3 and 4 (CE1, CE2, CE3, CE5, and 3′): alternative splicing of CEs can give rise to carboxy-terminally truncated AR isoforms. (B) Structure of three clinically relevant AR-Vs: AR-V7, AR-V9 and Arv567es.
Figure 4
Figure 4
Molecular features (recurrent genomic alterations) or prostate cancer (CRPC) subdivided into three subgroups according to the expression and signaling activity of AR into AR+ and AR- and to the presence or not of neuroendocrine features into NE+ and NE-. The data are reported in Bluemn et al. [215].
Figure 5
Figure 5
Frequency and distribution of genetic alterations of PTEN, RB1 and TP53 genes and measures of genomic instability in three groups of prostate cancer patients: L-CSPC (Localized Castration-Sensitive Prostate Cancer), M1-CSPC (Metastatic Castration-Sensitive Prostate Cancer), and M1-CRPC (Metastatic Castration-Resistant Prostate Cancer). TSG: Tumor Suppressor Gene. TMB: Tumor Mutation Burden. PGA: Percent of Genome Copy number Altered. Data are reported from Hamid et al., 2019 [233].
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Mellinger G.T. Prognosis of prostatic carcinoma. Recent Results Cancer Res. 1977;60:61–72. - PubMed
    1. Bailar J.C., Mellinger G.T., Gleason D.F. Survival rates of patients with prostatic cancer, tumor stage, and differentiation-preliminary report. Cancer Chemother. Rep. 1966;50:129–136. - PubMed
    1. Gleason D.F. Histological grading and staging of prostatic carcinoma. In: Tannenbaum M., editor. Urologic Pathology: The Prostate. Lea and Feibiger; Philadelphia, PA, USA: 1977. p. 171.
    1. Epstein J.I. Prostate cancer grading: A decade after the 2005 modified system. Modern Pathol. 2018;31:547–563. doi: 10.1038/modpathol.2017.133. - DOI - PubMed
    1. Epstein J.I., Zelefsky M.J., Sjoberg D.D., Nelson J.B., Egevad L., Magi-Galluzzi C., Vickers A.J., Parwani A.V., Reuter V.E., Fine S.W., et al. A contemporary prostate cancer grading system: A validated alternative to the Gleason score. Eur. Urol. 2016;69:428–435. doi: 10.1016/j.eururo.2015.06.046. - DOI - PMC - PubMed

LinkOut - more resources