medicines Review Cellular and Molecular Mechanisms Underlying Prostate Cancer Development: Therapeutic Implications Ugo Testa * , Germana Castelli and Elvira Pelosi Department of Oncology, Istituto Superiore di Sanità, Vaile Regina Elena 299, 00161 Rome, Italy * Correspondence: [email protected] Received: 26 June 2019; Accepted: 25 July 2019; Published: 30 July 2019 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 50 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: prostate cancer; cancer stem cells; tumor xenotrasplantation assay; gene sequencing; gene expression profiling 1. Introduction Prostate cancer is the most frequently diagnosed nonskin cancer and second most common cause of cancer-related deaths in men, with an estimated 1,600,000 cases and 366,000 deaths annually. Despite recent progresses, prostate cancer remains a great medical problem for the men affected, with absolute need to improve the efficacy of current therapies for metastatic disease and to reduce the unnecessary overtreatment of more benign disease. Prostate cancer is a clinically heterogeneous disease with many patients exhibiting an aggressive disease with progression and metastasis and other patients showing an indolent disease with low tendency to progression. The standard treatment of this cancer is based on surgery and radiotherapy; however, patients nonsuitable for radiotherapy or surgery are treated with androgen ablation therapy, which effectively shrinks androgen-dependent tumors. Medicines 2019, 6, 82; doi:10.3390/medicines6030082 www.mdpi.com/journal/medicines Medicines 2019, 6, 82 2 of 136 Unfortunately, this treatment is often followed by recurrent androgen-independent prostate cancer, with frequent metastases. The human prostate contains three cell types: luminal cells (columnar epithelial cells that express secretory proteins, differentiation antigens such as cytokeratin 8, prostate-specific antigen, and high levels of the androgen receptor), basal cells (localized to a lower level express markers such as cytokeratin 5, but express only low levels of androgen receptor), and rare neuroendocrine cells (characterized by the expression of endocrine markers). Three stages of development of human prostate tumors have been identified: (a) intraepithelial neoplasia that can be considered a precancerous state, characterized by hyperplasia of luminal cells and progressive loss of basal cells; (b) adenocarcinoma androgen-dependent (subdivided into two stages, adenocarcinoma latent and clinical), characterized by the complete loss of basal cells and the strong luminal phenotype: at this stage, the tumor is androgen-dependent and its growth can be controlled by androgen deprivation; and (c) adenocarcinoma androgen-independent (or castration resistant) that represents the evolution of adenocarcinoma and does not depend for its growth by androgens. During prostate cancer progression, the luminal compartment expands, and basal cells are lost. This corresponds to a luminal phenotype both at immunophenotypic and genotypic levels. Late stages of disease, characterized by castration-resistant prostate cancer and by the development of metastases, enrich for basal cell genes and stem cell genes. 2. Tumor Evolution of Prostate Cancer from Precursor Lesions The histological evaluation of prostate cancers, as well as of other solid tumors is of fundamental importance to assess the biology, the grade of development of the tumor and to have a prognostic projection. For clinical purposes, the histological evaluation of these tumors is expressed in terms of Gleason score: a scoring system that evaluates how much the bioptic prostatic specimen is similar to normal prostate gland (low score, 1 corresponding to normality) or is frankly tumorigenic (high score, 5 corresponding to lack of normal glands and presence of sheets of frankly abnormal tumor cells); between these two extreme grades, there are intermediate grades underlying a progressive transition from a normal tissutal architecture to the progressive loss of tissutal glands and to the acquisition of cellular atypia [1–3]. In this evaluation system, the scoring is, rather than assigning the worst grade as the grade of the tumor, the grade was defined as the sum of the two most common grade patterns and reported as the Gleason score [1–3]. This evaluation system was and is of fundamental importance in the clinical evaluation of a patient with a prostatic neoplasia. In the time, this scoring system was implemented and in 2014 accepted by the World Health Organization (WHO) [4]. In the actual evaluation system, the Gleason score 1 + 1 = 2 is a grade very rarely diagnosed and corresponding to adenosis (atypical adenomatous hyperplasia, AAH) [4]. Gleason scores 3 and 4 are of very difficult histologic evaluation and the criteria for their assessment are not solid and reproducible [4]. The Gleason pattern 3 (score 3 + 3) corresponds to the presence of highly variably sized and shaped glands, whose glandular architecture is conserved; the Gleason pattern 4 (score 4 + 4) corresponds to the presence of cribriform, poorly-formed, fused glands; finally, the Gleason pattern 5 (score 5 + 5) corresponds to the absence of glandular structures, replaced by sheets, cord, single cells, solid nests and necrotic areas [4]. The actual system of classification of prostate cancers reducing to five prognostic risk categories received support at clinical and genetic level [5]. On the basis of actual evaluation criteria, GS of 3 + 3 = 6 was reclassified into the lowest grade group (GG) of 1, GS of 3 + 4 = 7 to GG2, GS of 4 + 3 = 7 to GG3, GS of 4 + 4 to GG4, and GS of 4 + 5 or 5 + 4 or 5 + 5 to GG5 [5]. According to this classification, the quantity of GP4 or GP5 present in the tumor is a key determinant to assess the risk associated with this tumor. A 5-yr biochemical risk-free survival for prognostic grade groups of 97.5% for PGG1, 93.1% for PGG2, 78.3% for PGG3, 63.6% for PGG4, and 48.9% for PGG5 was reported [5]. The analysis of genetic abnormalities in a large set of prostate cancer specimens subdivided according to the PGG classification system showed that (i) the overall number of somatic mutations slightly increased in risk groups and was particularly significant when Medicines 2019, 6, 82 3 of 136 comparing lower (PGG1 and PGG2) with higher (PGG3, PGG4 and PGG5) risk groups; (ii) increasing copy number alterations (gain and losses) are observed with increasing PGG; (iii) the large majority of point mutations remained unmodified in the various PGGs, with the exception of TP53 increasing with PGG; and (iv) the frequent MYC amplification markedly increased with PGG [6]. A putative precursor lesion of prostate cancer is represented by high-grade prostatic intraepithelial neoplasia (HGPIN) that corresponds to a proliferation of prostate glandular epithelial cells displaying clear cytological atypia within the tissue limits of prostatic ducts and acini. HGPIN is considered a precursor lesion of prostate cancer based on two arguments: epidemiological data link HGPINs to the tumor glands and the later occurrence of invasive carcinoma during tumor surveillance; the morphological similarities between epithelial cells of HGPINs and invasive cancer; and colocalization of HGPIN with invasive prostate cancer and their mutually shared genetic rearrangements and other genetic alterations [7]. Thus, several studies have explored the clonal relationship existing between GP3 and GP4 lesions. Sowalski and coworkers have explored a series of adjacent GS3 and GS4 tumors in radical prostectomy specimens and observed that all were concordant for the TMPRSS2-ERG gene fusion: particularly, GS3 and GS4 tumors had identical