Genetics and biology of prostate cancer

Abstract

Despite the high long-term survival in localized prostate cancer, metastatic prostate cancer remains largely incurable even after intensive multimodal therapy. The lethality of advanced disease is driven by the lack of therapeutic regimens capable of generating durable responses in the setting of extreme tumor heterogeneity on the genetic and cell biological levels. Here, we review available prostate cancer model systems, the prostate cancer genome atlas, cellular and functional heterogeneity in the tumor microenvironment, tumor-intrinsic and tumor-extrinsic mechanisms underlying therapeutic resistance, and technological advances focused on disease detection and management. These advances, along with an improved understanding of the adaptive responses to conventional cancer therapies, anti-androgen therapy, and immunotherapy, are catalyzing development of more effective therapeutic strategies for advanced disease. In particular, knowledge of the heterotypic interactions between and coevolution of cancer and host cells in the tumor microenvironment has illuminated novel therapeutic combinations with a strong potential for more durable therapeutic responses and eventual cures for advanced disease. Improved disease management will also benefit from artificial intelligence-based expert decision support systems for proper standard of care, prognostic determinant biomarkers to minimize overtreatment of localized disease, and new standards of care accelerated by next-generation adaptive clinical trials.

Chromatin reprogramming as an adaptation mechanism in advanced prostate cancer

“…This drives the expression of so-called AR target genes. AR target gene transcriptional regulation is associated with extensive chromatin remodeling, which includes alteration of histone modifications (Wang et al 2018a). The chromatin packs DNA, histones (organized as octamers, collectively forming the nucleosomes) and other chromatin-associated proteins in a dynamic structure within the nucleus of cells.…”

Complexity of Neural Component of Tumor Microenvironment in Prostate Cancer

“…Neuroendocrine cells are the source of numerous peptide hormones, neuropeptides and biogenic amines acting on other components. The glandular structures surrounded with basal lamina are embedded in prominent fibromuscular stroma composed of smooth muscle cells admixed with fibroblasts and blood vessels [37][38][39]. Growth of stroma in a normal prostatic gland is positively regulated directly by growth factors such as epidermal growth factor and fibroblast growth factor.…”

“…In PC, the neoplastic glandular component devoid of basement membrane is directly embedded in stroma composed of smooth muscle cells admixed with specific fibroblasts and blood vessels [37,38]. The most prominent TME components are activated fibroblasts having myofibroblastic phenotype called CAF.…”

hPCL3S promotes proliferation and migration of androgen-independent prostate cancer cells

“…Initially, treatments with androgen depletion or AR blocking called androgen dependent therapy (ADT) are efficient. Unfortunately, however, most patients relapse and progress to androgen-independent more aggressive forms of prostate cancer termed castrationresistant prostate cancer (CRPC) with poor prognosis [1]. One of the mechanisms leading to this castration resistant disease is the manifestation of a neuroendocrine transdifferentiation (NE) following ADT and resulting in prostatic small cell neuroendocrine carcinomas (SCNC).…”