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.

Keywords: prostate cancer; therapy resistance; tumor microenvironment.

Figure 1.

The normal and neoplastic prostate. (A) Comparison of human and mousse normal prostates. Anatomically, the human prostate contains three zones: (1) the peripheral zone, where ∼60%–75% of prostate cancers arise (McNeal et al. 1988; Haffner et al. 2009); the central zone; and (3) the transition zone (McNeal 1969, 1981, 1988). In contrast, the mouse prostate consists of the following distinct lobes: the anterior prostate (AP), the ventral prostate (VP), and the dorsolateral prostate (DLP) (Cunha et al. 1987). The luminal cells produce secretory proteins and are defined by expression of cytokeratin 8 (CK8) and CK18 and androgen receptor (AR). The basal cells are nestled between the basal lamina and luminal cells and express high levels of CK5 and p63 and very low levels of AR. Neuroendocrine cells, a small population of endocrine–paracrine cells located on the basal cell layer, express neuroendocrine markers such as synaptophysin and chromogranin A and do not express AR. (B) Prostate cancer cell of origin. Studies have demonstrated that both luminal cells and basal cells can serve as the cell of origin for prostate cancer; however, it remains unknown whether neuroendocrine cells can be transformed to generate prostate cancer. Overexpression of oncogenes such as constitutively active myristoylated AKT1 (myrAKT1) transforms normal human prostate epithelial cells into prostate cancer cells, which display prostate adenocarcinoma and squamous cell carcinoma phenotypes. In addition, N-Myc and myrAKT1 in normal prostate epithelial cells resulted in the formation of prostate adenocarcinoma and NEPC (neuroendocrine prostate cancer). Conditional inactivation of tumor suppressor genes Pten, Smad4, and Trp53 in both basal cells and luminal cells (ARR2PB-Cre), in basal cells (CK14-CreER), and in luminal cells (CK8-CreER) resulted the formation of prostate adenocarcinoma. Interestingly, inactivation of Pten, Rb1, and Trp53 resulted in the formation of NEPC. Castration in mice bearing Pten/Rb1-deficient prostate adenocarcinoma or abiraterone treatment of Pten/Trp53-deficient prostate adenocarcinoma resulted in the formation of NEPC.

Figure 2.

Progression of prostate cancer and the development of mCRPC. The diagnosis of PIN is defined by luminal cell proliferation with dysplasia along the ducts. PIN in turn progresses to localized prostate adenocarcinoma, which then becomes locally invasive carcinoma as the basal cell layer is degraded and cancer cells invade through the basal lamina. Locally advanced prostate cancer metastasizes first to draining lymph nodes and then to distant organs, including the bones, liver, and lungs, with bone as the most common site of metastasis. In bone metastasis, there is a dynamic interaction between the cancer cells, osteoblasts, and osteoclasts, which results in a “vicious cycle” of bone formation and destruction—a process that supports cancer cell survival and tumor growth. AR-dependent localized advanced prostate adenocarcinoma can initially respond to ADT and then progress to CRPC. Localized advanced prostate adenocarcinoma can also display de novo resistance to ADT. Similarly, AR-dependent hormone-naïve metastatic tumors initially respond to ADT and then progress to mCRPC. AR-indifferent hormone-naïve metastatic tumors display de novo resistance. The treatment options for prostate cancer depend on tumor stage and previous treatments.

Figure 3.

The TME contributes to therapy resistance. (1) Chemoresistance. Cytotoxic chemotherapy (mitoxantrone and the docetaxel) induces WNT16B expression CAFs, which in turn activates WNT signaling in prostate cancer cells through binding to Lrp5/6 and Frizzle in a paracrine manner and subsequently promotes chemoresistance and tumor progression. Oxaliplatin induces Cxcl13 expression in CAFs, which promotes the recruitment of B cells to suppress immunogenic cell death induced by oxaliplatin; plasmocytes expressing immunoglobulin A, IL-10, and PD-L1 were identified as the immunosuppressive B cells that are directly involved in this process (Ammirante et al. 2014; Shalapour et al. 2015). (2) Castration resistance. Castration also induces Cxcl13 expression in CAFs, which promotes the recruitment of B cells. B-cell-derived lymphotoxin activates E2F/BMI1/Stat3 signaling to promote the development of CRPC. Castration also induced the expression of colony-stimulating factor 1 (Csf1) in prostate cancer cells to attract macrophages to promote the survival of prostate cancer cells. (3) Immunoresistance. Yap1 and Sox9 activation in prostate cancer cells leads to an increase in the expression of chemokine Cxcl5 and the subsequent recruitment of myeloid-derived suppressor cells (MDSCs) to promote prostate tumor progression and immunoresistance through multiple mechanisms, including the direct suppression of cytotoxic T cells. Castration induced the increased expression of IL-2 to recruit regulatory T cells (Tregs), which will limit the efficacy of the cytotoxic T cells. Various therapeutic agents have been used to target CAFs (Kakarla et al. 2012), B cells (Yuen et al. 2016), tumor-associated macrophages (TAMs) (Cannarile et al. 2017), MDSCs (Lu et al. 2017a), and Tregs (Liu et al. 2016).