Inflammatory microenvironment in Prostate Carcinogenesis

GUERON, GERALDINE; COTIGNOLA, JAVIER; VAZQUEZ, ELBA

Advances in Prostate Cancer

InTech

Lugar: Vienna; Año: 2013; p. 423 - 461

The association between prostate cancer and inflammation was first formally addressed in the nineteen century and since then many authors have confirmed the biological and clinical evidence of this association. However, the molecular mechanism involved is yet to be deciphered. There are two well established pathways linking inflammation and cancer: the extrinsic pathway from conditions that cause non-resolving smouldering inflammatory responses and the intrinsic pathway where the misregulation of oncogenes and tumor suppressor genes switch on the expression of inflammation-related programs. Prostate cancer is a complex and progressive disease. Over time the cells become resistance to hormonal therapies that are designed to block the release and/or the uptake of androgens. During this stage androgen receptor (AR) mutants are able to bind promiscuous steroids, and may convert AR antagonists to agonists. Other hormones and their receptors are involved in the abnormal growth of the gland. Particularly, oestrogens and oestrogen receptors define a subclass of prostate cancer with a very aggressive clinical phenotype (such as the TMPRSS2-ERG fusion). In addition, other signaling cascades are switched on bypassing the androgen/AR axis and favoring tumor progression. Among them, cyclooxygenase-2 (COX-2), neuroendocrine differentiation and the loss of the tumor suppressor phosphatase and tensin homolog (PTEN), with the concomitant inhibition of the PI3K/Akt, resulting in Bcl-2 overexpression and the burst of pro-inflammatory cytokines, chemokines and other growth factors production, contributing all to the progression to the hormonal-resistance disease. As in other malignancies in prostate cancer, reactive oxygen species (ROS) cause oxidative damage to macromolecules in epithelial cells and can react with other cellular components initiating a free radical chain reaction, thus sustaining the prostate carcinogenic process and its progression. The molecular mechanisms that prime the pathogenesis of cancer-related inflammation are complex and involve a delicate interplay between tumor and its microenvironment. In prostate tumors, the switch to an angiogenic phenotype is known to be critical for its progression. Unless a tumor can stimulate the formation of new blood vessels, it remains restricted to a microscopic size. Inflammation and hypoxia are widely accepted as key elements in the induction of angiogenesis. Dissection of the diversity of cancer-related inflammation is critical for the design of innovative diagnostic and therapeutic strategies in prostate cancer. Specifically, the following topics and molecular events are reviewed and discussed in this chapter: The cytokine and chemokine orchestration and the associated downstream genetic events that cause neoplastic transformation in the prostatic tissue. Acknowledging the oxidative stress imbalance in the tumoral niche as key mediators of signaling cascades. The relevance of microRNAs as oncogenes and tumor suppressor genes and how microRNAs expression profiles can be used for markers of prostate cancer prevention and therapeutics. The potential of prostate tumoral cells in the inflammatory microenvironment to express an endothelial-like phenotype and mimic vasculogenic networks.