Inflammatory genetic markers of prostate cancer risk

Abstract

Prostate cancer is the most common cancer in Western society males, with incidence rates predicted to rise with global aging. Etiology of prostate cancer is however poorly understood, while current diagnostic tools can be invasive (digital rectal exam or biopsy) and/or lack specificity for the disease (prostate-specific antigen (PSA) testing). Substantial histological, epidemiological and molecular genetic evidence indicates that inflammation is important in prostate cancer pathogenesis. In this review, we summarize the current status of inflammatory genetic markers influencing susceptibility to prostate cancer. The focus will be on inflammatory cytokines regulating T-helper cell and chemokine homeostasis, together with the Toll-like receptors as key players in the host innate immune system. Although association studies indicating a genetic basis for prostate cancer are presently limited mainly due to lack of replication, larger and more ethnically and clinically defined study populations may help elucidate the true contribution of inflammatory gene variants to prostate cancer risk.

Figure 1

Multi-step process of prostate cancer development. Under normal conditions, Th cytokines are maintained in a homeostatic state via self-regulating mechanisms and angiostatic chemokines are predominant. Regions of PIA are frequently associated with inflammation, possibly triggered by an infectious agent. The inflammatory response induces TLR-expressing inflammatory cells, which mediate cell proliferation and increase cytokine and chemokine production. As the inflammatory response progresses, self-regulating mechanisms fail leading to an overproduction of Treg, Th17 cytokines and angiogenic chemokines, which enhance DNA damage, cell proliferation and angiogenesis, promoting prostate cancer progression.