Phosphoinositide-Driven Epithelial Proliferation in Prostatic Inflammation
Funding:
Principal Investigator:
Travis Jerde, PhD (Wade Bushman, MD, PhD, Mentor)
Lab Website:
Project Summary:
Among the variety of genetic and environmental factors involved in the development of prostate cancer, chronic prostatic inflammation is believed to play a central role. Chronic inflammation is thought to create a microenvironment of sustained cell proliferation and activated stroma in which an abundance of inflammatory mediators, growth factors, and DNA damaging agents may initiate malignant transformation. Chronic inflammation is typically associated with dysplastic changes including nuclear polymorphism, cytoplasmic basophilia, and reactive epithelial hyperplasia. Interleukins (IL) 1 - beta and 6, tumor necrosis factor (TNF), and prostanoid release all play a role in prostatic inflammation and have also been implicated as growth promoters in prostate cancer.
Proliferative inflammatory atrophy (PIA) is a histologic lesion characterized by proliferating epithelial cells and activated inflammatory cells. PIA is often found in association with prostatic intra-epithelial neoplasia (PIN) and prostate cancer and has been postulated to represent a pre-malignant lesion Gene expression anomalies found in prostate cancer include several genes involved in inflammation, including PTEN, MSR-1, RNASEL, and COX-2 and these findings, together with the observations on PIA, have prompted the hypothesis that chronic inflammation is involved in the genesis or progression of prostate cancer.
The postulated causal relationship between inflammation and cancer in the prostate is a provocative and exciting proposal, but substantiation of such a relationship requires supporting evidence for inflammation-induced anomalies in growth regulation that could contributed to cancer development. Such studies are thus far lacking. This proposal addresses that deficiency by using a combination of in vitro and in vivo approaches to examine and elucidate the effect of inflammatory cytokines and acute/chronic inflammation on the PI3/Akt/PTEN pathway.
The PI3/Akt/PTEN pathway is critical to cell cycle progression and has long been an interest to cancer researchers due to the frequent finding of PI3 kinase induction, Akt phosphorylation and PTEN suppression in cancer. The PI3 kinase cascade is known to be induced by inflammation and inflammatory cytokines such as interleukins. We have recently shown hat inflammatory cytokines induce PI3 Kinase activation, Akt activation, PTEN suppression and proliferation in cell culture. Further, we have preliminary data showing that reactive hyperplasia and dysplasia in a recently described model of chronic prostatic inflammation is associated with PTEN suppression and Akt activation. Based on these observations, we propose to examine the hypothesis that inflammation induces prostatic epithelial proliferation in a PI3 Kinase cascade-dependent fashion.
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