The role of IL-17 in prostate cancer

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DESCRIPTION (provided by applicant): Chronic inflammation has been associated with a variety of human cancers. Although all surgical prostate specimens contain evidence of inflammation, the causal relationship between inflammation and prostate cancer has not been established. Interleulin-17 (IL-17) has been well accepted as a critical cytokine in inflammation. Both TH17 cells (T helper cells secreting IL-17) and IL-17 cytokine are increased in prostate cancer specimens, and the IL-17 receptors, IL-17RA and IL-17RC, are expressed in prostate cancer cells. However, the fundamental question of whether IL-17 plays an active role in prostate cancer needs to be determined. Our preliminary experiments revealed that in a mouse model of prostate cancer caused by conditionally mutant for Pten in the prostatic epithelium, IL- 17RC deficient (IL-17RC-) mice displayed smaller prostates and developed a reduced number of invasive prostate cancers with decreased inflammatory infiltration, reduced cellular proliferation, and increased apoptosis, compared to mice that express IL-17RC. Further, the fibromuscular stroma surrounding the prostatic glands was significantly thicker in IL-17RC- mice, a finding that we have associated with a decreased expression of matrix metalloproteinase 7 (MMP7). Addition of a recombinant mouse IL-17 induced the expression of MMP7 in the mouse prostate. Based on these findings, we have formulated a central hypothesis that, in prostate carcinogenesis caused by a Pten mutation, IL-17 facilitates prostate cancer formation and growth through an MMP7-mediated mechanism. This concept has clinical significance because blocking IL-17 or its downstream effectors such as MMP7 has the potential to be developed into new therapeutics in the prevention and treatment of prostate cancer; further, assessing the expression of IL-17- MMP7 signaling axis can be utilized as a prognostic indicator of prostate cancer. We propose to test our central hypothesis through the following three specific aims: Aim 1: Does MMP7 mediate IL-17's function in facilitating prostate cancer formation and growth in Pten- null mice? Aim 2: Assess the efficacy of targeting IL-17-MMP7 axis in preventing prostate cancer formation and growth in Pten-null mice. Aim 3: Determine the association between the IL-17-MMP7 axis and progression of human prostate cancer. Successful completion of the proposed studies will provide new insights into the molecular mechanisms underlying IL-17-mediated prostate carcinogenesis. Further, if any or all of the tested agents show efficacy, they can potentially be developed into preventive and/or therapeutic drugs against prostate cancer and other cancer types where IL-17 plays a role. The IL-17-MMP7 axis can potentially be utilized as new biomarkers in the prognosis of prostate cancer and in distinguishing between aggressive and indolent prostate cancers.