Inflammation and prostate cancer: Effects on carcinogenesis and the role of 1,25-dihydroxyvitamin D3 on the biology of infiltrating myeloid cells
Abstract
Evidence linking prostatitis and prostate cancer development is contradictory. To study this link, the POET3 mouse, an inducible model of prostatitis, was crossed with two Pten-loss mouse models of prostate cancer (Pten+/- and Pten-/-). Prostatitis was induced and prostate bioluminescence was tracked over 12 months (Pten+/-) and 6 months (Pten-/-), with lesion development, inflammatory infiltrate, and cytokine expression analyzed at various time points and compared to mice without induction of prostatitis. Acute prostatitis led to increased proliferation of the epithelium and enhanced bioluminescence in Pten+/-mice; however, 4 months after initiation of prostatitis, mice with induced inflammation had lower grade mPIN lesions. Pten+/- mice develop spontaneous inflammation, and prostatitis was similar among groups of mice at 8 and 12 months. Analyzed as one cohort, lesion number and grade were positively correlated with prostatitis. Specifically, numbers of the CD11b+Gr1+ subset of myeloid cells were correlated with lesion development. In Pten-/- mice, episodes of inflammation resulted in enhanced development of microinvasive carcinoma at 4 months of age, which were associated with decreased expression of cytokines IL-4 and IL-6. These results support the hypothesis that myeloid-based inflammation is associated with lesion development in the murine Pten+/- prostate, and previous bouts of CD8-driven prostatitis promotes invasion in the Pten-/- model of cancer. Additionally, the effects of the active form of the vitamin D hormone, 1, 25-dihydroxyvitaminD3, were investigated in myeloid-derived suppressor cells, which have been associated with enhanced development of certain human cancers, and were found to be positively correlated with lesion development in Pten+/- mice. Monocyte-like MDSC (M-MDSC) and Granulocyte-like MDSC (G-MDSC) were found to be viable targets of vitamin D, with M-MDSC responding to vitamin D with loss of immunosuppressive activity secondary to decreased NO production. Mice lacking the vitamin D receptor (VDR KO) were found to have M- and G-MDSC with greater activity than wild-type mice, further suggesting that vitamin D is important in the biology of myeloid cells.
Degree
Ph.D.
Advisors
Ratliff, Purdue University.
Subject Area
Cellular biology|Pathology|Immunology
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