All ETDs from UAB

Advisory Committee Chair

Selvarangan Ponnazhagan

Advisory Committee Members

Zdenek Hel

Richard D Lopez

John D Mountz

Gene P Siegal

Theresa V Strong

Document Type

Dissertation

Date of Award

2011

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

LL-37 is the only cathelicidin-derived anti-microbial peptide in humans and has been shown to stimulate proliferation, angiogenesis, cellular migration and inhibit apoptosis, in addition to serving as a chemoattractant for leukocytes. It is produced primarily by epithelial cells and leukocytes, and has recently been discovered to be over-expressed in breast, ovarian and lung cancers. Based on these findings, we compared levels of LL-37 expression in benign and cancerous human prostate tissues. Results of this investigation demonstrated that LL-37 is increasingly over-expressed in primary prostate tumors in a grade dependent manner and in metastatic lesions. Since the physiological mechanisms of LL-37 are also key factors that become exaggerated in prostate cancer (PCa) and based on our preliminary findings regarding the over-expression of LL-37 in PCa in a grade dependent manner, we hypothesized that LL-37 may have a significant role in the neoplastic progression of PCa and serve as a potential therapeutic target. We analogously examined the role of LL-37 in the neoplastic progression of PCa within an immunocompetent mouse PCa model, utilizing the murine orthologue of LL-37, Cathelicidin Related Anti-Microbial Peptide (CRAMP). Similar to the grade dependent over-expression of LL-37 in human PCa, we found CRAMP is increasingly over-expressed with advancing severity of primary prostate tumors and in metastatic lesions of the Transgenic Adenocarcinoma Mouse Prostate (TRAMP) model. Modulation of CRAMP within TRAMP PCa cell lines significantly altered in vitro and in vivo pro-tumorigenic mechanisms. Our study demonstrated that CRAMP modulates the proliferation, invasiveness and matrix metalloproteinase (MMP) levels of these cells in a positive manner through the Erk1/2 and Akt pathways. In addition to replicating these findings, CRAMP knockdown in TRAMP-C1 cells also led to a significant in vivo reduction in tumor burdens, angiogenesis and the number of myeloid-derived suppressor cells (MDSC) infiltrating into the tumor microenvironment. The effects of CRAMP modulation on cellular proliferation, angiogenesis, invasion, MMP levels and the chemoattraction of MDSC in a mouse PCa model, support our hypothesis that LL-37 has a significant role in the neoplastic progression of PCa and may serve as an efficacious therapeutic target for PCa, and other cancers over-expressing the peptide.

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