All ETDs from UAB

Advisory Committee Chair

Selvarangan Ponnazhagan

Advisory Committee Members

Gene Siegal

Theresa Strong

Rosa Serra

Douglas Hurst

Document Type

Dissertation

Date of Award

2015

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

A growing body of evidence indicates a positive correlation between the expression of human antimicrobial peptide leucine leucine 37 (LL-37) and the progression of epithelial cancers, including carcinomas of the breast, lung, ovary, and prostate. Although the molecular mechanisms for this correlation have not yet been clearly elucidated, the primary function of LL-37 as a chemotactic molecule for innate immune effector cells suggests its possible association in coordinating protumorigenic mechanisms mediated by tumor-infiltrating immune cells. Using a mouse model of epithelial prostate cancer (PCa), the present study identified a unique role for cathelicidin-related antimicrobial peptide (CRAMP), a murine orthologue of LL-37, in chemotaxis, and differentiation and polarization of immature myeloid progenitors (IMPs) to protumorigenic type 2 macrophages (M2) in tumor microenvironment (TME). By adoptively transferring IMPs into mice bearing CRAMP(+) and CRAMP(-) tumors, we identified that tumor-derived CRAMP facilitates differentiation and polarization of IMPs toward M2. Characterization of immune mechanisms using CRAMP deficient mouse (Cnlp-/- mouse), lacking CRAMP gene, further provided evidence that tumor-derived CRAMP plays a crucial role in protumorigenic immune cell conversion. Moreover, in vitro studies revealed that tumor-derived CRAMP regulates production of macrophage colony stimulating factor (M-CSF)/colony stimulating factor 1 (CSF1) and chemokine ligand 2 (CCL2)/monocyte chemoattractant protein 1 (MCP-1) in an autocrine mechanism, involving nuclear factor κB (NF- κB) p65, and regulates IMP-to-M2 differentiation/polarization through STAT3 activation. Using immunocompetent and immunodeficient mouse models, this study additionally demonstrates that tumor-derived CRAMP initially chemoattracts IMPs, neutrophils, and macrophages to TME. Thus, selective down-regulation of CRAMP in tumor cells in situ may benefit overcoming protumorigenic immune mechanisms in PCa.

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