have documented that upon the stimulation with Lewis lung carcinoma cell supernatant, macrophages from FPR2 deficient mice results in M2 phenotype by phosphorylation of STAT3 and STAT6 ( 12). However, in contrast to this report, Wang et al. have shown that receptor for CRAMP, formyl peptide receptor 2 (FPR2), expressed on human macrophages polarizes them into protumorigenic type 2 macrophages (M2) by upregulating monocyte chemoattractant protein-1 (MCP-1) and macrophage colony stimulating factor (M-CSF) partially depending on NF-κB pathway in human hepatocellular carcinoma model ( 9). The overexpression of LL-37/CRAMP correlates with increased chemotaxis of CD45 + leukocytes and mesenchymal stromal cells in human ovarian cancer and CD68 + myeloid cells in cigarette smoke-induced mouse models of lung cancer ( 6, 10, 11).

Recently, elevated level of LL-37/CRAMP has been documented in epithelial carcinomas of ovary, breast, and lung ( 6– 10). Originally, LL-37/CRAMP is known as an important effector molecule of innate immunity that provides a first-line host defense system by chemoattracting and activating the innate immune cells including neutrophils and macrophages to the inflammatory sites ( 3– 5). Previously, we have shown a positive correlation between the expression of antimicrobial peptide (AMP), human leucine leucine 37 (LL-37) and its mouse orthologue cathelicidin-related AMP (CRAMP), and the grade of tumor in both human and mouse PCa ( 2). Progression of prostate cancer (PCa) is associated with protumorigenic immune modulation ( 1). To identify mechanisms CRAMP function, macrophage colony stimulating factor (M-CSF) and monocyte chemoattractant protein 1 (MCP-1) gene expression was analyzed by QRT-PCR and STAT3 signaling was determined by immunoblotting. To differentiate protumorigenic events mediated by tumor-derived CRAMP from host immune cell-derived CRAMP, tumor challenge study was performed in CRAMP-deficient mice. The role of CRAMP in differentiation and polarization of immature myeloid progenitors (IMPs) to protumorigenic type 2 macrophages (M2) in TME was determined by adoptive transfer of IMPs into mice bearing CRAMP (+) and CRAMP (−) tumors. CRAMP-mediated chemotaxis of different innate immune cell types to the tumor microenvironment (TME). To investigate protumorigenic role(s) of cathelicidin-related antimicrobial peptide (CRAMP), a murine orthologue of LL-37, the present study compared tumor growth kinetics between mouse PCa cell lines with and without CRAMP expression (TRAMP-C1 and TRAMP-C1 CRAMP-sh, respectively) in immunocompetent mice.

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