Abstract 1339: Inhibition of chitinase-3-like-1 protein to suppress angiogenesis and enhance immune response in a mammary tumor model

Abstract

Abstract The purpose of this study is to determine whether inhibition of Chitinase-3-like 1 protein reduces the expression of angiogenic chemokines in macrophages while enhancing IFN-γ production in T cells. It is known that tumors can induce the upregulation of angiogenic and extracellular matrix degrading molecules. Tumor growth is often accompanied by immunosuppression. Our previous studies using the DA-3 mammary adenocarcinoma mouse model has shown that with tumor progression there is a profound down-regulation of interferon-gamma (IFN-γ), a crucial molecule involved in anti-tumor response. Additionally, angiogenic chemokines such as Monocyte Chemoattractant Protein-1 (CCL2/MCP-1) and Matrix Metalloproteinase-9 (MMP-9) are upregulated with mammary tumor growth. CCL2/MCP-1 is a known inflammatory chemoattractant for T cells and macrophages, and we have evidence that this molecule downregulates IFN-γ by the T lymphocytes. Recent studies have linked tumor progression with upregulation of Chitinase-3-like-1 protein (CHI3L1) in human breast cancer patients and that macrophages express this molecule during inflammatory processes. Our studies using DA-3 mammary breast cancer model indicate that CHI3L1 is expressed by DA-3 tumor cells. Expression of CHI3L1 in macrophages has been linked with upregulation of angiogenic chemokine, CCL2/MCP-1. Our studies indicate that macrophages from mammary tumor-bearing mice express higher levels of CHI3L1 compared to normal control mice and also secrete CCL2/MCP-1. We hypothesize that inhibition of CHI3L1 will suppress the production of CCL2/MCP-1 and enhance IFN-γ production in mammary tumor-bearing mice. One of the known ligands for CHI3L1 is chitin microparticle. Our in vitro studies of cultured splenocytes from normal and 5-week mammary tumor-bearing mice with chitin micro-particles revealed down-regulation of CHI3L1 and upregulation of IFN-γ. Therefore, it is expected that in vivo blocking of CHI3L1 with chitin microparticles will have a favorable anti-tumor response by inhibiting the production of angiogenic chemokines, metalloproteinase, MMP-9 and enhancing the production of IFN-γ. The results from these studies may provide new avenues for cancer treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1339.