Abstract 2072: Chitinase-3-like-1 protein expression associated with pulmonary inflammation accelerates metastasis to the lung

Abstract

Abstract Disseminated metastasis accounts for majority of breast cancer deaths. Recently, elevated serum levels of a glycoprotein known as chitinase-3-like-1 protein (CHI3L1) has been correlated with poor prognosis and shorter survival of patients with metastatic breast cancer. We found that there are elevated levels of CHI3L1 in plasma of mammary tumor-bearing mice. However, the biological and physiological functions of CHI3L1 are still unclear. We previously found that CHI3L1 has an inhibitory role on the expression of interferon-gamma, and in up-regulation of pro-inflammatory mediators such MCP-1, IL-8 and MMP-9 all of which contribute towards tumor growth and metastasis. In determining the cause of high levels of CHI3L1 in plasma, we found that in addition to tumor cells, splenic macrophages and more interestingly pulmonary macrophages from mammary tumor bearers secrete high levels of CHI3L1. Additionally, allergic mice also expressed higher levels of CHI3L1 in circulation and lung tissue. More specifically, CD11b+Ly6C+ cells from the lungs of allergic mice produced higher amounts of CHI3L1 compared to control mice. We have previously established that pulmonary myeloid cells through their production of CHI3L1 set up the proper microenvironment for growth of incoming mammary tumor cells. Thus, we hyphothesize that CHI3L1 levels in the lungs of mice with allergic pulmonary inflammation could accelerate metatstasis. To understand the role of CHI3L1 in accelerating pulmonary metastasis, pulmonary inflammation was induced by sensitization with ragweed allergen. Allergic mice implanted with either 4T1 or 67NR mammary tumors had a 5-fold increase in tumor volume, and formation of metastatic foci in their lungs compared to control mammary tumor bearers. Further, allergic mice showed accelerated tumor growth and shorter survival. In contrast, CHI3L1 null mice showed decreased tumor volume and metastasis, and increased survival compared to control mice. In vivo administration of chitin (β-(1-4)-poly-N-acetyl D-glucosamine) microparticles, the ligand for CHI3L1, to control and allergic mammary tumor bearers resulted in a significant reduction in pulmonary metastasis and tumor growth. These studies suggest that CHI3L1 plays a role in tumor progression and that chitin microparticles can inhibit the pleiotropic effects of CHI3L1 giving support to the idea that CHI3L1 is a useful target for treatment of breast cancer. Citation Format: Stephania Libreros, Ramon Garcia-Areas, Vijaya Iragavarapu-Charyulu. Chitinase-3-like-1 protein expression associated with pulmonary inflammation accelerates metastasis to the lung. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2072. doi:10.1158/1538-7445.AM2014-2072