Abstract 304: Proinflammatory secretory chemokine CXCL8 regulates intercellular cross-talk in the breast cancer tumor microenvironment

Abstract

Abstract The cellular composition of the tumor microenvironment (TME) and soluble effector molecules mediating intercellular cross-talk are important therapeutic and preventive targets for breast cancer. Chemokines released within the TME work in a synergistic and reciprocal manner to induce malignant progression of tumor cells. CXCL8, a proinflammatory CXC chemokine shown to be released within the TME, can act as a chemoattractant, angiogenic factor, and inflammatory factor via cellular receptors CXCR1 and CXCR2. However, the specific role of CXCL8 in the signaling cascades within the tumor microenvironment has yet to be fully classified and warrants further investigation. Treatment of human breast cancer cell lines MCF-7, MDA-MB-231, and T47D with 50nM exogenous CXCL8 enhanced the expression of CXCR2. The acquisition of chemokine receptors by tumor cells, in this case CXCR2, can mediate phenotypic changes that enhance migratory and invasive potential. Treatment of these human breast cancer cell lines with 50nM exogenous CXCL8 resulted in phenotypic morphology changes characteristic of an epithelial-to-mesenchymal transition (EMT), a phenomenon commonly exhibited by metastatic tumor cells. We validated this phenomenon with 50nM exogenous CXCL8 treatment, which led to enhanced expression of both Slug (Snail2) and Twist in all three human breast cancer cell lines. Furthermore, we observed that treatment with 50nM exogenous CXCL8 promoted the migration and invasion of these breast cancer cell lines in an in vitro modified Boyden chamber assay. These results suggest that CXCL2 secreted from cells within the TME act to induce characteristic changes in human breast cancer cells, propagating the transition to more aggressive tumors. Tumor-associated macrophages (TAMs) are an important component of the heterogeneous population of cells that make up the TME. Breast cancer cells exposed to conditioned media from human monocytic cell lines THP-1 and U937, previously differentiated with 12-O-tetradecanoylphorbol-13-acetate (TPA), exhibited distinct morphology changes characteristic of EMT and enhanced migratory and invasive ability, similar to exogenous CXCL8 treatment. Together, our results suggest that CXCL8 can have profound implications in determining the fate of tumor cells by engaging in extensive cross-talk within the TME, thus providing a potential target for the treatment and prevention of breast cancer tumor progression and metastasis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 304. doi:1538-7445.AM2012-304