Abstract B03: Hypoxia-induced carbonic anhydrase IX promotes MDSC recruitment and establishment of the breast cancer premetastatic niche by stimulating G-CSF production

Abstract

Abstract The recruitment of bone marrow-derived cells (BMDCs) to distant tissue sites prior to the arrival of disseminated tumor cells has been shown to facilitate metastasis in a preclinical setting through the establishment of the pre-metastatic niche. Primary tumor hypoxia has been shown to play a pivotal role in the production of chemokines and cytokines responsible for the mobilization of these BMDCs, especially in breast cancer. Carbonic anhydrase IX (CAIX) expression is highly upregulated by breast cancer cells in hypoxia where its activity contributes to cell survival through the buffering of intracellular pH. Preclinically, CAIX has been demonstrated to be required for breast tumor growth and metastasis, whereas clinically, CAIX is an established indicator of poor prognosis and distant metastasis in breast cancer patients. However, the mechanism by which CAIX exerts its pro-metastatic function is incompletely understood. We investigated whether CAIX function in the hypoxic niche of the primary tumor was involved in establishment of the pre-metastatic niche through the production of soluble mediators of this process. Using shRNA-mediated depletion of CAIX in the metastatic 4T1 murine breast cancer cells and orthotopic tumors, we demonstrate that CAIX is required for the mobilization and recruitment of myeloid-derived suppressor cells (MDSCs) to pre-metastatic niches through the stimulation of granulocyte colony stimulating factor (G-CSF) production, a potent stimulator of MDSC mobilization and recruitment to pre-metastatic niches. We further demonstrate that CAIX expression is required for the activation of NF-κB by hypoxic breast cancer cells and that constitutive activation of the NF-κB pathway upon reducing CAIX expression by shRNA restores G-CSF secretion by hypoxic breast cancer cells. This is the first demonstration of a role for CAIX in the pre-metastatic phase of breast cancer metastasis and indicates that CAIX regulates the expression of G-CSF and recruitment of granulocytic MDSCs to pre-metastatic niches. Citation Format: Shawn C. Chafe, Yuanmei Lou, Jaclyn Sceneay, Marylou Vallejo, Paul C. McDonald, Andreas Möller, Shoukat Dedhar. Hypoxia-induced carbonic anhydrase IX promotes MDSC recruitment and establishment of the breast cancer premetastatic niche by stimulating G-CSF production. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr B03. doi:10.1158/1538-7445.CHTME14-B03