Abstract 4232: Tumor-associated macrophages are responsible for EGF-R triggered upregulation of the Sox-2 signaling pathway in CSCs, which enhance tumorigenicity and tumor metastasis

The cancer stem cell (CSC) hypothesis has gained significant recognition as the descriptor of tumorigenesis. The Sox-2 signaling pathway has an important role in the maintenance of CSCs. Tumor-associated macrophages (TAMs) play an ambiguous role in this process. Here, we demonstrate that the expression of Sox-2 was up-regulated in CSC of 4T07 breast cancer cells, effects induced and enhanced by co-culture of tumor cells with TAMs. In fact, after co-culture, 4T07 tumor cells develop an increased number of CSCs with up-regulated expression of stem cell specific markers (Scal-1 and ABCG2), as well as partner genes of Sox-2, i. e. Oct-4 and Nanog. Down regulation of Sox-2 effectively blocks the ability of TAMs to maintain the phenotype of CSC among 4T07 cancer cells, and enhances tumor development and its pulmonary metastasis in a syngeneic Balb/c mouse model. Most importantly, in a mechanism study, we found that the Sox-2 up-regulation was induced by EGF-R activation in CSC that was triggered by EGF, Macrophage Conditioned Medium (MCM) or by co-culture with TAMs. These effects can all be blocked by inhibitors of EGF-R. Our results suggest that TAMs in the tumor microenvironment(TME) provide a niche which is critical in the development and maintenance of CSCs in breast carcinoma. This critical effect of TAMs on CSC development was achieved by up-regulation of the Sox-2 signaling pathway in CSC. This, in turn, was induced by marked activation of EGF-R achieved through interactions between CSCs and TAMs. In summary, over expression of Sox-2 in CSC of 4T07 breast cancer cells was enhanced by activation of EGF-R, which was induced by TAMs in TME. This series of events is responsible for maintaining the phenotype of CSCs which enhances tumor development and pulmonary metastasis in vivo.

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 4232.