演題

The Role of Endothelial Cells in Mediating Colorectal Cancer Cell Survival and Stem-ness

[演者] Lee M. Ellis:1
1:Department of Surgical Oncology, Division of Surgery, The University of Texas MD Anderson Cancer Center

The tumor microenvironment plays a major role in mediating cancer cell survival and resistance to therapy. A great deal of attention has been directed at the role of the tumor stroma in mediating resistance to therapies, but stromal therapy so far has not led to major therapeutic advances. The tumor vasculature has been a target for therapy as it is thought to be the conduit for the supply of tumor nutrients and oxygen. Interestingly, recent studies suggest that the endothelial cells are more than a conduit and can promote tumor growth and resistance to therapy in a paracrine manner. Rafii and associates were the first to demonstrate the “angiocrine” function of the vasculature in tissue regeneration and hematologic tumors. We hypothesized that endothelial cells could mediate the phenotype of adjacent colorectal cancer (CRC) cells. Our studies showed that endothelial cells secrete factors that lead to an increase in CRC cell stem-ness. The stem cell-like properties of CRC cells exposed to conditioned medium of endothelial cells were associated with chemoresistance and activation of the Notch signaling pathway. Proteomic studies of EC conditioned medium identified a soluble form of Jagged-1 that was cleaved by ADAM-17 to activate Notch signaling. These studies confirmed that ECs are potent regulators of CRC cell function.
Since CRC can metastasize to multiple sites, we sought to determine if ECs from different organs activated different pathways in CRC cells. We harvested normal endothelial cells from colon, lung, liver, and kidney (the latter since these were readily available). ECs collected from all organs could induce the CRC stem cell phenotype. However, during this analysis, we found that other pathways could mediate EC induced colon cancer cell stem-ness. Recent studies from our laboratory showed that ECs secrete factors that stimulate the Nanog8 pathway, a cancer stem cell pathway, in CRC cells. In further studies, we showed that the Nanog8 pathway mediated Akt activation and sphere formation, a phenotypic marker of cancer stem cells. More recent studies demonstrated that EC conditioned medium can activate Her-3 and subsequent Akt signaling that is independent of neuregulin, the classic Her-3 mediator. We are currently trying to identify the factor(s) that mediate this survival signaling.


Lu, Ye, Fan, Xia, Bhattacharya, Bellister, Tozzi, Sceusi, Zhou, Tachibana, Maru, Hawke, Rak, Mani, Zweidler-McKay, Ellis. Endothelial cells promote the colorectal cancer stem cell phenotype through a soluble form of Jagged-1. Cancer Cell. 2013
Wang, Ye, Bhattacharya, Boulbes, Fan, Xia, Ellis. A Disintegrin and Metalloproteinase Domain 17 Regulates Colorectal Cancer Stem Cells and Chemosensitivity Via Notch1 Signaling. Stem Cells Transl Med. 2016
Wang, Bhattacharya, Ye, Fan, Boulbes, Xia, Ellis. Endothelial cells activate the cancer stem cell-associated NANOGP8 pathway in colorectal cancer cells in a paracrine fashion. Mol Oncol. 2017
詳細検索