CD90+ stromal cells are the major source of IL‐6, which supports cancer stem‐like cells and inflammation in colorectal cancer |
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| Authors: | Phuong T Huynh Ellen J Beswick Yun A Coronado Paul Johnson Malaney R O'Connell Tammara Watts Pomila Singh Suimin Qiu Katherine Morris Don W Powell Irina V Pinchuk |
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| Institution: | 1. Departments of Internal Medicine, Institute of Translational Science at University of Texas Medical Branch, Galveston, TX;2. Department of Molecular Genetics, University of New Mexico, Albuquerque, NM;3. Departments of Surgery, Institute of Translational Science at University of Texas Medical Branch, Galveston, TX;4. Departments of Neuoroscience and Cell Biology, Institute of Translational Science at University of Texas Medical Branch, Galveston, TX;5. Departments of Otolaryngology, Institute of Translational Science at University of Texas Medical Branch, Galveston, TX;6. Departments of Pathology, Institute of Translational Science at University of Texas Medical Branch, Galveston, TX;7. Department of Surgery, University of New Mexico, Albuquerque, NM;8. Institute of Translational Science at University of Texas Medical Branch, Galveston, TX;9. Departments of Microbiology and Immunology, Institute of Translational Science at University of Texas Medical Branch, Galveston, TX |
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| Abstract: | IL‐6 is a pleiotropic cytokine increased in CRC and known to directly promote tumor growth. Colonic myofibroblasts/fibroblasts (CMFs or stromal cells) are CD90+ innate immune cells representing up to 30% of normal colonic mucosal lamina propria cells. They are expanded in CRC tumor stroma, where they also known as a cancer associated fibroblasts (CAFs). Cells of mesenchymal origin, such as normal myofibroblasts/fibroblasts, are known to secrete IL‐6; however, their contribution to the increase in IL‐6 in CRC and to tumor‐promoting inflammation is not well defined. Using in situ, ex vivo and coculture analyses we have demonstrated that the number of IL‐6 producing CMFs is increased in CRC (C‐CMFs) and they represent the major source of IL‐6 in T2‐T3 CRC tumors. Activity/expression of stem cell markers‐aldehyde dehydrogenase and LGR5‐ was significantly up‐regulated in colon cancer cells (SW480, Caco‐2 or HT29) cultured in the presence of conditioned medium from tumor isolated C‐CMFs in an IL‐6 dependent manner. C‐CMF and its derived condition medium, but not normal CMF isolated from syngeneic normal colons, induced differentiation of tumor promoting inflammatory T helper 17 cells (Th17) cell responses in an IL‐6 dependent manner. Our study suggests that CD90+ fibroblasts/myofibroblasts may be the major source of IL‐6 in T2‐T3 CRC tumors, which supports the stemness of tumor cells and induces an immune adaptive inflammatory response (a.k.a. Th17) favoring tumor growth. Taken together our data supports the notion that IL‐6 producing CAFs (a.k.a. C‐CMFs) may provide a useful target for treating or preventing CRCs. |
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| Keywords: | CD90+ fibroblasts colorectal cancer inflammation IL‐6 tumor stem cells |
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