title: CD90(+) stromal cells are the major source of IL-6, which supports cancer stem-like cells and inflammation in colorectal cancer.
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.
authors.affiliation: Departments of Internal Medicine, Institute of Translational Science at University of Texas Medical Branch, Galveston, TX.
authors.forename: Phuong T
authors.initials: PT
authors.lastname: Huynh
authors.affiliation: Department of Molecular Genetics, University of New Mexico, Albuquerque, NM.
authors.forename: Ellen J
authors.initials: EJ
authors.lastname: Beswick
authors.affiliation: Departments of Internal Medicine, Institute of Translational Science at University of Texas Medical Branch, Galveston, TX.
authors.forename: Yun A
authors.initials: YA
authors.lastname: Coronado
authors.affiliation: Departments of Surgery, Institute of Translational Science at University of Texas Medical Branch, Galveston, TX.
authors.forename: Paul
authors.initials: P
authors.lastname: Johnson
authors.affiliation: Departments of Neuoroscience and Cell Biology, Institute of Translational Science at University of Texas Medical Branch, Galveston, TX.
authors.forename: Malaney R
authors.initials: MR
authors.lastname: O'Connell
authors.affiliation: Departments of Otolaryngology, Institute of Translational Science at University of Texas Medical Branch, Galveston, TX.
authors.forename: Tammara
authors.initials: T
authors.lastname: Watts
authors.affiliation: Departments of Neuoroscience and Cell Biology, Institute of Translational Science at University of Texas Medical Branch, Galveston, TX.
authors.forename: Pomila
authors.initials: P
authors.lastname: Singh
authors.affiliation: Departments of Pathology, Institute of Translational Science at University of Texas Medical Branch, Galveston, TX.
authors.forename: Suimin
authors.initials: S
authors.lastname: Qiu
authors.affiliation: Department of Surgery, University of New Mexico, Albuquerque, NM.
authors.forename: Katherine
authors.initials: K
authors.lastname: Morris
authors.affiliation: Departments of Internal Medicine, Institute of Translational Science at University of Texas Medical Branch, Galveston, TX.|Departments of Neuoroscience and Cell Biology, Institute of Translational Science at University of Texas Medical Branch, Galveston, TX.|Institute of Translational Science at University of Texas Medical Branch, Galveston, TX.
authors.forename: Don W
authors.initials: DW
authors.lastname: Powell
authors.affiliation: Departments of Internal Medicine, Institute of Translational Science at University of Texas Medical Branch, Galveston, TX.|Institute of Translational Science at University of Texas Medical Branch, Galveston, TX.|Departments of Microbiology and Immunology, Institute of Translational Science at University of Texas Medical Branch, Galveston, TX.
authors.forename: Irina V
authors.initials: IV
authors.lastname: Pinchuk
mesh_terms: D015153:Blotting, Western; D018920:Coculture Techniques; D015179:Colorectal Neoplasms / Q000276:immunology / Q000473:pathology*; D005347:Fibroblasts / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D007249:Inflammation / Q000473:pathology; D015850:Interleukin-6 / Q000096:biosynthesis*; D018613:Microscopy, Confocal; D014411:Neoplastic Stem Cells / Q000473:pathology*; D060888:Real-Time Polymerase Chain Reaction; D017154:Stromal Cells / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology; D018800:Thy-1 Antigens / Q000276:immunology / Q000378:metabolism; D059016:Tumor Microenvironment / Q000276:immunology
chemical_list: D015850:Interleukin-6; D018800:Thy-1 Antigens
keywords: CD90+ fibroblasts; IL-6; colorectal cancer; inflammation; tumor stem cells