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.
|Number of pages||11|
|Journal||International Journal of Cancer|
|State||Published - Apr 15 2016|
Bibliographical noteFunding Information:
NIDDK; Grant number: 1R01DK103150-01A1; Grant sponsor: NCATS; Grant numbers: KL2TR000072 and ILTR000072; Grant sponsor: NCATS; Grant number: TR000071; Grant sponsor: NCI; Grant number: 3R01-CA97959 and P30CA118100; Grant sponsor: NCAT; Grant number: 8UL1TR000041; Grant sponsor: ACS; Grant number: RSG-10-159- 01-LIB The authors thank Dr. David Konkel for critically editing the manuscript.
© 2015 UICC.
- CD90+ fibroblasts
- colorectal cancer
- tumor stem cells
ASJC Scopus subject areas
- Cancer Research