CD90(+) stromal cells are the major source of IL-6, which supports cancer stem-like cells and inflammation in colorectal cancer.
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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DOI：
10.1002/ijc.29939
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发表时间：
2016-04-15
影响因子：
6.4
通讯作者：
Pinchuk IV
中科院分区：
文献类型：
--
作者：
Huynh PT;Beswick EJ;Coronado YA;Johnson P;O'Connell MR;Watts T;Singh P;Qiu S;Morris K;Powell DW;Pinchuk IV
IL-6是一种在CRC中增加的多效性细胞因子，已知可直接促进肿瘤生长。结肠肌成纤维细胞/成纤维细胞（CMF或基质细胞）是CD 90+先天免疫细胞，占正常结肠粘膜固有层细胞的30%。它们在CRC肿瘤基质中扩增，在那里它们也被称为癌症相关成纤维细胞（CAF）。已知间充质来源的细胞，如正常肌成纤维细胞/成纤维细胞分泌IL-6;然而，它们对CRC中IL-6增加和对肿瘤促进性炎症的贡献尚不明确。使用原位、离体和共培养分析，我们已经证明CRC（C-CMF）中产生IL-6的CMF的数量增加，并且它们代表T2-T3 CRC肿瘤中IL-6的主要来源。结肠癌细胞（SW 480、Caco-2或HT 29）在存在来自肿瘤分离的C-CMFs的条件培养基的情况下以IL-6依赖的方式培养时，干细胞标记物-醛脱氢酶（ALDH）和LGR 5-的表达显著上调。C-CMF及其衍生的条件培养基，但不是从同源正常结肠分离的正常CMF，诱导肿瘤的分化，以IL-6依赖的方式促进炎性Th 17细胞应答。我们的研究表明，CD 90+成纤维细胞/肌成纤维细胞可能是T2-T3 CRC肿瘤中IL-6的主要来源，其支持肿瘤细胞的干细胞性并诱导免疫适应性炎症反应（a.k.a. Th 17）有利于肿瘤生长。总之，我们的数据支持产生IL-6的CAF（a.k.a. C-CMF）可以提供用于治疗或预防CRC的有用靶标。
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 co-culture 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. Expression of stem cell markers-aldehyde dehydrogenase (ALDH) 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 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.