Loss of TGFβ signaling promotes colon cancer progression and tumor-associated inflammation.
Loss of TGFβ signaling promotes colon cancer progression and tumor-associated inflammation.
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DOI：
10.18632/oncotarget.9830
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发表时间：
2017-01-17
期刊：
影响因子：
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通讯作者：
Jung B
中科院分区：
文献类型：
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作者：
Principe DR;DeCant B;Staudacher J;Vitello D;Mangan RJ;Wayne EA;Mascariñas E;Diaz AM;Bauer J;McKinney RD;Khazaie K;Pasche B;Dawson DW;Munshi HG;Grippo PJ;Jung B
TGFβ对结肠癌具有抑癌和促癌作用。此外，TGFβ 可以影响肿瘤中炎症细胞的范围和组成，从而促进和抑制炎症。虽然结肠肿瘤表现出瘤内炎症，但 TGFβ 对此过程的贡献却知之甚少。在人类患者中，我们发现上皮细胞 TGFβ 信号传导的丧失与炎症负担的增加有关。然而，TGFβ 的过度表达也与炎症增加有关。这些发现在小鼠肿瘤发生的突变 APC 模型中得到了重现，其中 TGFBR2 的上皮截短导致由 IL8 和 TGFβ1 介导的致命炎症性疾病和侵袭性结肠癌。有趣的是，整体抑制 TGFβ 信号的突变 APC 小鼠表现出中间表型，表现为 IL8 介导的炎症总体增加并加速肿瘤形成，但在上皮 TGFBR 缺陷的小鼠中观察到疾病发作的潜伏期较长。这些结果表明，TGFβ信号传导的丧失，特别是在结肠上皮细胞中，会引发强烈的炎症反应并促进肿瘤进展。这意味着用 TGFβ 抑制剂治疗结肠癌患者可能会增强炎症反应，从而导致更糟糕的结果。
TGFβ has both tumor suppressive and tumor promoting effects in colon cancer. Also, TGFβ can affect the extent and composition of inflammatory cells present in tumors, contextually promoting and inhibiting inflammation. While colon tumors display intratumoral inflammation, the contributions of TGFβ to this process are poorly understood. In human patients, we found that epithelial loss of TGFβ signaling was associated with increased inflammatory burden; yet overexpression of TGFβ was also associated with increased inflammation. These findings were recapitulated in mutant APC models of murine tumorigenesis, where epithelial truncation of TGFBR2 led to lethal inflammatory disease and invasive colon cancer, mediated by IL8 and TGFβ1. Interestingly, mutant APC mice with global suppression of TGFβ signals displayed an intermediate phenotype, presenting with an overall increase in IL8-mediated inflammation and accelerated tumor formation, yet with a longer latency to the onset of disease observed in mice with epithelial TGFBR-deficiency. These results suggest that the loss of TGFβ signaling, particularly in colon epithelial cells, elicits a strong inflammatory response and promotes tumor progression. This implies that treating colon cancer patients with TGFβ inhibitors may result in a worse outcome by enhancing inflammatory responses.