Differential regulation of gastric tumor growth by cytokines that signal exclusively through the coreceptor gp130
Differential regulation of gastric tumor growth by cytokines that signal exclusively through the coreceptor gp130
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DOI：
10.1053/j.gastro.2005.06.068
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发表时间：
2005-09-01
期刊：
影响因子：
29.4
通讯作者：
Giraud, AS
中科院分区：
文献类型：
--
作者：
Howlett, M;Judd, LM;Giraud, AS
背景与目的：我们已经证明，白介素6家族细胞因子的信号转导受体gp130(gp130(757F/F))突变的小鼠会发生慢性胃炎，并发生与去调节的磷酸化STAT3表达相关的远端胃肿瘤。这个模型概括了人类肠型胃癌的许多特征。方法：通过比较gp130(757F/F)小鼠和缺乏IL-6或成熟T、B细胞的gp130757F/F小鼠的肿瘤特性，评价IL-6和IL-11作为配体对肿瘤生长和粘膜下侵袭的调节作用。结果：由于gp130757F/F突变，随着STAT3的激活和肿瘤的发生，IL-6和IL-11的表达显著上调。然而，IL-6或T、B细胞的缺乏并不影响肿瘤的生长。虽然IL-6不调节肿瘤生长或肿瘤血管形成，但gp130(757F/F/)IL-6(-/-)小鼠与gp130757F/F小鼠相比，肿瘤黏膜下侵袭增加10-20倍，单个核炎性细胞浸润减少，IL-11、基质金属蛋白酶(MMP13)-13和MMP9合成增加。基质金属蛋白酶-13的表达主要局限于肿瘤相关的间质，但基质金属蛋白酶-9也表达于多形核细胞和部分上皮细胞。此外，重组IL-11可刺激野生型小鼠胃中基质金属蛋白酶-13和基质金属蛋白酶-9的表达。结论：gp130(757F/F/)IL-6(-/-)小鼠粘膜下侵袭力的增加不能用血管形成的增加或免疫监视的减少来解释，但很可能是由于IL-11水平升高导致的金属蛋白酶活性的增强。
Background & Aims; We have shown that mice with a mutation in gp130 (gp130(757F/F)), the signal transducing receptor for interleukin (IL)-6 family cytokines, have chronic gastric inflammation and develop distal stomach tumors associated with deregulated phosphorylated STAT3 expression. This model recapitulates many characteristics of intestinal-type gastric cancer in humans. Methods: To evaluate the role of IL-6 and IL-11 as ligands regulating tumor growth and submucosal invasion, we compared tumor characteristics of gp130(757F/F) mice with gp130757F/F mice lacking IL-6 or mature T and B cells. Results: As a result of the gp130757F/F mutation, expression of IL-6 and IL-11 was greatly up-regulated concomitant with activation of STAT3 and development of tumors. However, the lack of IL-6 or T and B cells did not impact on tumor growth. While IL-6 did not regulate tumor growth or tumor vascularization, gp130(757F/F/)IL-6(-/-) mice showed similar to 10-20-fold more submucosal tumor invasion, reduced mononuclear inflammatory cell infiltrate, and greater IL-11 and matrix metalloproteinase (MMP)-13 and MMP-9 synthesis than gp130757F/F mice. Expression of MMP-13 was largely restricted to tumor-associated stroma, but MMP-9 was also expressed in polymorphonuclear cells and a subset of epithelial cells. In addition, treatment with recombinant IL-11 stimulated expression of MMP-13 and MMP-9 in stomachs of wild-type mice. Conclusions: Increased submucosal invasion in gp130(757F/F/)IL-6(-/-) mice could not be explained by increased vascularization or reduced immunosurveillance but was most likely facilitated by augmented metalloproteinase activity driven by elevated IL-11 levels.