Inhibiting Cxcr2 disrupts tumor-stromal interactions and improves survival in a mouse model of pancreatic ductal adenocarcinoma
Inhibiting Cxcr2 disrupts tumor-stromal interactions and improves survival in a mouse model of pancreatic ductal adenocarcinoma
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DOI：
10.1172/jci42754
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发表时间：
2011-10-01
影响因子：
15.9
通讯作者：
Moses, Harold L.
中科院分区：
文献类型：
--
作者：
Ijichi, Hideaki;Chytil, Anna;Moses, Harold L.
胰腺导管腺癌(PDAC)是最致命的肿瘤之一，其特征是间质扩张并伴有明显的纤维化(促纤维增生)。我们以前在Kras激活的背景下建立了胰腺上皮特异性转化生长因子-β受体II(TGFBR2)基因敲除小鼠(这里称为ICRAS(+)TGFBR2(KO)小鼠)，并发现它们发展出具有侵袭性的PDAC，概括了人类疾病的组织学表现。结缔组织生长因子(CTGF)是一种促纤维化和促肿瘤因子，小鼠PDAC组织中结缔组织生长因子(CTGF)在肿瘤-间质交界区有较强的表达，提示肿瘤-间质相互作用活跃。在这里，我们显示Kras(+)TGFBR2(KO)小鼠的PDAC细胞比小鼠胰腺上皮内肿瘤细胞分泌更高水平的几种CXC趋化因子，后者是侵袭前的。CXC趋化因子诱导胰腺间质成纤维细胞表达CTGF，而不是诱导PDAC细胞表达CTGF。皮下移植研究表明，成纤维细胞促进了同种异体PDAC细胞移植物的生长，这种作用可被CXCR2抑制而减弱。此外，用CXCR2抑制剂治疗Kras(+)TGFBR2(KO)小鼠可以减少肿瘤进展。肿瘤进展的减少与CTGF表达和血管生成的减少以及总体生存期的增加有关。综上所述，我们的数据表明，通过依赖CXCR2的趋化因子和CTGF轴的肿瘤-间质相互作用可以调节PDAC的进展。此外，我们的结果表明，抑制肿瘤-间质相互作用可能是PDAC的一种有前途的治疗策略。
Pancreatic ductal adenocarcinoma (PDAC), one of the most lethal neoplasms, is characterized by an expanded stroma with marked fibrosis (desmoplasia). We previously generated pancreas epithelium-specific TGF-beta receptor type II (Tgfbr2) knockout mice in the context of Kras activation (mice referred to herein as ICras(+)Tgfbr2(KO) mice) and found that they developed aggressive PDAC that recapitulated the histological manifestations of the human disease. The mouse PDAC tissue showed strong expression of connective tissue growth factor (Ctgf), a profibrotic and tumor-promoting factor, especially in the tumor-stromal border area, suggesting an active tumor-stromal interaction. Here we show that the PDAC cells in Kras(+)Tgfbr2(KO) mice secreted much higher levels of several Cxc chemokines compared with mouse pancreatic intraepithelial neoplasia cells, which are preinvasive. The Cxc chemokines induced Ctgf expression in the pancreatic stromal fibroblasts, not in the PDAC cells themselves. Subcutaneous grafting studies revealed that the fibroblasts enhanced growth of PDAC cell allografts, which was attenuated by Cxcr2 inhibition. Moreover, treating the Kras(+)Tgfbr2(KO) mice with the CXCR2 inhibitor reduced tumor progression. The decreased tumor progression correlated with reduced Ctgf expression and angiogenesis and increased overall survival. Taken together, our data indicate that tumor-stromal interactions via a Cxcr2-dependent chemokine and Ctgf axis can regulate PDAC progression. Further, our results suggest that inhibiting tumor-stromal interactions might be a promising therapeutic strategy for PDAC.