Release of TGFβig-h3 by gastric myofibroblasts slows tumor growth and is decreased with cancer progression
Release of TGFβig-h3 by gastric myofibroblasts slows tumor growth and is decreased with cancer progression
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DOI：
10.1093/carcin/bgs180
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发表时间：
2012-08-01
期刊：
影响因子：
4.7
通讯作者：
Varro, Andrea
中科院分区：
文献类型：
--
作者：
Holmberg, Chris;Quante, Michael;Varro, Andrea
肿瘤的进展与间质环境的变化有关。肌成纤维细胞是一种间质细胞，通常在肿瘤中增加，但它们在癌症进展中的作用尚不清楚。在这里，我们发现来自胃癌的肌成纤维细胞的分泌体[癌症相关肌纤维母细胞(CAMS)]与来自邻近组织的那些分泌体[邻近组织肌纤维母细胞(ATM)]在功能上有显著的不同。与ATM或正常组织肌成纤维细胞(NTM)相比，CAMs的迁移和增殖率增加。此外，与ATMS和NTMS的CM相比，CAMS的条件培养液(CM)显著刺激胃癌细胞的迁移、侵袭和增殖。肌成纤维细胞分泌体的蛋白质组学分析显示，细胞外基质(ECM)适配蛋白如转化生长因子诱导基因h3(TGFig-h3)在CAM中的丰度降低，这与淋巴转移和生存期缩短有关。TGFig-h3抑制IGF-II刺激的癌细胞和肌成纤维细胞的迁移和增殖，并抑制P42/44 MAPK的IGF-II激活；TGFig-h3基因敲除增加IGF-II和CM刺激的迁移。此外，给予TGFig-h3抑制了肌成纤维细胞刺激的胃癌异种移植瘤的生长。我们得出结论：间质细胞对肿瘤细胞既有抑制作用，也有刺激作用；TGFig-h3是一种基质抑制因子，随着胃癌的进展而减少。
Tumor progression has been linked to changes in the stromal environment. Myofibroblasts are stromal cells that are often increased in tumors but their contribution to cancer progression is not well understood. Here, we show that the secretomes of myofibroblasts derived from gastric cancers [cancer-associated myofibroblasts (CAMs)] differ in a functionally significant manner from those derived from adjacent tissue [adjacent tissue myofibroblasts (ATMs)]. CAMs showed increased rates of migration and proliferation compared with ATMs or normal tissue myofibroblasts (NTMs). Moreover, conditioned medium (CM) from CAMs significantly stimulated migration, invasion and proliferation of gastric cancer cells compared with CM from ATMs or NTMs. Proteomic analysis of myofibroblast secretomes revealed decreased abundance of the extracellular matrix (ECM) adaptor protein like transforming growth factor--induced gene-h3 (TGFig-h3) in CAMs, which was correlated with lymph node involvement and shorter survival. TGFig-h3 inhibited IGF-II-stimulated migration and proliferation of both cancer cells and myofibroblasts, and suppressed IGF-II activation of p42/44 MAPkinase; TGFig-h3 knockdown increased IGF-II- and CM-stimulated migration. Furthermore, administration of TGFig-h3 inhibited myofibroblast-stimulated growth of gastric cancer xenografts. We conclude that stromal cells exert inhibitory as well as stimulatory effects on tumor cells; TGFig-h3 is a stromal inhibitory factor that is decreased with progression of gastric cancers.