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首页> 外文期刊>Oncogene >Oncogenic mutations regulate tumor microenvironment through induction of growth factors and angiogenic mediators
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Oncogenic mutations regulate tumor microenvironment through induction of growth factors and angiogenic mediators

机译：致癌突变通过诱导生长因子和血管生成介质来调节肿瘤微环境。

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Activating mutations in the tyrosine kinase domain of HER2 (ErbB2) have been identified in human cancers. Compared with wild-type HER2, mutant HER2 shows constitutively activate kinase activity and increased oncogenicity. Cells transformed by mutant HER2 are resistant to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and exhibit an attenuated response to the HER2 antibody trastuzumab. We investigated herein pathways through which mutant HER2 alters the extracellular environment, potentially leading to drug resistance and the effect of simultaneously targeting HER2 and the tumor cell microenvironment with a therapeutic intent. Expression of mutant HER2 in mammary epithelial cells activated autocrine transforming growth factor (TGF) β1 signaling through a mechanism involving Rac1 and c-Jun N-terminal kinase-activating protein 1-dependent transcription. Cells transformed by an activating mutant of H-Ras (G12V) also expressed higher TGF-β1 level through Rac1 activation. In addition, mutant HER2 induced the EGFR ligands TGF-α and amphiregulin at the mRNA and protein levels. Vascular endothelial growth factor, a target of the TGF-β-Smad transcriptional regulation, was also induced as a result of expression of mutant HER2. Inhibition of TGF-β signaling with the Alk5 small molecule inhibitor LY2109761 reduced growth and invasiveness of cells expressing mutant HER2. Combined inhibition of intracellular and paracrine effects of mutant HER2 by trastuzumab and the EGFR antibody cetuximab were more efficient than single-agent therapies. These data suggest that mutations in oncogenes such as HER2 and Ras not only alter intracellular signaling but also influence on other components of the tumor microenvironment by inducing several pro-invasive growth factors. In turn, these serve as extracellular targets of novel therapeutic strategies directed at both cancer-driving oncogenes and the modified tumor microenvironment.
机译：HER2（ErbB2）的酪氨酸激酶域中的激活突变已在人类癌症中得到鉴定。与野生型HER2相比，突变体HER2显示出组成型激活激酶活性和增加的致癌性。由突变体HER2转化的细胞对表皮生长因子受体（EGFR）酪氨酸激酶抑制剂具有抗性，并且对HER2抗体曲妥珠单抗的反应减弱。我们在本文中研究了突变体HER2改变细胞外环境的途径，可能导致耐药性以及以治疗目的同时靶向HER2和肿瘤细胞微环境的作用。突变HER2在乳腺上皮细胞中的表达通过涉及Rac1和c-Jun N端激酶激活蛋白1依赖性转录的机制激活了自分泌转化生长因子（TGF）β1信号。由H-Ras活化突变体（G12V）转化的细胞也通过Rac1活化表达更高的TGF-β1水平。另外，突变体HER2在mRNA和蛋白质水平上诱导EGFR配体TGF-α和双调蛋白。突变的HER2的表达也诱导了血管内皮生长因子，它是TGF-β-Smad转录调控的靶标。用Alk5小分子抑制剂LY2109761抑制TGF-β信号传导会降低表达突变HER2的细胞的生长和侵袭性。曲妥珠单抗和EGFR抗体西妥昔单抗联合抑制突变体HER2对细胞内和旁分泌的作用比单药治疗更有效。这些数据表明，致癌基因如HER2和Ras中的突变不仅改变细胞内信号传导，而且还通过诱导几种前侵袭性生长因子而影响肿瘤微环境的其他组成部分。反过来，它们充当针对癌症驱动癌基因和修饰的肿瘤微环境的新型治疗策略的细胞外靶标。

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