Down-Regulation of Connective Tissue Growth Factor by Inhibition of Transforming Growth Factor β Blocks the Tumor-Stroma Cross-Talk and Tumor Progression in Hepatocellular Carcinoma
Down-Regulation of Connective Tissue Growth Factor by Inhibition of Transforming Growth Factor β Blocks the Tumor-Stroma Cross-Talk and Tumor Progression in Hepatocellular Carcinoma
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DOI：
10.1002/hep.23285
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发表时间：
2010-02-01
期刊：
影响因子：
13.5
通讯作者：
Giannelli, Gianluigi
中科院分区：
文献类型：
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作者：
Mazzocca, Antonio;Fransvea, Emilia;Giannelli, Gianluigi
肝细胞癌（HCC）中肿瘤-间质相互作用对肿瘤进展至关重要。在本研究中，我们发现HCC侵袭细胞产生高水平的结缔组织生长因子（CTGF），并产生具有高基质的肿瘤。异种移植模型中的组成部分。一种转化生长因子β (tgf - β)受体抑制剂LY2109761抑制CTGF的合成和释放，并降低肿瘤基质成分。此外，tgf - β依赖的CTGF下调通过抑制癌症相关成纤维细胞增殖，减少肿瘤生长、内腔和HCC细胞转移传播。相比之下，非侵袭性HCC细胞产生低水平的CTGF。在tgf - β 1刺激下，非侵袭性HCC细胞形成具有高基质含量和高CTGF表达的肿瘤，LY2109761可抑制其表达。此外，LY2109761阻断了tgf - β 1刺激后非侵袭性HCC细胞的获得性内渗和转移扩散。LY2109761阻断癌细胞和癌症相关成纤维细胞之间的串扰，导致HCC生长和传播显著减少。有趣的是，CTGF高表达的患者预后较差，这表明旨在降低tgf - β依赖性CTGF表达的治疗可能具有临床益处。结论：综上所述，我们的临床前。结果表明LY2109761靶向HCC与间质间的串扰，为未来的临床试验提供了理论依据。(肝脏病学51:523 2010;534)。
Tumor-stroma interactions in hepatocellular carcinoma (HCC) are of key importance to tumor progression. In this study, we show that HCC invasive cells produce high levels of connective tissue growth factor (CTGF) and generate tumors with a high stromal. component in a xenograft model. A transforming growth factor beta (TGF-beta) receptor inhibitor, LY2109761, inhibited the synthesis and release of CTGF, as well as reducing the stromal component of the tumors. In addition, the TGF-beta-dependent down-regulation of CTGF diminished tumor growth, intravasation, and metastatic dissemination of HCC cells by inhibiting cancer-associated fibroblast proliferation. By contrast, noninvasive HCC cells were found to produce low levels of CTGF. Upon TGF-beta 1 stimulation, noninvasive HCC cells form tumors with a high stromal content and CTGF expression, which is inhibited by treatment with LY2109761. In addition, the acquired intravasation and metastatic spread of noninvasive HCC cells after TGF-beta 1 stimulation was blocked by LY2109761. LY2109761 interrupts the cross-talk between cancer cells and cancer-associated fibroblasts, leading to a significant reduction of HCC growth and dissemination. Interestingly, patients with high CTGF expression had poor prognosis, suggesting that treatment aimed at reducing TGF-beta-dependent CTGF expression may offer clinical benefits. Conclusion: Taken together, our preclinical. results indicate that LY2109761 targets the cross-talk between HCC and the stroma and provide a rationale for future clinical trials. (HEPATOLOGY 2010;51:523-534.)