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JCI:发现胃肠道癌潜在新的治疗方法

来源:生物谷 2013-01-17 21:56

2013年1月13日讯 /生物谷BIOON/ --近日,研究人员确定一蛋白质能促进某些类型的结肠癌和胃癌生长,并表明该蛋白质有可能是一种新的治疗潜在靶点。

先前mTORC1已被证实与其他一些癌症的发生发展相关,但是这是第一次证明mTORC1能促进结肠和胃癌的生长。结果在线发表在Journal of Clinical Investigation杂志上。

助理教授Ernst表示:许多类型的结肠癌和胃癌与慢性炎症相关。我们先前已经表明免疫系统的炎症反应可促进肿瘤的生长。

在消化系统中,持久性的炎症性疾病与肿瘤生长相关,有胃溃疡或胃炎的患者胃壁更易患胃癌,而炎症是患结肠癌风险增加的潜在因素。

该研究小组发现炎症相关的胃癌和结肠癌中mTORC1被激活,促进癌细胞生长。许多类型的癌症依赖于mTORC1来生长,mTORC1抑制剂来治疗癌症有相当大的开发价值。

mTORC1抑制剂可以治疗炎症相关的结肠癌和胃癌的生长。我们很高兴能在实验室模型中发现mTORC1抑制剂可以预防的这些癌症,mTORC1抑制剂已经在临床试验中研究对其他类型癌症的治疗功效。

研究人员说:在未来,我们希望这一发现可能会导致出现治疗结肠癌和胃癌更好的药物。同时,其他与炎症有关的癌症类型也可能受益于mTORC1抑制剂治疗。(生物谷:Bioon.com)

mTORC1 inhibition restricts inflammation-associated gastrointestinal tumorigenesis in mice

Stefan Thiem1, Thomas P. Pierce1, Michelle Palmieri1, Tracy L. Putoczki1, Michael Buchert1, Adele Preaudet1, Ryan O. Farid1, Chris Love1, Bruno Catimel1, Zhengdeng Lei2, Steve Rozen2, Veena Gopalakrishnan3, Fred Schaper4, Michael Hallek5, Alex Boussioutas6, Patrick Tan3, Andrew Jarnicki1 and Matthias Ernst1

Gastrointestinal cancers are frequently associated with chronic inflammation and excessive secretion of IL-6 family cytokines, which promote tumorigenesis through persistent activation of the GP130/JAK/STAT3 pathway. Although tumor progression can be prevented by genetic ablation of Stat3 in mice, this transcription factor remains a challenging therapeutic target with a paucity of clinically approved inhibitors. Here, we uncovered parallel and excessive activation of mTOR complex 1 (mTORC1) alongside STAT3 in human intestinal-type gastric cancers (IGCs). Furthermore, in a preclinical mouse model of IGC, GP130 ligand administration simultaneously activated mTORC1/S6 kinase and STAT3 signaling. We therefore investigated whether mTORC1 activation was required for inflammation-associated gastrointestinal tumorigenesis. Strikingly, the mTORC1-specific inhibitor RAD001 potently suppressed initiation and progression of both murine IGC and colitis-associated colon cancer. The therapeutic effect of RAD001 was associated with reduced tumor vascularization and cell proliferation but occurred independently of STAT3 activity. We analyzed the mechanism of GP130-mediated mTORC1 activation in cells and mice and revealed a requirement for JAK and PI3K activity but not for GP130 tyrosine phosphorylation or STAT3. Our results suggest that GP130-dependent activation of the druggable PI3K/mTORC1 pathway is required for inflammation-associated gastrointestinal tumorigenesis. These findings advocate clinical application of PI3K/mTORC1 inhibitors for the treatment of corresponding human malignancies.

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