Inflammation-mediated genetic and epigenetic alterations drive cancer development in the neighboring epithelium upon stromal abrogation of TGF-β signaling.
Inflammation-mediated genetic and epigenetic alterations drive cancer development in the neighboring epithelium upon stromal abrogation of TGF-β signaling.
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DOI：
10.1371/journal.pgen.1003251
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发表时间：
2013
期刊：
影响因子：
4.5
通讯作者：
Yang L
中科院分区：
文献类型：
--
作者：
Achyut BR;Bader DA;Robles AI;Wangsa D;Harris CC;Ried T;Yang L
间质成纤维细胞中肿瘤抑制基因的缺失诱导上皮癌的发展，表明间质在上皮细胞内稳态中的重要作用。然而，其潜在机制仍有待阐明。在这里，我们报告了在基质成纤维细胞（Tgfbr 2fspKO）中编码TGFβ受体2（Tgfbr 2）的基因的缺失诱导前胃邻近上皮细胞的炎症和显著的DNA损伤。这导致细胞周期蛋白依赖性激酶抑制剂p15、p16和p21的丢失或下调，这有助于浸润性鳞状细胞癌（SCC）的发展。抗炎治疗恢复了p21表达，延迟了肿瘤发生，并增加了Tgfbr 2fspKO小鼠的存活率。我们的数据首次表明，炎症是肿瘤进展中p21表观遗传沉默的关键因素。对人食管鳞状细胞癌的检查显示，基质成纤维细胞中TGFβ受体2（TβRII）下调，炎症增加，DNA损伤，p15/p16表达缺失或降低。我们的研究表明，抗炎可能是治疗基质中TβRII下调的人SCC的一种新的治疗选择。癌症不再仅仅被认为是癌细胞的问题。癌症的发展和转移显然涉及宿主的许多方面。我们试图确定由于基质细胞的改变导致上皮癌发展的分子机制。使用TGF-β信号在基质成纤维细胞中缺失的动物模型，我们发现炎症和DNA损伤在上皮区室中诱导，并且是细胞周期依赖性激酶抑制剂丢失的原因，导致上皮细胞周期控制的妥协。这些结果对于理解近年来肿瘤生物学中的一个重要焦点--间质-肿瘤串扰具有重要意义。我们的研究结果表明，仔细检查间质室是重要的，抗炎治疗可能是一种新的化学预防选择上皮癌的发展。
Deletion of tumor suppressor genes in stromal fibroblasts induces epithelial cancer development, suggesting an important role of stroma in epithelial homoeostasis. However, the underlying mechanisms remain to be elucidated. Here we report that deletion of the gene encoding TGFβ receptor 2 (Tgfbr2) in the stromal fibroblasts (Tgfbr2fspKO) induces inflammation and significant DNA damage in the neighboring epithelia of the forestomach. This results in loss or down-regulation of cyclin-dependent kinase inhibitors p15, p16, and p21, which contribute to the development of invasive squamous cell carcinoma (SCC). Anti-inflammation treatment restored p21 expression, delayed tumorigenesis, and increased survival of Tgfbr2fspKO mice. Our data demonstrate for the first time that inflammation is a critical player in the epigenetic silencing of p21 in tumor progression. Examination of human esophageal SCC showed a down-regulation of TGFβ receptor 2 (TβRII) in the stromal fibroblasts, as well as increased inflammation, DNA damage, and loss or decreased p15/p16 expression. Our study suggests anti-inflammation may be a new therapeutic option in treating human SCCs with down-regulation of TβRII in the stroma. Cancer is no longer regarded as a problem of solely cancer cells. The development and metastasis of cancers clearly involves many aspects of the host. We sought to identify the molecular mechanisms underlying epithelial cancer development due to alterations in stromal cells. Using an animal model in which TGF-β signaling is deleted in stromal fibroblasts, we found that inflammation and DNA damage are induced in the epithelial compartment and are responsible for the loss of cell cycle–dependent kinase inhibitors, leading to the compromise of epithelial cell cycle control. These results are important in understanding the stromal-tumor cross talk which has been an important focus in cancer biology in recent years. Our findings suggest that careful examination of the stromal compartment is important and that anti-inflammation therapy may be a new chemoprevention option for epithelial cancer development.
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影响因子：
11.2
作者：
Bierie, Brian;Stover, Daniel G.;Moses, Harold L.
通讯作者：
Moses, Harold L.
影响因子：
30.8
作者：
Bass, Adam J.;Watanabe, Hideo;Mermel, Craig H.;Yu, Soyoung;Perner, Sven;Verhaak, Roel G.;Kim, So Young;Wardwell, Leslie;Tamayo, Pablo;Gat-Viks, Irit;Ramos, Alex H.;Woo, Michele S.;Weir, Barbara A.;Getz, Gad;Beroukhim, Rameen;O'Kelly, Michael;Dutt, Amit;Rozenblatt-Rosen, Orit;Dziunycz, Piotr;Komisarof, Justin;Chirieac, Lucian R.;LaFargue, Christopher J.;Scheble, Veit;Wilbertz, Theresia;Ma, Changqing;Rao, Shilpa;Nakagawa, Hiroshi;Stairs, Douglas B.;Lin, Lin;Giordano, Thomas J.;Wagner, Patrick;Minna, John D.;Gazdar, Adi F.;Zhu, Chang Qi;Brose, Marcia S.;Cecconello, Ivan;Ribeiro, Ulysses, Jr.;Marie, Suely K.;Dahl, Olav;Shivdasani, Ramesh A.;Tsao, Ming-Sound;Rubin, Mark A.;Wong, Kwok K.;Regev, Aviv;Hahn, William C.;Beer, David G.;Rustgi, Anil K.;Meyerson, Matthew
通讯作者：
Meyerson, Matthew
影响因子：
11.2
作者：
Franco OE;Jiang M;Strand DW;Peacock J;Fernandez S;Jackson RS 2nd;Revelo MP;Bhowmick NA;Hayward SW
通讯作者：
Hayward SW
DOI：
10.1158/1541-7786.mcr-07-2203
发表时间：
2008-10
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
Cheng N;Chytil A;Shyr Y;Joly A;Moses HL
通讯作者：
Moses HL
影响因子：
56.9
作者：
Janssen, Aniek;van der Burg, Marja;Medema, Rene H.
通讯作者：
Medema, Rene H.