STAT3 activation regulates growth, inflammation, and vascularization in a mouse model of gastric tumorigenesis
STAT3 activation regulates growth, inflammation, and vascularization in a mouse model of gastric tumorigenesis
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DOI：
10.1053/j.gastro.2006.07.018
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发表时间：
2006-10-01
期刊：
影响因子：
29.4
通讯作者：
Giraud, Andrew S.
中科院分区：
文献类型：
--
作者：
Judd, Louise M.;Bredin, Karin;Giraud, Andrew S.
背景与目的：gp130（757F/F）小鼠是一种特征明确且稳健的远端胃肿瘤发生模型，显示出人类肠型胃癌的许多特征。在该模型以及许多人类肿瘤发展的例子中，肿瘤发展的关键是转录因子 STAT3 的过度激活。这项研究解决了肿瘤发生过程中 STAT3 激活的要求，并表征了肿瘤发展所需的 STAT3 下游的一些基因。此外，还评估了 STAT3、微生物环境和肿瘤发生之间的相互作用。方法：在显示 STAT3 活性降低的 gp130(757F/Y757F):STAT3(+/-) 小鼠中详细评估 STAT3 在胃肿瘤发展中的作用。对肿瘤大小进行形态学量化，并对内分泌细胞群、新血管形成和炎症细胞浸润的影响以及 STAT3 激活对许多与生长和炎症相关的基因转录的结果进行量化。结果：gp130(757F/F) 小鼠中一个 STAT3 等位基因的缺失，由于抑制了增殖诱导的腺体增生，从而降低了肿瘤发生的频率和速率。炎症浸润程度、细胞因子和趋化因子表达、血管生成以及金属蛋白酶和生长因子表达也随之减少。 gp130(757F/F) 小鼠的抗菌治疗减缓了肿瘤生长，同时巨噬细胞和中性粒细胞浸润减少。结论：STAT3 的激活和微生物环境对于 gp130(757F/F) 小鼠胃肿瘤的发生和发展至关重要，因此支持了 STAT3 激活可能在人类胃癌发展中发挥作用的观点。
Background & Aims: The gp130(757F/F) mouse is a well-characterized and robust model of distal gastric tumorigenesis displaying many of the characteristics of human intestinal type gastric cancer. Key to the development of tumors in this model, and in many examples of human tumor development, is hyperactivation of the transcription factor STAT3. This study addressed the requirement for STAT3 activation in tumor initiation and characterized some of the genes downstream of STAT3 required for tumor development. Furthermore, the interaction among STAT3, the microbial environment, and tumorigenesis was evaluated. Methods: The role of STAT3 in gastric tumor development was assessed in detail in gp130(757F/Y757F):STAT3(+/-) mice displaying reduced STAT3 activity. Tumor size was quantified morphologically, and the effects on endocrine cell populations, neovascularization, and inflammatory cell infiltration as well as the outcome of STAT3 activation on transcription of a number of genes relevant in growth and inflammation were quantified. Results: Loss of one STAT3 allele in gp130(757F/F) mice reduced the frequency and rate of tumor development because of inhibition of proliferation-induced glandular hyperplasia. There was also a concomitant reduction in the degree of inflammatory infiltration and cytokine and chemokine expression, angiogenesis, and expression of meralloproteinases and growth factors. Antimicrobial treatment of gp130(757F/F) mice slowed tumor growth coincident with reduced macrophage and neutrophil infiltration. Conclusions: Activation of STAT3 and the microbial environment are pivotal for gastric tumor initiation and development in the gp130(757F/F) mouse, thus supporting the notion that STAT3 activation may play a role in human gastric cancer development.