Insulin resistance in vascular endothelial cells promotes intestinal tumour formation.
Insulin resistance in vascular endothelial cells promotes intestinal tumour formation.
复制标题
DOI：
10.1038/onc.2017.107
复制
发表时间：
2017-08-31
期刊：
影响因子：
8
通讯作者：
Rask-Madsen C
中科院分区：
文献类型：
--
作者：
Wang X;Häring MF;Rathjen T;Lockhart SM;Sørensen D;Ussar S;Rasmussen LM;Bertagnolli MM;Kahn CR;Rask-Madsen C
The risk of several cancers, including colorectal cancer, is increased in patients with obesity and type 2 diabetes, conditions characterized by hyperinsulinemia and insulin resistance. Because hyperinsulinemia itself is an independent risk factor for cancer development, we examined tissue-specific insulin action in intestinal tumor formation. In vitro, insulin increased proliferation of primary cultures of intestinal tumor epithelial cells from ApcMin/+ mice by over 2-fold. Surprisingly, targeted deletion of insulin receptors in intestinal epithelial cells in ApcMin/+ mice did not change intestinal tumor number or size distribution on either a low or high-fat diet. We therefore asked whether cells in the tumor stroma might explain the association between tumor formation and insulin resistance. To this end, we generated ApcMin/+ mice with loss of insulin receptors in vascular endothelial cells. Strikingly, these mice had 42% more intestinal tumors than controls, no change in tumor angiogenesis, but increased expression of vascular cell adhesion molecule-1 (VCAM-1) in primary culture of tumor endothelial cells. Insulin decreased VCAM-1 expression and leukocyte adhesion in quiescent tumor endothelial cells with intact insulin receptors and partly prevented increases in VCAM-1 and leukocyte adhesion after treatment with tumor necrosis factor-α. Knockout of insulin receptors in endothelial cells also increased leukocyte adhesion in mesenteric venules and increased the frequency of neutrophils in tumors. We conclude that although insulin is mitogenic for intestinal tumor cells in vitro, its action on tumor cells in vivo is via signals from the tumor microenvironment. Insulin resistance in tumor endothelial cells produces an activated, proinflammatory state that promotes tumorigenesis. Improvement of endothelial dysfunction may reduce colorectal cancer risk in patients with obesity and type 2 diabetes.
登录
查看更多内容
影响因子：
15.8
作者：
Elmunzer BJ;Hayward RA;Schoenfeld PS;Saini SD;Deshpande A;Waljee AK
通讯作者：
Waljee AK
DOI：
10.1161/atvbaha.108.169722
发表时间：
2008-11
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Kim F;Pham M;Maloney E;Rizzo NO;Morton GJ;Wisse BE;Kirk EA;Chait A;Schwartz MW
通讯作者：
Schwartz MW
影响因子：
158.5
作者：
Bertagnolli, Monica M.;Eagle, Craig J.;Hawk, Ernest T.
通讯作者：
Hawk, Ernest T.
影响因子：
2.5
作者：
Alva, JA;Zovein, AC;Iruela-Arispe, ML
通讯作者：
Iruela-Arispe, ML
CXCR2 的抑制可显着抑制炎症驱动和自发性肿瘤发生
影响因子：
15.9
作者：
Jamieson, Thomas;Clarke, Mairi;Sansom, Owen J.
通讯作者：
Sansom, Owen J.