| Autor: |
Wang X; Joslin Diabetes Center and Harvard Medical School, Boston, MA, USA.; Huashan Hospital, Fudan University, Shanghai, People's Republic of China., Häring MF; Joslin Diabetes Center and Harvard Medical School, Boston, MA, USA.; Division of Clinical Chemistry and Pathobiochemistry, Department of Internal Medicine IV, University Hospital Tuebingen, Tuebingen, Germany., Rathjen T; Joslin Diabetes Center and Harvard Medical School, Boston, MA, USA.; Novo Nordisk A/S, Måløv, Denmark., Lockhart SM; Joslin Diabetes Center and Harvard Medical School, Boston, MA, USA.; Queen's University Belfast, Belfast, UK., Sørensen D; Joslin Diabetes Center and Harvard Medical School, Boston, MA, USA.; Odense University Hospital, University of Southern Denmark, Odense, Denmark.; Danish Diabetes Academy, Odense, Denmark., Ussar S; Joslin Diabetes Center and Harvard Medical School, Boston, MA, USA.; JRG Adipocytes and Metabolism, Institute for Diabetes and Obesity, Helmholtz Center Munich-Neuherberg, Germany.; German Center for Diabetes Research (DZD), Neuherberg, Germany., Rasmussen LM; Odense University Hospital, University of Southern Denmark, Odense, Denmark., Bertagnolli MM; Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA., Kahn CR; Joslin Diabetes Center and Harvard Medical School, Boston, MA, USA., Rask-Madsen C; Joslin Diabetes Center and Harvard Medical School, Boston, MA, USA. |
| Abstrakt: |
The risk of several cancers, including colorectal cancer, is increased in patients with obesity and type 2 diabetes, conditions characterised by hyperinsulinaemia and insulin resistance. Because hyperinsulinaemia itself is an independent risk factor for cancer development, we examined tissue-specific insulin action in intestinal tumour formation. In vitro, insulin increased proliferation of intestinal tumour epithelial cells by almost two-fold in primary culture of tumour cells from Apc Min/+ mice. Surprisingly, targeted deletion of insulin receptors in intestinal epithelial cells in Apc Min/+ mice did not change intestinal tumour number or size distribution on either a low or high-fat diet. We therefore asked whether cells in the tumour stroma might explain the association between tumour formation and insulin resistance. To this end, we generated Apc Min/+ mice with loss of insulin receptors in vascular endothelial cells. Strikingly, these mice had 42% more intestinal tumours than controls, no change in tumour angiogenesis, but increased expression of vascular cell adhesion molecule-1 (VCAM-1) in primary culture of tumour endothelial cells. Insulin decreased VCAM-1 expression and leukocyte adhesion in quiescent tumour endothelial cells with intact insulin receptors and partly prevented increases in VCAM-1 and leukocyte adhesion after treatment with tumour necrosis factor-α. Knockout of insulin receptors in endothelial cells also increased leukocyte adhesion in mesenteric venules and increased the frequency of neutrophils in tumours. We conclude that although insulin is mitogenic for intestinal tumour cells in vitro, impaired insulin action in the tumour microenvironment may be more important in conditions where hyperinsulinaemia is secondary to insulin resistance. Insulin resistance in tumour 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. |
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