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Reference SummaryWang X, Oncogene 2017 Aug 31;36(35):4987-4996

Title	Insulin resistance in vascular endothelial cells promotes intestinal tumour formation.
Authors	Wang X; Haring MF; Rathjen T; Lockhart SM; Sorensen D; Ussar S; Rasmussen LM; Bertagnolli MM; Kahn CR; Rask-Madsen C
Journal	Oncogene
Volume	36
Issue	35
Year	2017
Pages	4987-4996
Abstract	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 ApcMin/+ mice. Surprisingly, targeted deletion of insulin receptors in intestinal epithelial cells in ApcMin/+ 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 ApcMin/+ 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-alpha. 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.
Links	J:248166 – MGI References 28459466 – National Library of Medicine/PubMed

Models
Strain	Model Name	Treatment Agent(s)	Organ Affected	Frequency	Model Details
C57BL/6-Apc^Min/+ Insr^tm1Khn Tg(Vil1-cre)997Gum	Intestine - Small Intestine - Jejunum tumor		Intestine - Small Intestine - Jejunum	observed
C57BL/6-Apc^Min/+ Insr^tm1Khn	Intestine - Small Intestine - Jejunum tumor		Intestine - Small Intestine - Jejunum	observed
C57BL/6-Apc^Min/+ Insr^tm1Khn Tg(Cdh5-cre)7Mlia	Intestine - Small Intestine adenoma		Intestine - Small Intestine	observed
C57BL/6-Apc^Min/+ Gt(ROSA)26Sor^{tm4(ACTB-tdTomato,-EGFP)Luo} Tg(Cdh5-cre)7Mlia	Intestine - Small Intestine adenoma		Intestine - Small Intestine	observed
C57BL/6-Apc^Min/+ Insr^tm1Khn	Intestine - Small Intestine tumor	low fat	Intestine - Small Intestine	observed
C57BL/6-Apc^Min/+ Insr^tm1Khn Tg(Vil1-cre)997Gum	Intestine - Small Intestine tumor	low fat	Intestine - Small Intestine	observed
C57BL/6-Apc^Min/+ Insr^tm1Khn Tg(Cdh5-cre)7Mlia	Intestine - Small Intestine tumor		Intestine - Small Intestine	observed
C57BL/6-Apc^Min/+ Gt(ROSA)26Sor^{tm4(ACTB-tdTomato,-EGFP)Luo} Tg(Cdh5-cre)7Mlia	Intestine - Small Intestine tumor		Intestine - Small Intestine	observed
C57BL/6J-Apc^Min/+	Intestine polyp		Intestine	observed
C57BL/6-Apc^Min/+ Insr^tm1Khn Tg(Cdh5-cre)7Mlia	Intestine polyp		Intestine	observed
C57BL/6-Apc^Min/+ Gt(ROSA)26Sor^{tm4(ACTB-tdTomato,-EGFP)Luo} Tg(Cdh5-cre)7Mlia	Intestine polyp		Intestine	observed
C57BL/6J-Apc^Min/+	Intestine tumor		Intestine	observed
C57BL/6-Apc^Min/+ Insr^tm1Khn Tg(Vil1-cre)997Gum	Intestine tumor		Intestine	observed
C57BL/6-Apc^Min/+ Insr^tm1Khn	Intestine tumor		Intestine	observed
C57BL/6-Apc^Min/+ Insr^tm1Khn	Intestine tumor		Intestine	observed
C57BL/6-Apc^Min/+ Insr^tm1Khn Tg(Cdh5-cre)7Mlia	Intestine tumor		Intestine	observed
C57BL/6-Apc^Min/+ Gt(ROSA)26Sor^{tm4(ACTB-tdTomato,-EGFP)Luo} Tg(Cdh5-cre)7Mlia	Intestine tumor		Intestine	observed
C57BL/6J-Apc^Min/+	Intestine tumor - epithelial		Intestine	observed