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 |
Strain | Model Name | Treatment Agent(s) | Organ Affected | Frequency | Model Details |
---|---|---|---|---|---|
C57BL/6-ApcMin/+ Insrtm1Khn Tg(Vil1-cre)997Gum | Intestine - Small Intestine - Jejunum tumor | Intestine - Small Intestine - Jejunum |
observed |
||
C57BL/6-ApcMin/+ Insrtm1Khn | Intestine - Small Intestine - Jejunum tumor | Intestine - Small Intestine - Jejunum |
observed |
||
C57BL/6-ApcMin/+ Insrtm1Khn Tg(Cdh5-cre)7Mlia | Intestine - Small Intestine adenoma | Intestine - Small Intestine |
observed |
||
C57BL/6-ApcMin/+ Gt(ROSA)26Sortm4(ACTB-tdTomato,-EGFP)Luo Tg(Cdh5-cre)7Mlia | Intestine - Small Intestine adenoma | Intestine - Small Intestine |
observed |
||
C57BL/6-ApcMin/+ Insrtm1Khn | Intestine - Small Intestine tumor |
|
Intestine - Small Intestine |
observed |
|
C57BL/6-ApcMin/+ Insrtm1Khn Tg(Vil1-cre)997Gum | Intestine - Small Intestine tumor |
|
Intestine - Small Intestine |
observed |
|
C57BL/6-ApcMin/+ Insrtm1Khn Tg(Cdh5-cre)7Mlia | Intestine - Small Intestine tumor | Intestine - Small Intestine |
observed |
||
C57BL/6-ApcMin/+ Gt(ROSA)26Sortm4(ACTB-tdTomato,-EGFP)Luo Tg(Cdh5-cre)7Mlia | Intestine - Small Intestine tumor | Intestine - Small Intestine |
observed |
||
C57BL/6J-ApcMin/+ | Intestine polyp | Intestine |
observed |
||
C57BL/6-ApcMin/+ Insrtm1Khn Tg(Cdh5-cre)7Mlia | Intestine polyp | Intestine |
observed |
||
C57BL/6-ApcMin/+ Gt(ROSA)26Sortm4(ACTB-tdTomato,-EGFP)Luo Tg(Cdh5-cre)7Mlia | Intestine polyp | Intestine |
observed |
||
C57BL/6J-ApcMin/+ | Intestine tumor | Intestine |
observed |
||
C57BL/6-ApcMin/+ Insrtm1Khn Tg(Vil1-cre)997Gum | Intestine tumor | Intestine |
observed |
||
C57BL/6-ApcMin/+ Insrtm1Khn | Intestine tumor | Intestine |
observed |
||
C57BL/6-ApcMin/+ Insrtm1Khn | Intestine tumor | Intestine |
observed |
||
C57BL/6-ApcMin/+ Insrtm1Khn Tg(Cdh5-cre)7Mlia | Intestine tumor | Intestine |
observed |
||
C57BL/6-ApcMin/+ Gt(ROSA)26Sortm4(ACTB-tdTomato,-EGFP)Luo Tg(Cdh5-cre)7Mlia | Intestine tumor | Intestine |
observed |
||
C57BL/6J-ApcMin/+ | Intestine tumor - epithelial | Intestine |
observed |