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Insulin Resistance in Vascular Endothelial Cells Promotes Intestinal Tumor Formation

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...

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Autores principales: Wang, Xuanchun, Häring, Max-Felix, Rathjen, Thomas, Lockhart, Samuel M., Sørensen, Ditte, Ussar, Siegfried, Rasmussen, Lars Melholt, Bertagnolli, Monica M., Kahn, C. Ronald, Rask-Madsen, Christian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5578899/
https://www.ncbi.nlm.nih.gov/pubmed/28459466
http://dx.doi.org/10.1038/onc.2017.107
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author Wang, Xuanchun
Häring, Max-Felix
Rathjen, Thomas
Lockhart, Samuel M.
Sørensen, Ditte
Ussar, Siegfried
Rasmussen, Lars Melholt
Bertagnolli, Monica M.
Kahn, C. Ronald
Rask-Madsen, Christian
author_facet Wang, Xuanchun
Häring, Max-Felix
Rathjen, Thomas
Lockhart, Samuel M.
Sørensen, Ditte
Ussar, Siegfried
Rasmussen, Lars Melholt
Bertagnolli, Monica M.
Kahn, C. Ronald
Rask-Madsen, Christian
author_sort Wang, Xuanchun
collection PubMed
description 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 Apc(Min/+) mice by over 2-fold. Surprisingly, targeted deletion of insulin receptors in intestinal epithelial cells in Apc(Min/+) 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 Apc(Min/+) 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.
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spelling pubmed-55788992017-11-01 Insulin Resistance in Vascular Endothelial Cells Promotes Intestinal Tumor Formation Wang, Xuanchun Häring, Max-Felix Rathjen, Thomas Lockhart, Samuel M. Sørensen, Ditte Ussar, Siegfried Rasmussen, Lars Melholt Bertagnolli, Monica M. Kahn, C. Ronald Rask-Madsen, Christian Oncogene Article 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 Apc(Min/+) mice by over 2-fold. Surprisingly, targeted deletion of insulin receptors in intestinal epithelial cells in Apc(Min/+) 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 Apc(Min/+) 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. 2017-05-01 2017-08-31 /pmc/articles/PMC5578899/ /pubmed/28459466 http://dx.doi.org/10.1038/onc.2017.107 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Wang, Xuanchun
Häring, Max-Felix
Rathjen, Thomas
Lockhart, Samuel M.
Sørensen, Ditte
Ussar, Siegfried
Rasmussen, Lars Melholt
Bertagnolli, Monica M.
Kahn, C. Ronald
Rask-Madsen, Christian
Insulin Resistance in Vascular Endothelial Cells Promotes Intestinal Tumor Formation
title Insulin Resistance in Vascular Endothelial Cells Promotes Intestinal Tumor Formation
title_full Insulin Resistance in Vascular Endothelial Cells Promotes Intestinal Tumor Formation
title_fullStr Insulin Resistance in Vascular Endothelial Cells Promotes Intestinal Tumor Formation
title_full_unstemmed Insulin Resistance in Vascular Endothelial Cells Promotes Intestinal Tumor Formation
title_short Insulin Resistance in Vascular Endothelial Cells Promotes Intestinal Tumor Formation
title_sort insulin resistance in vascular endothelial cells promotes intestinal tumor formation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5578899/
https://www.ncbi.nlm.nih.gov/pubmed/28459466
http://dx.doi.org/10.1038/onc.2017.107
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