Adiponectin limits tumor angiogenesis-the missing link between obesity and increased risk of developing cancer?

DailyUpdates 5nd March - Obesity is related to an increased risk of developing cancer. Researchers at the Karolinska Institute in Sweden have now reported that this increased risk may be due to a reduction in adiponectin levels which these researchers have shown to act as a brake on angiogenesis, a key component of tumor progression.

It is estimated that somewhere between 34 and 61 million people in the US are obese and in much of the developing world this incidence is increasing by about 1% per year. As a general guide, obesity increases the likelihood of death from all causes by 20%, and plays a major role in the development of coronary heart disease, stroke and diabetes. Obesity also increases the risk of cancer, particularly endometrial, breast and renal cell cancers which have been consistently linked to obesity. Obese postmenopausal women have a 2.36-fold increase in the risk of developing breast cancer.

Researchers at the Karolinska Institute in Sweden have now identified the down-regulation of adiponectin in obese individuals as a possible link to the increased risk of cancer.

The adipose tissue produces several growth factors/hormones including leptin, tumor necrosis factor alpha, and adiponectin. It has been found that adiponectin levels are reduced in obesity. In vitro, adiponectin potently inhibits endothelial cell proliferation and migration. In their February Proceedings of the National Academy of Science report, Brakenhielm report that in the chick chorioallantoic membrane and the mouse corneal angiogenesis assays, adiponectin remarkably prevents new blood vessel growth.

Tumor vascularization is key to the development of solid tumors and the vast majority of pharmaceutical activity surrounding angiogenesis relates to the development of therapeutic strategies to destroy existing tumor vasculature or to prevent neovascularization. The Karolinska group show that in addition to preventing angiogenesis in the chick and mouse assays, adiponectin also significantly inhibits neovascularization of tumors in vivo and reduces primary tumor growth. In further mechanistic studies the antiendothelial mechanisms of adiponectin were found to involve activation of caspase-mediated endothelial cell apoptosis. Adiponectin induces a cascade activation of caspases-8, -9, and -3, which leads to cell death.

These data demonstrate induction of endothelial apoptosis as an unique mechanism of adiponectin-induced antiangiogenesis. Adiponectin, is therefore suggested to be a direct endogenous angiogenesis inhibitor, and the reduction of adiponectin during obesity may facilitate tumor development.

(source DailyUpdates 5nd March; for a full abstract of the original paper see Proc Natl Acad Sci U S A. 2004 Feb 24;101(8):2476-81.)

In this edition of DailyUpdates, LeadDiscovery also highlights a randomized controlled trial of amantadine plus interferon-alpha2a vs. interferon-alpha2a alone in naive patients with chronic hepatitis C...the coordinated activation of VEGFR-1 and VEGFR-2 as a potent arteriogenic stimulus leading to enhancement of regional perfusion...the stimulation of hepatocyte glucose metabolism by novel small molecule glucokinase activators... and AS601245, a JNK inhibitor with neuroprotective properties.