12 April 2011 00:00 hrs.
Heparanase powers a chronic inflammatory circuit that promotes colitis-associated tumorigenesis.

Dr. Michael Elkin, Tumor Biology Research Unit, department of Oncology, Hadassah-Hebrew University Medical Center Jerusalem, Israel


Dr. Johan van der Vlag, Department of Nephrology, RUNMC, Nijmegen

12-04-2011 00:00:00Europe/AmsterdamHeparanase powers a chronic inflammatory circuit that promotes colitis-associated tumorigenesis.

Remarks / more information:

Michael-ElkinChronic inflammatory conditions in the colon are closely associated with cancer. Our recent findings demonstrate the importance of the heparanase enzyme (the only known mammalian endoglycosidase that cleaves heparan sulfate) in sustaining immune-epithelial crosstalk underlying colitis-associated tumorigenesis. Applying histological specimens derived from patients with chronically-inflamed colon and a mouse model of chronic colitis, we found that heparanase is constantly overexpressed and activated throughout the disease. Employing heparanase-overexpressing transgenic mice, we demonstrated that heparanase overexpression markedly increased the incidence and severity of colitis-associated colonic tumors. We found that highly coordinated interactions between the epithelial compartment (contributing heparanase) and mucosal macrophages preserves chronic inflammatory conditions and creates a tumor-promoting microenvironment characterized by enhanced NF-κB signaling and induction of STAT3. Thus, heparanase generates a vicious cycle that powers colitis and the associated tumorigenesis: heparanase, acting synergistically with the intestinal flora, stimulates macrophage activation, while macrophages induce production (via TNFα-dependent mechanism) and activation (via secretion of cathepsin L) of heparanase contributed by the colon epithelium. Interestingly, our most recent findings indicate that the heparanase-driven chronic inflammatory circuit by may be highly relevant to pathogenesis of additional disorders, including diabetic kidney disease (J. Clin. Invest., In press).

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