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Heparanase powers a chronic inflammatory circuit that promotes colitis-associated tumorigenesis in mice
Immanuel Lerner, … , Israel Vlodavsky, Michael Elkin
Immanuel Lerner, … , Israel Vlodavsky, Michael Elkin
Published April 1, 2011
Citation Information: J Clin Invest. 2011;121(5):1709-1721. https://doi.org/10.1172/JCI43792.
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Research Article

Heparanase powers a chronic inflammatory circuit that promotes colitis-associated tumorigenesis in mice

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Abstract

Ulcerative colitis (UC) is a chronic inflammatory bowel disease that is closely associated with colon cancer. Expression of the enzyme heparanase is clearly linked to colon carcinoma progression, but its role in UC is unknown. Here we demonstrate for what we believe to be the first time the importance of heparanase in sustaining the immune-epithelial crosstalk underlying colitis-associated tumorigenesis. Using histological specimens from UC patients and a mouse model of dextran sodium sulfate–induced colitis, we found that heparanase was constantly overexpressed and activated throughout the disease. We demonstrate, using heparanase-overexpressing transgenic mice, 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 preserved chronic inflammatory conditions and created a tumor-promoting microenvironment characterized by enhanced NF-κB signaling and induction of STAT3. Our results indicate that 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 TNF-α–dependent mechanisms) and activation (via secretion of cathepsin L) of heparanase contributed by the colon epithelium. Thus, disruption of the heparanase-driven chronic inflammatory circuit is highly relevant to the design of therapeutic interventions in colitis and the associated cancer.

Authors

Immanuel Lerner, Esther Hermano, Eyal Zcharia, Dina Rodkin, Raanan Bulvik, Victoria Doviner, Ariel M. Rubinstein, Rivka Ishai-Michaeli, Ruth Atzmon, Yoav Sherman, Amichay Meirovitz, Tamar Peretz, Israel Vlodavsky, Michael Elkin

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Figure 1

Expression of heparanase and CatL is induced during the course of colitis.

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Expression of heparanase and CatL is induced during the course of coliti...
(A) Heparanase expression in acute and chronic phases of UC. Tissue specimens derived from normal colon tissue (left) and UC patients in acute (middle) and chronic (right) phases of the disease were stained with anti-heparanase antibody (red staining). Photographs are representative of control (n = 29) and UC (n = 10) samples (original magnification, ×200). (B) Schematic representation of mouse model of DSS colitis (top) and AOM/DSS-induced colitis–associated carcinoma (bottom), induced as described in Methods. Mouse colonic tissues were harvested at indicated time points and analyzed as described below for C–G. (C) Heparanase (Hpa; left) and CatL (right) mRNA expression during the course of DSS-induced colitis, measured by qRT-PCR and normalized to actin mRNA (n = 5) *P < 0.05, **P < 0.01, ***P < 0.001. (D) Heparanase and CatL protein levels. Lysates of distal colons were harvested at the indicated time points and analyzed for heparanase and CatL protein by immunoblotting. Pro-, latent 65 kDa proenzyme; Active-, enymatically-active 50 kDa heparanase. (E) Densitometric quantification of total (65 kDa and 50 kDa, left) and active (50 kDa, right) heparanase presented in D. (F) Heparanase activity. Punch biopsies were harvested on day 59 from DSS-untreated (Cont) and treated (DSS) mice and cultured for 24 hours. Heparanase activity was determined in the conditioned medium. (G) Immunostaining (brown) of mouse colonic serial tissue sections with anti-heparanase (top) and CatL (bottom) antibodies. Note heparanase staining in the epithelial compartment and CatL staining in the stromal compartment (original magnification, ×200).

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