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

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

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 5

TNF-α induces heparanase expression in Colo205 colonic carcinoma cells and in normal mouse colonic epithelium ex vivo and in vivo.

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TNF-α induces heparanase expression in Colo205 colonic carcinoma cells a...
(A–C) Colo205 cells were incubated (16 hours) in triplicate in the absence or presence of 15 ng/ml TNF-α. Heparanase expression was assessed 16 hours later by (A) immunofluorescent staining (scale bars: 20 μm), (B) qRT-PCR determination of mRNA levels, and (C) enzymatic activity assay. (D and E) Heparanase induction in colonic explants treated with TNF-α ex vivo. Explants harvested from healthy mouse colon as described in Methods were cultured ex vivo for 16 hours in the absence and presence of TNF-α (15 ng/ml). Heparanase expression was assessed 16 hours later by (D) qRT-PCR determination of mRNA levels and (E) immunofluorescent (yellow) staining (scale bars: 50 μm). (F) Induction of heparanase expression in mouse colonic epithelium following TNF-α administration in vivo. Colonic tissue specimens derived from healthy BALB/c mice injected i.p. with PBS or TNF-α (1 μg/mouse, 24 hours) were stained with anti-heparanase antibody (brown staining). Note heparanase staining in colon epithelium derived from TNF-α–treated but not PBS-treated mice (original magnification, ×200).