title: 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.affiliation: Sharett Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Immanuel
authors.initials: I
authors.lastname: Lerner
authors.forename: Esther
authors.initials: E
authors.lastname: Hermano
authors.forename: Eyal
authors.initials: E
authors.lastname: Zcharia
authors.forename: Dina
authors.initials: D
authors.lastname: Rodkin
authors.forename: Raanan
authors.initials: R
authors.lastname: Bulvik
authors.forename: Victoria
authors.initials: V
authors.lastname: Doviner
authors.forename: Ariel M
authors.initials: AM
authors.lastname: Rubinstein
authors.forename: Rivka
authors.initials: R
authors.lastname: Ishai-Michaeli
authors.forename: Ruth
authors.initials: R
authors.lastname: Atzmon
authors.forename: Yoav
authors.initials: Y
authors.lastname: Sherman
authors.forename: Amichay
authors.initials: A
authors.lastname: Meirovitz
authors.forename: Tamar
authors.initials: T
authors.lastname: Peretz
authors.forename: Israel
authors.initials: I
authors.lastname: Vlodavsky
authors.forename: Michael
authors.initials: M
authors.lastname: Elkin
mesh_terms: D000818:Animals; D001706:Biopsy; D045744:Cell Line, Tumor; D003092:Colitis / Q000378:metabolism*; D004789:Enzyme Activation; D015972:Gene Expression Regulation, Neoplastic; D005966:Glucuronidase / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007249:Inflammation; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010641:Phenotype; D011134:Polysaccharides / Q000737:chemistry; D011994:Recombinant Proteins / Q000737:chemistry; D000099175:Heparanase
chemical_list: D005966:Glucuronidase; D011134:Polysaccharides; D011994:Recombinant Proteins; D000099175:Heparanase