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Citations to this article

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 Article has an altmetric score of 6

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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Total citations by year

Year: 2025 2024 2023 2022 2021 2020 2019 2018 2017 2016 2015 2014 2013 2012 2011 2009 Total
Citations: 1 4 9 6 11 12 6 9 9 4 9 6 10 5 3 1 105
Citation information
This citation data is accumulated from CrossRef, which receives citation information from participating publishers, including this journal. Not all publishers participate in CrossRef, so this information is not comprehensive. Additionally, data may not reflect the most current citations to this article, and the data may differ from citation information available from other sources (for example, Google Scholar, Web of Science, and Scopus).

Citations to this article in year 2013 (10)

Title and authors Publication Year
Proteoglycans and their roles in brain cancer
A Wade, AE Robinson, JR Engler, C Petritsch, CD James, JJ Phillips
FEBS Journal 2013
Involvement of heparanase in atherosclerosis and other vessel wall pathologies
I Vlodavsky, M Blich, JP Li, RD Sanderson, N Ilan
Matrix Biology 2013
Modification of heparanase gene expression in response to conditioning and LPS treatment: strong correlation to rs4693608 SNP
O Ostrovsky, A Shimoni, P Baryakh, Y Morgulis, M Mayorov, K Beider, A Shteingauz, N Ilan, I Vlodavsky, A Nagler
Journal of leukocyte biology 2013
Macrophage Activation by Heparanase Is Mediated by TLR-2 and TLR-4 and Associates With Plaque Progression
M Blich, A Golan, G Arvatz, A Sebbag, I Shafat, E Sabo, V Cohen-Kaplan, S Petcherski, S Avniel-Polak, A Eitan, H Hammerman, D Aronson, E Axelman, N Ilan, G Nussbaum, I Vlodavsky
Arteriosclerosis, thrombosis, and vascular biology 2013
Heparanase is preferentially expressed in human psoriatic lesions and induces development of psoriasiform skin inflammation in mice
I Lerner, E Zcharia, T Neuman, E Hermano, AM Rubinstein, I Vlodavsky, M Elkin
Cellular and Molecular Life Sciences 2013
Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms
E Elinav, R Nowarski, CA Thaiss, B Hu, C Jin, RA Flavell
Nature Reviews Cancer 2013
Versatile role of heparanase in inflammation
R Goldberg, A Meirovitz, N Hirshoren, R Bulvik, A Binder, AM Rubinstein, M Elkin
Matrix Biology 2013
Heparanase in inflammation and inflammation-associated cancer
A Meirovitz, R Goldberg, A Binder, AM Rubinstein, E Hermano, M Elkin
FEBS Journal 2013
Induction of heparanase by HPV E6 oncogene in head and neck squamous cell carcinoma
N Hirshoren, R Bulvik, T Neuman, AM Rubinstein, A Meirovitz, M Elkin
Journal of Cellular and Molecular Medicine 2013
Heparanase and autoimmune diabetes
CJ Simeonovic, AF Ziolkowski, Z Wu, FJ Choong, C Freeman, CR Parish
Frontiers in immunology 2013

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