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 Rubinstein,Rivka Ishai-Michaeli,Ruth Atzmon,Yoav Sherman,Amichay Meirovitz,Tamar Peretz,Israel Vlodavsky,Michael Elkin +13 more
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TLDR
It is 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.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.read more
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Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms.
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TL;DR: It is proposed that understanding this microbial influence will be crucial for targeted therapy in modern cancer treatment and the recently suggested role of commensal microorganisms in inflammation-induced cancer is discussed.
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TL;DR: Cancers are not just masses of malignant cells but complex ‘rogue’ organs, to which many other cells are recruited and can be corrupted by the transformed cells.
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The pulmonary endothelial glycocalyx regulates neutrophil adhesion and lung injury during experimental sepsis
Eric P. Schmidt,Yimu Yang,William J. Janssen,Aneta Gandjeva,Mario J. Perez,Lea Barthel,Rachel L. Zemans,Joel Bowman,Dan Koyanagi,Zulma X. Yunt,Lynelle P. Smith,Sara S Cheng,Katherine H. Overdier,Kathy R. Thompson,Mark W. Geraci,Ivor S. Douglas,David B. Pearse,Rubin M. Tuder +17 more
TL;DR: Using intravital microscopy, it is found that endotoxemia in mice rapidly induced pulmonary microvascular glycocalyx degradation via tumor necrosis factor-α (TNF-α)-dependent mechanisms, which attenuated sepsis-induced ALI and mortality in mice.
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Periodontal pathogens Porphyromonas gingivalis and Fusobacterium nucleatum promote tumor progression in an oral-specific chemical carcinogenesis model
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TL;DR: It is reported that chronic bacterial infection promotes OSCC, and that augmented signaling along the IL-6-STAT3 axis underlies this effect, the first demonstration of a mechanistic role for oral bacteria in chemically induced OSCC tumorigenesis.
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Significance of Heparanase in Cancer and Inflammation
Israel Vlodavsky,Phillip Beckhove,Immanuel Lerner,Claudio Pisano,Amichai Meirovitz,Neta Ilan,Michael Elkin +6 more
TL;DR: Combining radiotherapy with heparanase inhibition is an effective strategy to prevent tumor resistance and dissemination in IR-treated pancreatic cancer patients, and accumulating evidence indicate that peptides derived from human heParanase elicit a potent anti-tumor immune response, suggesting that he paranase represents a promising target antigen for immunotherapeutic approaches against a broad variety of tumours.
References
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