Heparanase enzyme in chronic inflammatory bowel disease and colon cancer

Abstract

Heparanase is the sole mammalian endoglycosidase that cleaves heparan sulfate, the key polysaccharide of the extracellular matrix and basement membranes. Enzymatic cleavage of heparan sulfate profoundly affects a variety of physiological and pathological processes, including morphogenesis, neovascularization, inflammation, and tumorigenesis. Critical involvement of heparanase in colorectal tumor progression and metastatic spread is widely documented; however, until recently a role for heparanase in the initiation of colon carcinoma remained underappreciated. Interestingly, the emerging data that link heparanase to chronic inflammatory bowel conditions, also suggest contribution of the enzyme to colonic tumor initiation, at least in the setting of colitis-associated cancer. Highly coordinated interplay between intestinal heparanase and immune cells (i.e., macrophages) preserves chronic inflammatory conditions and creates a tumor-promoting microenvironment. Here we review the action of heparanase in colon tumorigenesis and discuss recent findings, pointing to a role for heparanase in sustaining immune cell-epithelial crosstalk that underlies intestinal inflammation and the associated cancer.

Heparanase: From basic research to therapeutic applications in cancer and inflammation

“…However, non-tumor (host) cells including T lymphocytes, B lymphocytes, neutrophils, monocyte/macrophages, endothelial cells, osteoclasts and fibroblasts can also upregulate heparanase expression upon activation and thereby contribute not only to cancer progression (Arvatz et al, 2011b; Barash et al, 2014; Edovitsky et al, 2004; Lerner et al, 2011; Ramani et al, 2016; Vlodavsky et al, 2012), but also to acute and chronic inflammation (Goldberg et al, 2013; Li et al, 2008; Vlodavsky et al, 2012), autoimmunity (de Mestre et al, 2007; Li et al, 2008), atherosclerosis (Vlodavsky et al, 2013), tissue fibrosis (Secchi et al, 2015), kidney dysfunction (Garsen et al, 2016a; Garsen et al, 2016b; van den Hoven et al, 2007), ocular surface dysfunction (McKown et al, 2009; Zhang et al, 2010) diabetes (Parish et al, 2013) and diabetic complications (Gil et al, 2012; Wang et al, 2013). Noteworthy, heparanase appears to activate cells of the innate immune system and soluble HS fragments generated by heparanase trigger the expression and secretion of pro-inflammatory cytokines through toll-like receptors (TLR) (Blich et al, 2013; Brunn et al, 2005; Goodall et al, 2014; Hermano et al, 2012). Moreover, we have recently revealed a linear cascade by which heparanase activates Erk, p38 and JNK signaling in macrophages, leading to increased c-Fos levels and induction of cytokine expression (Gutter-Kapon et al, unpublished results).…”

“…Given that heparanase activity is implicated in multiple chronic inflammatory processes (Hermano et al, 2012; Lerner et al, 2011; Naggi et al, 2005), we searched for a potential role of the enzyme in neutrophil emigration to lungs subjected to a prolonged smoke exposure. A daily exposure of wt mice to high levels of tobacco smoke for 2 weeks resulted in a significant infiltration of neutrophils to the lung parenchyma and a small fraction of these neutrophils also penetrated the bronchoalveolar space (Petrovich et al, 2016).…”

“…Several up-to-date reviews successfully describe basic and translational aspects related to the involvement of heparanase in cancer and inflammation (Hermano et al, 2012; Li and Vlodavsky, 2009; McKenzie, 2007; Vreys and David, 2007). The present review focuses primarily on recent new developments in the ‘heparanase field’, including its function in the tumor microenvironment, hematological malignancies, exosome formation, autophagy, chemoresistance, polarization of macrophages and toll-like receptor activation.…”

Heparanase is preferentially expressed in human psoriatic lesions and induces development of psoriasiform skin inflammation in mice

“…In particular, ability of heparanase to stimulate macrophage activation and direct macrophage responses toward chronic inflammatory pattern was highlighted in our studies focusing on inflammatory bowel disease [21,62], mechanistically related to psoriasis. The exact mechanism underlying heparanase-dependent sensitization of macrophages is not fully understood, however generation of soluble HS degradation fragments (shown to stimulate TLR signaling both in vitro and in vivo [63,64]) may play a role.…”

Intestinal anti-inflammatory activity of Ground Cherry (Physalis angulataL.) standardized CO2phytopharmaceutical preparation

“…A complex network involving heparanase and other inflammatory pathways, such as hsp70 and NF-κB, has been proposed to explain the immunomodulatory response in inflammatory conditions[46,47]. Heparanase has an important role in body physiology and inflammatory responses, where its expression is an important mechanism underlying chronic colonic inflammation[48].…”