Heparanase expression by Barrett's epithelium and during esophageal carcinoma progression

Abstract

Enzymatic activity responsible for the cleavage of heparan sulfate, commonly known as heparanase, is abundant in tumor-derived cells. Heparanase cleaves heparan sulfate side chains, presumably at sites of low sulfation, thus facilitating structural alterations of the extracellular matrix and basement membrane underlying epithelial and endothelial cells. Traditionally, heparanase activity was correlated with the metastatic potential of tumor-derived cells, attributed to enhanced cell dissemination as a consequence of heparan sulfate cleavage and remodeling of the extracellular matrix barrier. More recently, heparanase upregulation was documented in an increasing number of human carcinomas and hematological malignancies, correlating with increased tumor metastasis, vascular density, and shorter post-operative survival of cancer patients. Although heparanase upregulation and its pro-malignant features are well documented, the instance of its induction in the course of tumor development was less investigated. Here, we used immunohistochemical analysis to investigate heparanase expression in normal esophagus, Barrett's esophagus without dysplasia, Barrett's esophagus with low-grade dysplasia, Barrett's esophagus with high-grade dysplasia, and adenocarcinoma of the esophagus. We report that heparanase expression is already induced in Barrett's epithelium without dysplasia, and is further increased during progression through distinct pathological stages, namely, low-grade dysplasia, highgrade dysplasia, and adenocarcinoma. Notably, heparanase induction correlated with increased cell proliferation index revealed by Ki-67 staining. These findings suggest that heparanase function is not limited to the process of tumor metastasis, but rather is engaged at the early stages of esophagus carcinoma initiation and progression. Modern Pathology ( Keywords: heparanase; Barrett's epithelium; esophageal; adenocarcinoma; staining; localization Heparanase is an endo-b-D-glucuronidase, the predominant enzyme that degrades heparan sulfate side chains of heparan sulfate proteoglycans. 1,2 These complex macromolecules are highly abundant in the extracellular matrix and are thought to have an important structural role, contributing to extracellular matrix integrity and insolubility. 3,4 Traditionally, heparanase activity was correlated with the metastatic potential of tumor-derived cells, attributed to enhanced cell dissemination as a consequence of heparan sulfate cleavage and remodeling of the extracellular matrix barrier. 1,2 A proof-of-concept to this notion has been established by using specific anti-heparanase ribozyme and siRNA methodologies, clearly implicating heparanase-mediated heparan sulfate cleavage as a critical requisite for metastatic spread. 5 Similarly, heparanase activity was implicated in cell dissemination associated with inflammation and angiogenesis. 5,6 More recently, heparanase upregulation was documented in an increasing number of human carcinomas and hematological malignancies. 7,8 In many cases, heparanase ind...

Heparanase Cooperates with Ras to Drive Breast and Skin Tumorigenesis

“…In several examples (i.e., colon and esophagus) (36, 37), heparanase expression is induced already at the very early stages of tumor initiation. Results of the current study suggest that elevated levels of heparanase early on have a prominent impact on tumor expansion and aggressiveness.…”

Versatile role of heparanase in inflammation

“…Progression of Barrett's oesophagus to adenocarcinoma (Picardo et al, 2012); chronic gastritis to intestinal-type gastric carcinoma, chronic hepatitis C to hepatocellular carcinoma (Chiba et al, 2012); pancreatitis to pancreatic adenocarcinoma (Lowenfels et al, 1993) and colitis to colorectal cancer (Gupta et al, 2007) are well-known examples of inflammation-driven tumorigenesis. Remarkably, induction of heparanase prior to the appearance of malignancy was reported in essentially all of the above-mentioned inflammatory conditions, i.e., Barrett's oesophagus (Brun et al, 2009; Sonoda et al, 2010), hepatitis C infection (El-Assal et al, 2001), chronic pancreatitis (Koliopanos et al, 2001), Crohn disease and ulcerative colitis (Lerner et al, 2011; Waterman et al, 2007). Given the causal role the enzyme plays in tumor progression in tissues in which cancer-related inflammation typically occurs [i.e., gastrointestinal tract, pancreas, liver (Brun et al, 2009; El-Assal et al, 2001; Hoffmann et al, 2008; Koliopanos et al, 2001; Naomoto et al, 2005; Nobuhisa et al, 2005; Sonoda et al, 2010; Xiong et al, 2012; Zhang et al, 2007)], it is conceivable that inflammation-induced heparanase may be involved in coupling inflammation and cancer.…”

“…Remarkably, induction of heparanase prior to the appearance of malignancy was reported in essentially all of the above-mentioned inflammatory conditions, i.e., Barrett's oesophagus (Brun et al, 2009; Sonoda et al, 2010), hepatitis C infection (El-Assal et al, 2001), chronic pancreatitis (Koliopanos et al, 2001), Crohn disease and ulcerative colitis (Lerner et al, 2011; Waterman et al, 2007). Given the causal role the enzyme plays in tumor progression in tissues in which cancer-related inflammation typically occurs [i.e., gastrointestinal tract, pancreas, liver (Brun et al, 2009; El-Assal et al, 2001; Hoffmann et al, 2008; Koliopanos et al, 2001; Naomoto et al, 2005; Nobuhisa et al, 2005; Sonoda et al, 2010; Xiong et al, 2012; Zhang et al, 2007)], it is conceivable that inflammation-induced heparanase may be involved in coupling inflammation and cancer. The findings obtained in a study utilizing mouse model of colitis-associated colon carcinoma support this notion (Lerner et al, 2011).…”

Adipocyte differentiation influences the proliferation and migration of normal and tumoral breast epithelial cells

“…Therefore, the observed increase in nMuMG cell proliferation in cells incubated with cM may at least in part be due to the stimulation of this enzyme's activity. an increase in heparanase activity has previously been described in relation to an increase in the metastatic activity of tumor cells (8); however, our findings indicate that heparanase may also be involved in the proliferation of normal breast epithelial cells (22). in terms of MMP-9 activity, basal expression was observed in the nMuMG cells, and was not modified following incubation with any of the three types of cM.…”

“…in this study, we demonstrated that the state of adipocyte differentiation influences normal and tumoral breast epithelial cell proliferation and migration. Heparanase and MMP-9 are potentially involved in this regulation (22). The proliferation of NMuMG cells was significantly increased in cells incubated with the three types of conditioned media, as well as in cells grown on the prea, pda and Ma 3T3-l1 stromal support cells.…”