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.
Renal involvement is a major medical concern in the diabetic population, and with the global epidemic of diabetes, diabetic nephropathy (DN) became the leading cause of end-stage renal failure in the Western world. Heparanase (the only known mammalian endoglycosidase that cleaves heparan sulfate) is essentially involved in DN pathogenesis. Nevertheless, the exact mode of heparanase action in sustaining the pathology of DN remains unclear. Here we describe a previously unrecognized combinatorial circuit of heparanase-driven molecular events promoting chronic inflammation and renal injury in individuals with DN. These events are fueled by heterotypic interactions among glomerular, tubular, and immune cell compartments, as well as diabetic milieu (DM) components. We found that under diabetic conditions latent heparanase, overexpressed by glomerular cells and posttranslationally activated by cathepsin L of tubular origin, sustains continuous activation of kidneydamaging macrophages by DM components, thus creating chronic inflammatory conditions and fostering macrophage-mediated renal injury. Elucidation of the mechanism underlying the enzyme action in diabetic kidney damage is critically important for the proper design and future implementation of heparanase-targeting therapeutic interventions (which are currently under intensive development and clinical testing) in individuals with DN and perhaps other complications of diabetes.
Recent years have seen a growing body of evidence that enzymatic remodeling of heparan sulfate proteoglycans profoundly affects a variety of physiological and pathological processes, including inflammation, neovasvularization and tumor development. Heparanase is the sole mammalian endoglycosidase that cleaves heparan sulfate. Extensively studied in cancer progression and aggressiveness, heparanase enzyme was recently implicated in several inflammatory disorders as well. Although the precise mode of heparanase action in inflammatory reactions is still not completely understood, the fact that heparanase activity is mechanistically important both in malignancy and in inflammation argues that this enzyme is a candidate molecule linking inflammation and tumorigenesis in inflammation-associated cancers. The elucidation of the specific effects of heparanase in cancer development, particularly when inflammation is a causal factor, will accelerate the development of novel therapeutic/chemopreventive interventions and help to better define target patient populations in which heparanase-targeting therapies could be particularly beneficial.
Pancreatic cancer is characterized by very low survival rates because of high intrinsic resistance to conventional therapies. Ionizing radiation (IR)-enhanced tumor invasiveness is emerging as one mechanism responsible for the limited benefit of radiotherapy in pancreatic cancer. In this study, we establish the role of heparanase-the only known mammalian endoglycosidase that cleaves heparan sulfate-in modulating the response of pancreatic cancer to radiotherapy. We found that clinically relevant doses of IR augment the invasive capability of pancreatic carcinoma cells in vitro and in vivo by upregulating heparanase. Changes in the levels of the transcription factor Egr-1 occurred in pancreatic cancer cells following radiation, underlying the stimulatory effect of IR on heparanase expression. Importantly, the specific heparanase inhibitor SST0001 abolished IR-enhanced invasiveness of pancreatic carcinoma cells in vitro, whereas combined treatment with SST0001 and IR, but not IR alone, attenuated the spread of orthotopic pancreatic tumors in vivo. Taken together, our results suggest that combining radiotherapy with heparanase inhibition is an effective strategy to prevent tumor resistance and dissemination, observed in many IR-treated pancreatic cancer patients.
Porphyromonas gingivalis is a member of the dysbiotic oral microbiome associated with oral inflammation and periodontal disease. Intriguingly, epidemiological studies link P. gingivalis to an increased risk of pancreatic cancer. Given that oral bacteria are detected in human pancreatic cancer, and both mouse and human pancreata harbor microbiota, we explored the involvement of P. gingivalis in pancreatic tumorigenesis using cell lines and a xenograft model. Live P. gingivalis induced proliferation of pancreatic cancer cells; however, surprisingly, this effect was independent of Toll-like receptor 2, the innate immune receptor that is engaged in response to P. gingivalis on other cancer and immune cells, and is required for P. gingivalis to induce alveolar bone resorption. Instead, we found that P. gingivalis survives inside pancreatic cancer cells, a trait that can be enhanced in vitro and is increased by hypoxia, a central characteristic of pancreatic cancer. Increased tumor cell proliferation was related to the degree of intracellular persistence, and infection of tumor cells with P. gingivalis led to enhanced growth in vivo. To the best of our knowledge, this study is the first to demonstrate the direct effect of exposure to P. gingivalis on the tumorigenic behavior of pancreatic cancer cell lines. Our findings shed light on potential mechanisms underlying the pancreatic cancer–periodontitis link.
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