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

Abstract

Heparanase, the sole heparan sulfate degrading endoglycosidase, regulates multiple biological activities that enhance tumor growth, angiogenesis and metastasis. Heparanase expression is enhanced in almost all cancers examined including various carcinomas, sarcomas and hematological malignancies. Numerous clinical association studies have consistently demonstrated that upregulation of heparanase expression correlates with increased tumor size, tumor angiogenesis, enhanced metastasis and poor prognosis. In contrast, knockdown of heparanase or treatments of tumor-bearing mice with heparanase-inhibiting compounds, markedly attenuate tumor progression further underscoring the potential of anti-heparanase therapy for multiple types of cancer. Heparanase neutralizing monoclonal antibodies block myeloma and lymphoma tumor growth and dissemination; this is attributable to a combined effect on the tumor cells and/or cells of the tumor microenvironment. In fact, much of the impact of heparanase on tumor progression is related to its function in mediating tumor-host crosstalk, priming the tumor microenvironment to better support tumor growth, metastasis and chemoresistance. The repertoire of the physiopathological activities of heparanase is expanding. Specifically, heparanase regulates gene expression, activates cells of the innate immune system, promotes the formation of exosomes and autophagosomes, and stimulates signal transduction pathways via enzymatic and non-enzymatic activities. These effects dynamically impact multiple regulatory pathways that together drive inflammatory responses, tumor survival, growth, dissemination and drug resistance; but in the same time, may fulfill some normal functions associated, for example, with vesicular traffic, lysosomal-based secretion, stress response, and heparan sulfate turnover. Heparanase is upregulated in response to chemotherapy in cancer patients and the surviving cells acquire chemoresistance, attributed, at least in part, to autophagy. Consequently, heparanase inhibitors used in tandem with chemotherapeutic drugs overcome initial chemoresistance, providing a strong rationale for applying anti-heparanase therapy in combination with conventional anti-cancer drugs. Heparin-like compounds that inhibit heparanase activity are being evaluated in clinical trials for various types of cancer. Heparanase neutralizing monoclonal antibodies are being evaluated in pre-clinical studies, and heparanase-inhibiting small molecules are being developed based on the recently resolved crystal structure of the heparanase protein. Collectively, the emerging premise is that heparanase expressed by tumor cells, innate immune cells, activated endothelial cells as well as other cells of the tumor microenvironment is a master regulator of the aggressive phenotype of cancer, an important contributor to the poor outcome of cancer patients and a prime target for therapy.

The Role of Heparanase in the Pathogenesis of Acute Pancreatitis: A Potential Therapeutic Target

“…Heparanase activity is implicated in the regulation of various physiological and pathological processes 9–12 . Cleavage of HS by heparanase facilitates structural alterations of the ECM and thereby promotes cell invasion associated with inflammation, tumor metastasis and angiogenesis 10–14 .…”

Design, synthesis, and evaluation of heparan sulfate mimicking glycopolymers for inhibiting heparanase activity

“…1 This enzyme is regarded as a regulator of aggressive tumor behavior as recent clinical studies have demonstrated that raised heparanase levels correlated with increased tumor size, 1c amplified tumor angiogenesis, 1d enhanced metastasis, 1e and poor patient prognosis. 1f The enzyme cleaves GlcAβ1,4)GlcNS glycosidic bonds (Figure 1) of the HS chains releasing sequestered pools of HS oligosaccharide-binding growth factors for signaling activation to promote angiogenesis. 2 Cleavage of HS also degrades the structural integrity of the basement membrane and ECM, permitting malignant cells to enter the blood stream and metastasis.…”

“…8 In the crystal structure the ligand was bound inside a 10Å binding cleft with the GlcAβ1,4)GlcNS in the +1 and −1 subsites (Figure 1), 9 adjacent to the catalytic residues (Glu225 and Glu343). 1 This cleft is flanked by heparin-binding domains (HBD-1 and HBD-2). 8 Inhibitors of heparanase are anticancer therapeutics, with carbohydrate mimetics being advanced to clinical trials.…”

“…8 Inhibitors of heparanase are anticancer therapeutics, with carbohydrate mimetics being advanced to clinical trials. 1 …”

Microvessel Density as a Surrogate Prognostic Marker in Patients with Multiple Myeloma: A Meta-Analysis

“…Along with the establishment of high-dose therapy followed by autologous stem cell transplantation as a routine procedure, numerous drug therapies have emerged for the treatment of MM, including immunomodulating agents (namely thalidomide, lenalidomide, and pomalidomide), proteasome inhibitors (namely bortezomib and carfilzomib) and monoclonal antibodies, such as daratumumab (anti-CD38) [4,5,6]. These agents now form the basis of many current standard-of-care approaches for relapsed/refractory MM, while active research into new therapies may soon result in the rational use of treatments that target specifically angiogenesis [7,8]. …”