Targeting heparanase for cancer therapy at the tumor–matrix interface

Sanderson, Ralph D.; Iozzo, Renato V.

doi:10.1016/j.matbio.2012.05.001

Cited by 25 publications

(22 citation statements)

References 9 publications

(11 reference statements)

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“…Fig. 1B, C), in agreement with the decisive role of heparanase in myeloma progression 38, 39 . Many of the pro-tumorigenic effects of heparanase in myeloma have been shown to relay upon increased expression and shedding of syndecan-1 38 .…”

Section: Discussionsupporting

confidence: 85%

Heparanase enhances myeloma progression via CXCL10 downregulation

Barash¹,

Zohar²,

Wildbaum³

et al. 2014

Leukemia

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In order to explore the mechanism(s) underlying the pro-tumorigenic capacity of heparanase we established an inducible Tet-on system. Heparanase expression was markedly increased following addition of doxycycline (Dox) to the culture medium of CAG human myeloma cells infected with the inducible heparanase gene construct, resulting in increased colony number and size in soft agar. Moreover, tumor xenografts produced by CAG-heparanase cells were markedly increased in mice supplemented with Dox in their drinking water compared with control mice maintained without Dox. Consistently, we found that heparanase induction is associated with decreased levels of CXCL10, suggesting that this chemokine exerts tumor suppressor properties in myeloma. Indeed, recombinant CXCL10 attenuated the proliferation of CAG, U266 and RPMI-8266 myeloma cells. Similarly, CXCL10 attenuated the proliferation of human umbilical vein endothelial cells (HUVEC), implying that CXCL10 exhibits anti-angiogenic capacity. Strikingly, development of tumor xenografts produced by CAG-heparanase cells over expressing CXCL10 was markedly reduced compared with control cells. Moreover, tumor growth was significantly attenuated in mice inoculated with human or mouse myeloma cells and treated with CXCL10-Ig fusion protein, indicating that CXCL10 functions as a potent anti-myeloma cytokine.

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Section: Discussionsupporting

confidence: 85%

Heparanase enhances myeloma progression via CXCL10 downregulation

Barash¹,

Zohar²,

Wildbaum³

et al. 2014

Leukemia

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“…Heparanase promotes myeloma growth, dissemination, and angiogenesis (53, 54), and heparanase inhibitor (Roneparstat = SST0001) is being tested in phase I clinical trial in myeloma patients. The aggressive phenotype exerted by heparanase in myeloma is largely attributed to increased syndecan-1 expression and shedding because this proteoglycan is considered critical determinant of myeloma cell survival and growth (55-57). Co-operation with Ras may provide another mechanism for the pro-tumorigenic function of heparanase in myeloma and possibly other hematological and solid malignancies carrying Ras mutation (58).…”

Section: Discussionmentioning

confidence: 99%

Heparanase Cooperates with Ras to Drive Breast and Skin Tumorigenesis

Boyango¹,

Barash²,

Naroditsky

et al. 2014

Cancer Research

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Heparanase has been implicated in cancer but its contribution to the early stages of cancer development is uncertain. In this study, we utilized non-transformed human MCF10A mammary epithelial cells and two genetic mouse models (Hpa-transgenic and knockout mice) to explore heparanase function at early stages of tumor development. Heparanase overexpression resulted in significantly enlarged asymmetrical acinar structures, indicating increased cell proliferation and decreased organization. This phenotype was enhanced by co-expression of heparanase variants with a mutant H-Ras gene, which was sufficient to enable growth of invasive carcinoma in vivo. These observations were extended in vivo by comparing the response of Hpa-transgenic (Hpa-Tg) mice to a classical two-stage DMBA/TPA protocol for skin carcinogenesis. Hpa-Tg mice overexpressing heparanase were far more sensitive than control mice to DMBA/TPA treatment, exhibiting a 10-fold increase in the number and size of tumor lesions. Conversely, DMBA/TPA-induced tumor formation was greatly attenuated in Hpa-KO mice lacking heparanase, pointing to a critical role of heparanase in skin tumorigenesis. In support of these observations, the heparanase inhibitor PG545 potently suppressed tumor progression in this model system. Taken together, our findings establish that heparanase exerts pro-tumorigenic properties at early stages of tumor initiation, co-operating with Ras to dramatically promote malignant development.

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“…A marked inhibition of tumor growth and dissemination was also exerted by heparanase neutralizing monoclonal antibodies in xenograft models of lymphoma and myeloma, emphasizing the significance of the enzymatic activity of heparanase in promoting tumorigenesis (Weissmann et al, 2016). In addition, both enzymatically active and inactive heparanase promotes signal transduction, including Akt, STAT, Src, Erk, HGF-, IGF- and EGF-receptor signaling (Barash et al, 2010; Ilan et al, 2006; Sanderson and Iozzo, 2012), highlighting the notion that non-enzymatic activities of heparanase play a significant role in heparanase-driven tumor progression (Fux et al, 2009a; Fux et al, 2009b). Moreover, heparanase induces the transcription of pro-angiogenic (i.e., VEGF-A, VEGF-C, COX-2, MMP-9), pro-thrombotic (i.e., tissue factor), pro-inflammatory (i.e., TNFα, IL-1, IL-6), pro-fibrotic (i.e., TGFβ), mitogenic (i.e., HGF), osteolyic (RANKL) and various other genes (Cohen-Kaplan et al, 2008b; Goodall et al, 2014; Ilan et al, 2006; Nadir et al, 2006; Parish et al, 2013; Purushothaman et al, 2008), thus significantly expanding its functional repertoire and mode of action in promoting aggressive tumor behavior (Barash et al, 2010; Ilan et al, 2006; Sanderson and Iozzo, 2012).…”

Section: Introduction/prefacementioning

confidence: 99%

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

Vlodavsky¹,

Singh²,

Boyango³

et al. 2016

Drug Resistance Updates

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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.

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Targeting heparanase for cancer therapy at the tumor–matrix interface

Cited by 25 publications

References 9 publications

Heparanase enhances myeloma progression via CXCL10 downregulation

Heparanase enhances myeloma progression via CXCL10 downregulation

Heparanase Cooperates with Ras to Drive Breast and Skin Tumorigenesis

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

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