Heparanase: A Potential Therapeutic Target in Sarcomas

Cassinelli, Giuliana; Lanzi, Cinzia

doi:10.1007/978-3-030-34521-1_15

Cited by 3 publications

(8 citation statements)

References 132 publications

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“…Our findings supported the induction of EGR1 as a stress-related and tumor defensive mechanism also mediating pro-survival/ pro-metastatic signals. In fact, independently of EGR1 basal levels and kinetics of induction by HDACi, the transcription factor upregulation was associated with increased expression of heparanase, a pleiotropic player in tumorigenesis and disease progression [27][28][29][30][31][32]. In keeping with observations in other contexts [75,82], we demonstrated that heparanase, in turn, sustained EGR1 expression in a pathologic loop resembling networks/ circuits implicated in self-renewal, differentiation and developmental programs, and likely recruited by SS cells to promote escape from HDAC inhibition.…”

Section: Discussionsupporting

confidence: 81%

“…Heparanase has been shown to be an actionable target in various sarcoma models [28,29] and we have reported that both heparin derivatives and small molecule heparanase inhibitors produce a remarkable impact on SS cell malignant behavior in vitro and in vivo [37][38][39]60].…”

Section: Hdaci Cooperate With the Hs Mimetic/heparanase Inhibitor Sst0001 To Inhibit Ss Growthmentioning

confidence: 99%

“…the heparan sulfate (HS) chains of HS proteoglycans (HSPGs), in critical processes of the pathobiology of several tumor types including sarcomas (e.g. growth, angiogenesis, inflammation, metastasis, drug resistance) [27][28][29][30][31][32]. A deregulated heparanase/HSPG system profoundly impacts on tumor aggressiveness by acting both in the tumor microenvironment and inside the tumor cells.…”

Section: Introductionmentioning

confidence: 99%

“…A potential relationship between deregulated heparanase/HSPG axis and oncogenic players in the different sarcoma subtypes remains to be elucidated. Heparanase is expressed in SS cell lines and tumor specimens [36,37] and preclinical studies using HS mimetics and small molecule heparanase inhibitors have indicated heparanase and HSPGs as druggable targets in different types of sarcoma models including SS [29,[37][38][39][40].…”

Section: Introductionmentioning

confidence: 99%

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Upregulation of ERK-EGR1-heparanase axis by HDAC inhibitors provides targets for rational therapeutic intervention in synovial sarcoma

Lanzi

Favini

et al. 2021

J Exp Clin Cancer Res

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Background Synovial sarcoma (SS) is an aggressive soft tissue tumor with limited therapeutic options in advanced stage. SS18-SSX fusion oncogenes, which are the hallmarks of SS, cause epigenetic rewiring involving histone deacetylases (HDACs). Promising preclinical studies supporting HDAC targeting for SS treatment were not reflected in clinical trials with HDAC inhibitor (HDACi) monotherapies. We investigated pathways implicated in SS cell response to HDACi to identify vulnerabilities exploitable in combination treatments and improve the therapeutic efficacy of HDACi-based regimens. Methods Antiproliferative and proapoptotic effects of the HDACi SAHA and FK228 were examined in SS cell lines in parallel with biochemical and molecular analyses to bring out cytoprotective pathways. Treatments combining HDACi with drugs targeting HDACi-activated prosurvival pathways were tested in functional assays in vitro and in a SS orthotopic xenograft model. Molecular mechanisms underlying synergisms were investigated in SS cells through pharmacological and gene silencing approaches and validated by qRT-PCR and Western blotting. Results SS cell response to HDACi was consistently characterized by activation of a cytoprotective and auto-sustaining axis involving ERKs, EGR1, and the β-endoglycosidase heparanase, a well recognized pleiotropic player in tumorigenesis and disease progression. HDAC inhibition was shown to upregulate heparanase by inducing expression of the positive regulator EGR1 and by hampering negative regulation by p53 through its acetylation. Interception of HDACi-induced ERK-EGR1-heparanase pathway by cell co-treatment with a MEK inhibitor (trametinib) or a heparanase inhibitor (SST0001/roneparstat) enhanced antiproliferative and pro-apoptotic effects. HDAC and heparanase inhibitors had opposite effects on histone acetylation and nuclear heparanase levels. The combination of SAHA with SST0001 prevented the upregulation of ERK-EGR1-heparanase induced by the HDACi and promoted caspase-dependent cell death. In vivo, the combined treatment with SAHA and SST0001 potentiated the antitumor efficacy against the CME-1 orthotopic SS model as compared to single agent administration. Conclusions The present study provides preclinical rationale and mechanistic insights into drug combinatory strategies based on the use of ERK pathway and heparanase inhibitors to improve the efficacy of HDACi-based antitumor therapies in SS. The involvement of classes of agents already clinically available, or under clinical evaluation, indicates the transferability potential of the proposed approaches.

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Section: Discussionsupporting

confidence: 81%

Section: Hdaci Cooperate With the Hs Mimetic/heparanase Inhibitor Sst0001 To Inhibit Ss Growthmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Upregulation of ERK-EGR1-heparanase axis by HDAC inhibitors provides targets for rational therapeutic intervention in synovial sarcoma

Lanzi

Favini

et al. 2021

J Exp Clin Cancer Res

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“…Another enzyme playing an important role in accessing the blood circulation is heparanase, which cleaves HS polysaccharides located in the basement membrane and on the cancer cell surface, leading to increased invasive behavior of cancers (Sanderson et al, 2017;Masola et al, 2018;Elgundi et al, 2019). Several studies have provided evidence that heparanase plays a major role in progression of a variety of cancers including liver cancer (Koliopanos et al, 2001), sarcomas (Cassinelli and Lanzi, 2020), ovarian cancer (Zhang et al, 2013), breast cancer (Maxhimer et al, 2005), and colon cancer (Nobuhisa et al, 2005). In addition to this, it has recently been shown that overexpression of heparanase promotes the formation of cell clusters in MDA-MB-231 breast cancer cells, most likely by modulating the level of intercellular adhesion molecule 1 FIGURE 5 | CD44 is connected to several mechanisms of circulating tumor cell (CTC) survival and plasticity.…”

Section: Epithelial-to-mesenchymal Transition Migration and Intravamentioning

confidence: 99%

The Role of Proteoglycans in Cancer Metastasis and Circulating Tumor Cell Analysis

Ahrens

Bang-Christensen

Jørgensen³

et al. 2020

Front. Cell Dev. Biol.

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Circulating tumor cells (CTCs) are accessible by liquid biopsies via an easy blood draw. They represent not only the primary tumor site, but also potential metastatic lesions, and could thus be an attractive supplement for cancer diagnostics. However, the analysis of rare CTCs in billions of normal blood cells is still technically challenging and novel specific CTC markers are needed. The formation of metastasis is a complex process supported by numerous molecular alterations, and thus novel CTC markers might be found by focusing on this process. One example of this is specific changes in the cancer cell glycocalyx, which is a network on the cell surface composed of carbohydrate structures. Proteoglycans are important glycocalyx components and consist of a protein core and covalently attached long glycosaminoglycan chains. A few CTC assays have already utilized proteoglycans for both enrichment and analysis of CTCs. Nonetheless, the biological function of proteoglycans on clinical CTCs has not been studied in detail so far. Therefore, the present review describes proteoglycan functions during the metastatic cascade to highlight their importance to CTCs. We also outline current approaches for CTC assays based on targeting proteoglycans by their protein cores or their glycosaminoglycan chains. Lastly, we briefly discuss important technical aspects, which should be considered for studying proteoglycans.

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Radiation-Induced Nephropathy in the Murine Model Is Ameliorated by Targeting Heparanase

et al. 2023

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Agents used to reduce adverse effects common in cancer treatment modalities do not typically possess tumor-suppressing properties. We report that heparanase, an extracellular matrix-degrading enzyme, is a promising candidate for preventing radiation nephropathy. Heparanase promotes tumor development and progression and is upregulated in tumors found in the abdominal/pelvic cavity, whose radiation treatment may result in radiation nephropathy. Additionally, heparan sulfate degradation by heparanase has been linked to glomerular and tubular/interstitial injury in several kidney disorders. In this study, heparanase mRNA levels were measured in HK-2- and HEK-293-irradiated kidney cells and in a murine radiation nephropathy model by qRT-PCR. Roneparstat (specific heparanase inhibitor) was administered to irradiated mice, and 24 h urinary albumin was measured. Kidneys were harvested and weighed 30 weeks post-irradiation. Clinically relevant doses of ionizing radiation upregulated heparanase expression in both renal cells and mice kidneys. A murine model of abdominal radiation therapy revealed that Roneparstat abolished radiation-induced albuminuria—the hallmark of radiation nephropathy. Given the well-documented anti-cancer effects of heparanase inhibition, our findings attest this enzyme to be a unique target in cancer therapy due to its dual action. Targeting heparanase exerts not only direct anti-tumor effects but protects against radiation-induced kidney damage—the backbone of cancer therapy across a range of malignancies.

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Heparanase: A Potential Therapeutic Target in Sarcomas

Cited by 3 publications

References 132 publications

Upregulation of ERK-EGR1-heparanase axis by HDAC inhibitors provides targets for rational therapeutic intervention in synovial sarcoma

Upregulation of ERK-EGR1-heparanase axis by HDAC inhibitors provides targets for rational therapeutic intervention in synovial sarcoma

The Role of Proteoglycans in Cancer Metastasis and Circulating Tumor Cell Analysis

Radiation-Induced Nephropathy in the Murine Model Is Ameliorated by Targeting Heparanase

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