The heparanase/syndecan‐1 axis in cancer: mechanisms and therapies

Ramani, Vishnu C.; Purushothaman, Anurag; Stewart, Mark; Thompson, Camilla A.; Vlodavsky, Israël; Au, Jessie L.-S.; Sanderson, Ralph D.

doi:10.1111/febs.12168

Cited by 163 publications

(198 citation statements)

References 119 publications

(136 reference statements)

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“…4D). Of note, CD138, which is highly expressed and released as a soluble molecule from MM cells, including SKO-007(J3) cells (35), was reduced in ADAM17-silenced cells, making evident the specific effect of ADAM10-silencing on MICB shedding (Fig. 4E).…”

Section: Adam10 Is Involved In Drug-induced Micb Release From MM Cellsmentioning

confidence: 93%

Genotoxic Stress Induces Senescence-Associated ADAM10-Dependent Release of NKG2D MIC Ligands in Multiple Myeloma Cells

Zingoni

Cecere

Vulpis

et al. 2015

The Journal of Immunology

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Genotoxic stress can promote antitumor NK cell responses by upregulating the surface expression of activating ligands on cancer cells. Moreover, a number of studies suggested a role for soluble NK group 2D ligands in the impairment of NK cell tumor recognition and killing. We investigated whether genotoxic stress could promote the release of NK group 2D ligands (MHC class I-related chain [MIC]A and MICB), as well as the molecular mechanisms underlying this event in human multiple myeloma (MM) cells. Our results show that genotoxic agents used in the therapy of MM (i.e., doxorubicin and melphalan) selectively affect the shedding of MIC molecules that are sensitive to proteolytic cleavage, whereas the release of the short MICA*008 allele, which is frequent in the white population, is not perturbed. In addition, we found that a disintegrin and metalloproteinase 10 expression is upregulated upon chemotherapeutic treatment both in patient-derived CD138(+)/CD38(+) plasma cells and in several MM cell lines, and we demonstrate a crucial role for this sheddase in the proteolytic cleavage of MIC by means of silencing and pharmacological inhibition. Interestingly, the drug-induced upregulation of a disintegrin and metalloproteinase 10 on MM cells is associated with a senescent phenotype and requires generation of reactive oxygen species. Moreover, the combined use of chemotherapeutic drugs and metalloproteinase inhibitors enhances NK cell-mediated recognition of MM cells, preserving MIC molecules on the cell surface and suggesting that targeting of metalloproteinases in conjunction with chemotherapy could be exploited for NK cell-based immunotherapeutic approaches, thus contributing to avoid the escape of malignant cells from stress-elicited immune responses

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Section: Adam10 Is Involved In Drug-induced Micb Release From MM Cellsmentioning

confidence: 93%

Genotoxic Stress Induces Senescence-Associated ADAM10-Dependent Release of NKG2D MIC Ligands in Multiple Myeloma Cells

Zingoni

Cecere

Vulpis

et al. 2015

The Journal of Immunology

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“…In most cases, however, it is unclear whether misexpressed syndecans are contributors or bystanders in tumour progression. However, in the case of myeloma, syndecan-1 expression has been causally related to tumour growth and malignancy [205]. In addition, there appears to be an important role for heparanase, an enzyme that cleaves heparan sulfate chains into oligosaccharides that may retain important biological functions [205].…”

Section: Syndecans and Cancermentioning

confidence: 99%

“…However, in the case of myeloma, syndecan-1 expression has been causally related to tumour growth and malignancy [205]. In addition, there appears to be an important role for heparanase, an enzyme that cleaves heparan sulfate chains into oligosaccharides that may retain important biological functions [205]. There are now several tumour types where heparanase is implicated in progression and an inhibitor is now in the early stages of clinical trials.…”

Section: Syndecans and Cancermentioning

confidence: 99%

Extracellular matrix component signaling in cancer

Multhaupt

Leitinger

Gullberg

et al. 2016

Advanced Drug Delivery Reviews

160

109

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“…Heparanase, an endoglycosidase that cleaves HS side chains and liberates the HSPG-bound GFs, is also active in regulation of HSPG shedding (Purushothaman et al, 2008;Ramani et al, 2013). We hypothesized that heparanase is involved in HPV release from primary attachment factors and, thus, regulates HPV infectivity.…”

Section: Heparanase and Mmps Affect Hpv16 Infectious Transfer From Thmentioning

confidence: 99%

Interaction of human papillomavirus type 16 particles with heparan sulfate and syndecan-1 molecules in the keratinocyte extracellular matrix plays an active role in infection

Surviladze

Sterkand

Ozbun

2015

Journal of General Virology

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Oncogenic human papillomaviruses (HPVs) attach predominantly to extracellular matrix (ECM) components during infection of cultured keratinocytes and in the rodent vaginal challenge model in vivo. However, the mechanism of virion transfer from the ECM to receptors that mediate entry into host cells has not been determined. In this work we strove to assess the role of heparan sulfate (HS) chains in HPV16 binding to the ECM and determine how HPV16 release from the ECM is regulated. We also assessed the extent to which capsids released from the ECM are infectious. We show that a large fraction of HPV16 particles binds to the ECM via HS chains, and that syndecan-1 (snd-1) molecules present in the ECM are involved in virus binding. Inhibiting the normal processing of snd-1 and HS molecules via matrix metalloproteinases and heparanase dramatically reduces virus release from the ECM, cellular uptake and infection. Conversely, exogenous heparinase activates each of these processes. We confirm that HPV16 released from the ECM is infectious in keratinocytes. Use of a specific inhibitor shows furin is not involved in HPV16 release from ECM attachment factors and corroborates other studies showing only the intracellular activity of furin is responsible for modulating HPV infectivity. These data suggest that our recently proposed model, describing the action of HS proteoglycan processing enzymes in releasing HPV16 from the cell surface in complex with the attachment factor snd-1, is also relevant to the release of HPV16 particles from the ECM to promote efficient infection of keratinocytes.

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The heparanase/syndecan‐1 axis in cancer: mechanisms and therapies

Cited by 163 publications

References 119 publications

Genotoxic Stress Induces Senescence-Associated ADAM10-Dependent Release of NKG2D MIC Ligands in Multiple Myeloma Cells

Genotoxic Stress Induces Senescence-Associated ADAM10-Dependent Release of NKG2D MIC Ligands in Multiple Myeloma Cells

Extracellular matrix component signaling in cancer

Interaction of human papillomavirus type 16 particles with heparan sulfate and syndecan-1 molecules in the keratinocyte extracellular matrix plays an active role in infection

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