title: Latent heparanase facilitates VLA-4-mediated melanoma cell binding and emerges as a relevant target of heparin in the interference with metastatic progression.
abstract: Heparanase is an endo-β-glucuronidase that enzymatically cleaves heparan sulfates (HS) and heparan sulfate proteoglycan (HSPG) structures. Heparanase expression levels by tumors were correlated with cell invasion, angiogenic activity, and poor prognosis. Heparanase can also possess pro-tumorigenic effects independent of its enzymatic activity. Using human melanoma MV3 cells, we demonstrate that latent heparanase activates in a tightly temporary-regulated manner the binding function of the integrin very late antigen-4 (VLA-4), an important component in the metastatic spread of melanoma cells. shRNA-mediated knockdown of syndecan-4 (SDC-4) indicated that this proteoglycan is the key element to convey heparanase binding via focal adhesion complex formation, detected by vinculin staining, to an upregulated VLA-4 binding function. This inside-out signaling pathway of VLA-4 involved activated FAK and Akt, but apparently not PKCα/δ. VLA-4, however, appears representative of other integrins which together impact the heparanase/integrin activation axis in tumorigenicity. Biosensor measurements provided an insight as to how heparin can interfere with this activation process. While low-molecular-weight heparin (LMWH) cannot replace heparanase bound to SDC-4, LMWH can compete with SDC-4 binding of heparanase. Since blockade of heparanase by LMWH has functional consequences for reduced VLA-4 binding, latent heparanase appears as a novel, so far unnoticed target of heparin, underlying its antimetastatic activity.
authors: Department of Pharmacy, Rheinische Friedrich-Wilhelms-University Bonn, Bonn, Germany.
authors: Ursula
authors: U
authors: Gerber
authors: Department of Pharmacy, Rheinische Friedrich-Wilhelms-University Bonn, Bonn, Germany.
authors: Sebastian G
authors: SG
authors: Hoß
authors: Cancer and Vascular Biology Research Center, Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors: Anna
authors: A
authors: Shteingauz
authors: Center of Surgery, Research Laboratory, Frankfurt University Hospital, Frankfurt am Main, Germany.
authors: Eva
authors: E
authors: Jüngel
authors: Department of Pharmacy, Rheinische Friedrich-Wilhelms-University Bonn, Bonn, Germany.
authors: Bastian
authors: B
authors: Jakubzig
authors: Cancer and Vascular Biology Research Center, Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors: Neta
authors: N
authors: Ilan
authors: Center of Surgery, Research Laboratory, Frankfurt University Hospital, Frankfurt am Main, Germany.
authors: Roman
authors: R
authors: Blaheta
authors: Department of Pharmacy, Rheinische Friedrich-Wilhelms-University Bonn, Bonn, Germany.
authors: Martin
authors: M
authors: Schlesinger
authors: Cancer and Vascular Biology Research Center, Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors: Israel
authors: I
authors: Vlodavsky
authors: Department of Pharmacy, Rheinische Friedrich-Wilhelms-University Bonn, Bonn, Germany.
authors: Gerd
authors: G
authors: Bendas
mesh_terms: D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D019763:Heparin Lyase / Q000235:genetics / Q000378:metabolism*; D006495:Heparin, Low-Molecular-Weight / Q000494:pharmacology*; D006801:Humans; D039041:Integrin alpha4beta1 / Q000235:genetics / Q000378:metabolism*; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D006495:Heparin, Low-Molecular-Weight; D039041:Integrin alpha4beta1; D009363:Neoplasm Proteins; D019763:Heparin Lyase