title: Chemotherapy stimulates syndecan-1 shedding: a potentially negative effect of treatment that may promote tumor relapse.
abstract: In patients with multiple myeloma, the heparan sulfate proteoglycan syndecan-1 (CD138) is shed from the surface of tumor cells and accumulates in the serum and within the extracellular matrix of the bone marrow where it promotes tumor growth and metastasis. In the present study we discovered that commonly used anti-myeloma drugs stimulate syndecan-1 shedding both in vitro and in animals bearing myeloma tumors. Enhanced shedding is accompanied by increased syndecan-1 synthesis prior to drug induced tumor cell death. Addition of a caspase inhibitor blocks the drug-induced shedding of syndecan-1 in vitro indicating that shedding is linked to the onset of apoptosis. ADAM inhibitors or siRNA targeting ADAMs blocked drug-induced shedding suggesting that upregulation or activation of ADAMs is responsible for cleaving syndecan-1 from the tumor cell surface. These results reveal that myeloma chemotherapy stimulates synthesis and shedding of syndecan-1, a potentially negative side effect that may lead to the accumulation of high levels of syndecan-1 to establish a microenvironment that nurtures relapse and promotes tumor progression. Interestingly, we also found that chemotherapeutic drugs stimulated syndecan-1 shedding from pancreatic cancer cells as well, indicating that drug-induced shedding of syndecan-1 may occur in many cancer types. Overall, our results indicate that the use of metalloproteinase inhibitors (to inhibit syndecan-1 shedding) in combination with chemotherapy may represent a novel therapeutic strategy to prevent re-establishment of a microenvironment conducive for tumor relapse.
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Vishnu C
authors.initials: VC
authors.lastname: Ramani
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA; Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address: sanderson@uab.edu.
authors.forename: Ralph D
authors.initials: RD
authors.lastname: Sanderson
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000378:metabolism; D015153:Blotting, Western; D001853:Bone Marrow / Q000378:metabolism*; D061945:Caspase Inhibitors / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D061965:Matrix Metalloproteinase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction; D012008:Recurrence; D053668:Syndecan-1 / Q000096:biosynthesis / Q000097:blood / Q000378:metabolism*; D013778:Tetrazolium Salts; D013844:Thiazoles; D059016:Tumor Microenvironment / Q000502:physiology*
chemical_list: D000970:Antineoplastic Agents; D061945:Caspase Inhibitors; D017931:DNA Primers; D061965:Matrix Metalloproteinase Inhibitors; C508241:SDC1 protein, human; D053668:Syndecan-1; D013778:Tetrazolium Salts; D013844:Thiazoles; D051722:ADAM Proteins; C022616:thiazolyl blue
keywords: Batimastat; Chemotherapy; Hepatocyte growth factor; Multiple myeloma; Shed syndecan-1; Shedding