title: A HGF/cMET autocrine loop is operative in multiple myeloma bone marrow endothelial cells and may represent a novel therapeutic target.
abstract: OBJECTIVE
  The aim of this study was to investigate the angiogenic role of the hepatocyte growth factor (HGF)/cMET pathway and its inhibition in bone marrow endothelial cells (EC) from patients with multiple myeloma versus from patients with monoclonal gammopathy of undetermined significance (MGUS) or benign anemia (control group).
  
  
  METHODS
  The HGF/cMET pathway was evaluated in ECs from patients with multiple myeloma (multiple myeloma ECs) at diagnosis, at relapse after bortezomib- or lenalidomide-based therapies, or on refractory phase to these drugs; in ECs from patients with MGUS (MGECs); and in those patients from the control group. The effects of a selective cMET tyrosine kinase inhibitor (SU11274) on multiple myeloma ECs' angiogenic activities were studied in vitro and in vivo.
  
  
  RESULTS
  Multiple myeloma ECs express more HGF, cMET, and activated cMET (phospho (p)-cMET) at both RNA and protein levels versus MGECs and control ECs. Multiple myeloma ECs are able to maintain the HGF/cMET pathway activation in absence of external stimulation, whereas treatment with anti-HGF and anti-cMET neutralizing antibodies (Ab) is able to inhibit cMET activation. The cMET pathway regulates several multiple myeloma EC activities, including chemotaxis, motility, adhesion, spreading, and whole angiogenesis. Its inhibition by SU11274 impairs these activities in a statistically significant fashion when combined with bortezomib or lenalidomide, both in vitro and in vivo.
  
  
  CONCLUSIONS
  An autocrine HGF/cMET loop sustains multiple myeloma angiogenesis and represents an appealing new target to potentiate the antiangiogenic management of patients with multiple myeloma.
authors.affiliation: Internal Medicine Unit, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy.
authors.forename: Arianna
authors.initials: A
authors.lastname: Ferrucci
authors.affiliation: Internal Medicine Unit, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Moschetta
authors.affiliation: General Pathology Unit, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy.
authors.forename: Maria Antonia
authors.initials: MA
authors.lastname: Frassanito
authors.affiliation: Internal Medicine Unit, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Berardi
authors.affiliation: Internal Medicine Unit, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy.
authors.forename: Ivana
authors.initials: I
authors.lastname: Catacchio
authors.affiliation: Internal Medicine Unit, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Ria
authors.affiliation: Internal Medicine Unit, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy.
authors.forename: Vito
authors.initials: V
authors.lastname: Racanelli
authors.affiliation: Laboratory of Pre-Clinical and Translational Research, IRCCS-CROB, Rionero in Vulture, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Caivano
authors.affiliation: Internal Medicine Unit, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy.
authors.forename: Antonio Giovanni
authors.initials: AG
authors.lastname: Solimando
authors.affiliation: Laboratory of General Physiology, Department of Biological and Environmental Sciences and Technologies, University of Salento, Lecce, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Vergara
authors.affiliation: Laboratory of General Physiology, Department of Biological and Environmental Sciences and Technologies, University of Salento, Lecce, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Maffia
authors.affiliation: Laboratory of General Physiology, Department of Biological and Environmental Sciences and Technologies, University of Salento, Lecce, Italy.
authors.forename: Dominga
authors.initials: D
authors.lastname: Latorre
authors.affiliation: Laboratory of General Physiology, Department of Biological and Environmental Sciences and Technologies, University of Salento, Lecce, Italy.
authors.forename: Antonia
authors.initials: A
authors.lastname: Rizzello
authors.affiliation: Pathological Anatomy Unit, Di Venere Hospital, Bari, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Zito
authors.affiliation: Hematology Unit, Di Venere Hospital, Bari, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Ditonno
authors.affiliation: Pathological Anatomy Unit, University of Bari Medical School, Bari, Italy.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Maiorano
authors.affiliation: Section of Human Anatomy and Histology, Department of Basic Medical Sciences, Neurosciences, and Sensory Organs, University of Bari Medical School, and National Cancer Institute "Giovanni Paolo II", Bari, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Ribatti
authors.affiliation: Internal Medicine Unit, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy. angelo.vacca@uniba.it.
authors.forename: Angelo
authors.initials: A
authors.lastname: Vacca
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D019898:Autocrine Communication; D001854:Bone Marrow Cells / Q000378:metabolism*; D002465:Cell Movement; D016207:Cytokines / Q000096:biosynthesis; D042783:Endothelial Cells / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D008998:Monoclonal Gammopathy of Undetermined Significance / Q000235:genetics / Q000378:metabolism; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D020543:Proteome; D040901:Proteomics; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: C478479:((3Z)-N-(3-chlorophenyl)-3-((3,5-dimethyl-4-((4-methylpiperazin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-N-methyl-2-oxo-2,3-dihydro-1H-indole-5-sulfonamide); D020533:Angiogenesis Inhibitors; D016207:Cytokines; D007211:Indoles; D010879:Piperazines; D020543:Proteome; D013449:Sulfonamides; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met