title: A MCP1 fusokine with CCR2-specific tumoricidal activity.
abstract: BACKGROUND
  The CCL2 chemokine is involved in promoting cancer angiogenesis, proliferation and metastasis by malignancies that express CCR2 receptor. Thus the CCL2/CCR2 axis is an attractive molecular target for anticancer drug development.
  
  
  METHODS
  We have generated a novel fusion protein using GMCSF and an N-terminal truncated version of MCP1/CCL2 (6-76) [hereafter GMME1] and investigated its utility as a CCR2-specific tumoricidal agent.
  
  
  RESULTS
  We found that distinct to full length CCL2 or its N-truncated derivative (CCL2 5-76), GMME1 bound to CCR2 on mouse lymphoma EG7, human multiple myeloma cell line U266, or murine and human medulloblastoma cell lines, and led to their death by apoptosis. We demonstrated that GMME1 specifically blocked CCR2-associated STAT3 phosphorylation and up-regulated pro-apoptotic BAX. Furthermore, GMME1 significantly inhibited EG7 tumor growth in C57BL/6 mice, and induced apoptosis of primary myeloma cells from patients.
  
  
  CONCLUSIONS
  Our data demonstrate that GMME1 is a fusokine with a potent, CCR2 receptor-mediated pro-apoptotic effect on tumor cells and could be exploited as a novel biological therapy for CCR2+ malignancies including lymphoid and central nervous system malignancies.
authors.affiliation: The Montreal Center for Experimental Therapeutics in Cancer, McGill University, Montreal, Canada.
authors.forename: Moutih
authors.initials: M
authors.lastname: Rafei
authors.forename: Jiusheng
authors.initials: J
authors.lastname: Deng
authors.forename: Marie-Noëlle
authors.initials: MN
authors.lastname: Boivin
authors.forename: Patrick
authors.initials: P
authors.lastname: Williams
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Matulis
authors.forename: Shala
authors.initials: S
authors.lastname: Yuan
authors.forename: Elena
authors.initials: E
authors.lastname: Birman
authors.forename: Kathy
authors.initials: K
authors.lastname: Forner
authors.forename: Liangping
authors.initials: L
authors.lastname: Yuan
authors.forename: Craig
authors.initials: C
authors.lastname: Castellino
authors.forename: Lawrence H
authors.initials: LH
authors.lastname: Boise
authors.forename: Tobey J
authors.initials: TJ
authors.lastname: MacDonald
authors.forename: Jacques
authors.initials: J
authors.lastname: Galipeau
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000235:genetics*; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics*; D006801:Humans; D008223:Lymphoma; D008527:Medulloblastoma; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D054390:Receptors, CCR2 / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: D015703:Antigens, CD; D000970:Antineoplastic Agents; C491768:Ccl2 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D054390:Receptors, CCR2; D011993:Recombinant Fusion Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor