A MCP1 fusokine with CCR2-specific tumoricidal activity

• Authors: Moutih Rafei, McGill University; Jiusheng Deng, Emory University; Marie-Noelle Boivin, McGill University; Patrick Williams, McGill University; Shannon M Matulis, Emory University; Shala Yuan, McGill University; Elena Birman, McGill University; Kathy Forner, McGill University; Liangping Yuan, Emory University; Robert Craig Castellino, Emory University; Lawrence Boise, Emory University; Tobey MacDonald, Emory University; Jacques Galipeau, Emory University
• Journal Title: Molecular Cancer
• Volume: Volume 10, Number 121
• Publisher: BioMed Central | 2011-09-24, Pages 1-11
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1186/1476-4598-10-121
• Subjects: Health Sciences, Oncology

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. Conclusion 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.