Open Access Research

A MCP1 fusokine with CCR2-specific tumoricidal activity

Moutih Rafei12, Jiusheng Deng3, Marie-Noëlle Boivin1, Patrick Williams1, Shannon M Matulis3, Shala Yuan13, Elena Birman1, Kathy Forner1, Liangping Yuan4, Craig Castellino4, Lawrence H Boise3, Tobey J MacDonald4 and Jacques Galipeau134*

Author Affiliations

1 The Montreal Center for Experimental Therapeutics in Cancer, McGill University, Montreal, Canada

2 The Institute for Research in Immunology and Cancer, Montreal University, Montreal, Canada

3 Department of Hematology and Oncology, Emory University, 1365B Clifton Road, Clinic B, Atlanta, GA 30322, USA

4 Department of Pediatrics, Winship Cancer Institute, Emory University, 1365B Clifton Road, Atlanta, GA, 30322, USA

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Molecular Cancer 2011, 10:121  doi:10.1186/1476-4598-10-121

Published: 24 September 2011

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.