Chemotrap-1: An Engineered Soluble Receptor That Blocks Chemokine-Induced Migration of Metastatic Cancer CellsIn vivo
Open Access
- 13 October 2010
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 70 (20), 8138-8148
- https://doi.org/10.1158/0008-5472.can-10-0175
Abstract
Cancer and dendritic cells recognize and migrate toward chemokines secreted from lymphatics and use this mechanism to invade the lymphatic system, and cancer cells metastasize through it. The lymphatic-secreted chemokine ligand CCL21 has been identified as a key regulatory molecule in the switch to a metastatic phenotype in melanoma and breast cancer cells. However, it is not known whether CCL21 inhibition is a potential therapeutic strategy for inhibition of metastasis. Here, we describe an engineered CCL21-soluble inhibitor, Chemotrap-1, which inhibits migration of metastatic melanoma cells in vivo. Two-hybrid, pull-down, and coimmunoprecipitation assays allowed us to identify a naturally occurring human zinc finger protein with CCL21 chemokine-binding properties. Further analyses revealed a short peptide (∼70 amino acids), with a predicted coiled-coil structure, which is sufficient for association with CCL21. This CCL21 chemokine-binding peptide was then fused to the Fc region of human IgG1 to generate Chemotrap-1, a human chemokine-binding Fc fusion protein. Surface plasmon resonance and chemotaxis assays showed that Chemotrap-1 binds CCL21 and inhibits CCL21-induced migration of melanoma cells in vitro with subnanomolar affinity. In addition, Chemotrap-1 blocked migration of melanoma cells toward lymphatic endothelial cells in vitro and in vivo. Finally, Chemotrap-1 strongly reduced lymphatic invasion, tracking, and metastasis of CCR7-expressing melanoma cells in vivo. Together, these results show that CCL21 chemokine inhibition by Chemotrap-1 is a potential therapeutic strategy for metastasis and provide further support for the hypothesis that lymphatic-mediated metastasis is a chemokine-dependent process. Cancer Res; 70(20); 8138–48. ©2010 AACR.Keywords
This publication has 28 references indexed in Scilit:
- High CCR7 mRNA expression of cancer cells is associated with lymph node involvement in patients with esophageal squamous cell carcinomaInternational Journal of Oncology, 2009
- Chemokine-mediated migration of melanoma cells towards lymphatics – a mechanism contributing to metastasisOncogene, 2006
- Expression and function of the chemokine receptor CCR7 in thyroid carcinomasJournal of Endocrinology, 2006
- CCL21 Chemokine Regulates Chemokine Receptor CCR7 Bearing Malignant Melanoma CellsClinical Cancer Research, 2004
- Expression Pattern of Chemokine Receptor 6 (CCR6) and CCR7 in Squamous Cell Carcinoma of the Head and Neck Identifies a Novel Metastatic PhenotypeCancer Research, 2004
- THAP1 is a nuclear proapoptotic factor that links prostate-apoptosis-response-4 (Par-4) to PML nuclear bodiesOncogene, 2003
- Disruption of CCL21-Induced Chemotaxis In Vitro and In Vivo by M3, a Chemokine-Binding Protein Encoded by Murine Gammaherpesvirus 68Journal of Virology, 2003
- Coiled coils: a highly versatile protein folding motifTrends in Cell Biology, 2001
- MultiCoil: A program for predicting two‐and three‐stranded coiled coilsProtein Science, 1997
- Recognition by Elam-1 of the Sialyl-Le x Determinant on Myeloid and Tumor CellsScience, 1990