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Eotaxin-2 and Colorectal Cancer: A Potential Target for Immune Therapy

Authors' Affiliations: ¹ Cancer Research UK Department of Medical Oncology and ² Histology Unit, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, University of Manchester; and ³ Department of Surgery, North Manchester Healthcare NHS Trust, Manchester, United Kingdom

Requests for reprints: David E. Gilham, Cancer Research UK Department of Medical Oncology, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, University of Manchester, Wilmslow Road, Manchester M20 4BX, United Kingdom. Phone: 44-161-4463236; Fax: 44-161-4463269; E-mail: DGilham{at}picr.man.ac.uk.

Purpose: To study the production of chemokines by colorectal hepatic metastases.

Experimental Design: Biopsies of resected colorectal hepatic metastases and nonneoplastic adjacent liver tissue were screened for chemokines using protein arrays and results were confirmed by ELISA and immunohistochemistry.

Results: Two chemokines, eotaxin-2 and MCP-1, were found at elevated levels within the tumor biopsy compared with adjacent liver. The relative increase in expression from tumor was much higher for eotaxin-2 than MCP-1, with 10 of 25 donors having a >100-fold increase in expression compared with 0 of 24 donors for MCP-1. In a parallel analysis, eotaxin-2 was also found at elevated levels in the tumor region of primary colorectal cancer biopsies. Immunohistochemical staining indicated that carcinoembryonic antigen–positive tumor cells stained strongly for eotaxin-2, implicating these cells as the predominant source of the chemokine. In vitro studies confirmed that several colorectal tumor lines produce eotaxin-2 and that secretion of this chemokine could be depressed by IFN- and enhanced by the Th2-type cytokines interleukin-4 and interleukin-13. Jurkat T cells were engineered to express the receptor for eotaxin-2 (CCR3). These cells effectively migrated in response to eotaxin-2 protein, suggesting that immune cells gene modified to express a chemokine receptor may have improved abilities to home to tumor.

Conclusions: Taken together, these observations confirm eotaxin-2 as a chemokine strongly associated with primary and metastatic tumors of colorectal origin. Furthermore, the importance of this result may be a useful tool in the development of targeted therapeutic approaches to colorectal tumors.