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Direct Evidence that Bevacizumab, an Anti-VEGF Antibody, Up-regulates SDF1, CXCR4, CXCL6, and Neuropilin 1 in Tumors from Patients with Rectal Cancer

¹ Department of Radiation Oncology, ² Division of Gastroenterology, Departments of ³ Pathology, ⁴ Surgery, and ⁵ Hematology/Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; and Departments of ⁶ Radiation Oncology, ⁷ Gastroenterology, and ⁸ Pathology, Duke University Medical Center, Durham, North Carolina

Requests for reprints: Rakesh K. Jain, Massachusetts General Hospital, EL Steele Lab, 100 Blossom Street, Cox 734, Boston, MA 02114. Phone: 617-726-3914; Fax: 617-726-4172; E-mail: jain{at}steele.mgh.harvard.edu or Christopher G. Willett, Department of Radiation Oncology, Duke University Medical Center, Box 3085, Durham, North Carolina 27710. Phone: 919-668-5640; Fax: 919-668-7345; E-mail: christopher.willett{at}duke.edu.

Key Words: anti-VEGF • cancer • cytokines

Clinical studies converge on the observation that circulating cytokines are elevated in most cancer patients by anti–vascular endothelial growth factor (VEGF) therapy. However, the source of these molecules and their relevance in tumor escape remain unknown. We examined the gene expression profiles of cancer cells and tumor-associated macrophages in tumor biopsies before and 12 days after monotherapy with the anti-VEGF antibody bevacizumab in patients with rectal carcinoma. Bevacizumab up-regulated stromal cell–derived factor 1 (SDF1), its receptor CXCR4, and CXCL6, and down-regulated PlGF, Ang1, and Ang2 in cancer cells. In addition, bevacizumab decreased Ang1 and induced neuropilin 1 (NRP1) expression in tumor-associated macrophages. Higher SDF1 plasma levels during bevacizumab treatment significantly associated with distant metastasis at three years. These data show that VEGF blockade up-regulates inflammatory pathways and NRP1, which should be evaluated as potential targets for improving anti-VEGF therapy. [Cancer Res 2009;69(20):7905–10]