Direct evidence that bevacizumab, an anti-VEGF antibody, up-regulates SDF1alpha, CXCR4, CXCL6, and neuropilin 1 in tumors from patients with rectal cancer

Cancer Res. 2009 Oct 15;69(20):7905-10. doi: 10.1158/0008-5472.CAN-09-2099. Epub 2009 Oct 13.

Abstract

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 1alpha (SDF1alpha), 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 SDF1alpha 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / therapeutic use*
  • Antibodies, Monoclonal / therapeutic use*
  • Antibodies, Monoclonal, Humanized
  • Bevacizumab
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism
  • Chemokine CXCL12 / genetics*
  • Chemokine CXCL12 / metabolism
  • Chemokine CXCL6 / genetics*
  • Chemokine CXCL6 / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immunoenzyme Techniques
  • Liver Neoplasms / drug therapy
  • Liver Neoplasms / genetics
  • Liver Neoplasms / secondary
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics
  • Lung Neoplasms / secondary
  • Lymphatic Metastasis
  • Neovascularization, Pathologic / prevention & control
  • Neuropilin-1 / genetics*
  • Neuropilin-1 / metabolism
  • Oligonucleotide Array Sequence Analysis
  • Prognosis
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, CXCR4 / genetics*
  • Receptors, CXCR4 / metabolism
  • Rectal Neoplasms / drug therapy*
  • Rectal Neoplasms / genetics
  • Rectal Neoplasms / pathology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Up-Regulation
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • Angiogenesis Inhibitors
  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Biomarkers, Tumor
  • CXCL12 protein, human
  • CXCL6 protein, human
  • CXCR4 protein, human
  • Chemokine CXCL12
  • Chemokine CXCL6
  • RNA, Messenger
  • Receptors, CXCR4
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • Neuropilin-1
  • Bevacizumab