title: VEGF-C-VEGFR3/Flt4 axis regulates mammary tumor growth and metastasis in an autocrine manner.
abstract: OBJECTIVE
  Lymphangiogenic factors, such as vascular endothelial growth factor-C (VEGF-C) and VEGFC-D, and their receptor, VEGF receptor-3 (VEGFR3), play a pivotal role in the promotion of metastasis to regional lymph nodes. In the present study we explored the role of VEGF-C as an autocrine growth factor for breast cancer cells.
  
  
  METHODS
  We examined the expression of VEGF-C and VEGFR3 in mammary tumor cells lines and examined whether blocking the VEGF-C-VEGFR3/Flt4 pathway using a VEGFR3 antagonist would inhibit proliferation of mammary tumor cells resulting in a decrease in tumor growth and metastasis.
  
  
  RESULTS
  We report expression of VEGF-C and its receptor VEGFR3 by mammary tumor cells, and their association with aggressiveness. Inhibition of VEGF-C-VEGFR3/Flt4 in mammary tumor cells decreased their proliferation and survival. Mammary tumor bearing mice treated with a VEGFR3 antagonist showed a significant decrease in tumor growth and the extent of spontaneous and experimental lung metastases.
  
  
  CONCLUSIONS
  These findings demonstrate the VEGF-C-VEGFR3/Flt4 autocrine signaling pathway regulates mammary tumor cell survival and proliferation and that neutralization of VEGFR3 signaling might lead to development of a novel therapeutic approach for malignant breast cancer.
authors.affiliation: Department of Pathology and Microbiology, The University of Nebraska Medical Center, 985900 Nebraska Medical Center Omaha, NE 68198-5900.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Varney
authors.affiliation: Department of Pathology and Microbiology, The University of Nebraska Medical Center, 985900 Nebraska Medical Center Omaha, NE 68198-5900.
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Singh
keywords: Breast cancer; lymphangiogenesis; metastasis; vascular endothelial growth factor receptor-3; vascular endothelial growth factor-C