VEGF-C and VEGF-D blockade inhibits inflammatory skin carcinogenesis

Cancer Res. 2013 Jul 15;73(14):4212-21. doi: 10.1158/0008-5472.CAN-12-4539. Epub 2013 May 21.

Abstract

VEGF-C and VEGF-D were identified as lymphangiogenic growth factors and later shown to promote tumor metastasis, but their effects on carcinogenesis are poorly understood. Here, we have studied the effects of VEGF-C and VEGF-D on tumor development in the murine multistep chemical carcinogenesis model of squamous cell carcinoma by using a soluble VEGF-C/VEGF-D inhibitor. After topical treatment with a tumor initiator and repeated tumor promoter applications, transgenic mice expressing a soluble VEGF-C/VEGF-D receptor (sVEGFR-3) in the skin developed significantly fewer squamous cell tumors with a delayed onset when compared with wild-type mice or mice expressing sVEGFR-3 lacking the ligand-binding site. Epidermal proliferation was reduced in the carcinogen-treated transgenic skin, whereas epidermal keratinocyte proliferation in vitro was not affected by VEGF-C or VEGF-D, indicating indirect effects of sVEGFR-3 expression. Importantly, transgenic mouse skin was less sensitive to tumor promoter-induced inflammation, with reduced angiogenesis and blood vessel leakage. Cutaneous leukocytes, especially macrophages, were reduced in transgenic skin without major changes in macrophage polarization or blood monocyte numbers. Several macrophage-associated cytokines were also reduced in transgenic papillomas, although the dermal macrophages themselves did not express VEGFR-3. These findings indicate that VEGF-C/VEGF-D are involved in shaping the inflammatory tumor microenvironment that regulates early tumor progression. Our results support the use of VEGF-C/VEGF-D-blocking agents not only to inhibit metastatic progression, but also during the early stages of tumor growth.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinogenesis / chemically induced
  • Carcinogenesis / drug effects*
  • Carcinogenesis / metabolism
  • Carcinogens
  • Carcinoma, Squamous Cell / chemically induced
  • Carcinoma, Squamous Cell / drug therapy
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / pathology
  • Cell Proliferation / drug effects
  • Cytokines / metabolism
  • Epidermis / drug effects
  • Epidermis / metabolism
  • Epidermis / pathology
  • Female
  • Inflammation / drug therapy*
  • Inflammation / metabolism
  • Inflammation / pathology
  • Keratinocytes / drug effects
  • Keratinocytes / metabolism
  • Keratinocytes / pathology
  • Leukocytes / drug effects
  • Leukocytes / metabolism
  • Leukocytes / pathology
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Macrophages / pathology
  • Mice
  • Mice, Transgenic
  • Neovascularization, Pathologic / drug therapy
  • Neovascularization, Pathologic / metabolism
  • Neovascularization, Pathologic / pathology
  • Skin / drug effects*
  • Skin / metabolism
  • Skin / pathology
  • Skin Neoplasms / chemically induced
  • Skin Neoplasms / drug therapy*
  • Skin Neoplasms / metabolism
  • Skin Neoplasms / pathology
  • Vascular Endothelial Growth Factor C / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor C / metabolism
  • Vascular Endothelial Growth Factor D / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor D / metabolism
  • Vascular Endothelial Growth Factor Receptor-3 / metabolism

Substances

  • Carcinogens
  • Cytokines
  • Vascular Endothelial Growth Factor C
  • Vascular Endothelial Growth Factor D
  • vascular endothelial growth factor C, mouse
  • Vascular Endothelial Growth Factor Receptor-3