The Wilms' tumour suppressor Wt1 is a major regulator of tumour angiogenesis and progression

Nat Commun. 2014 Dec 16:5:5852. doi: 10.1038/ncomms6852.

Abstract

Angiogenesis, activation of metastasis and avoidance of immune destruction are important for cancer progression. These biological capabilities are, apart from cancer cells, mediated by different cell types, including endothelial, haematopoietic progenitor and myeloid-derived suppressor cells. We show here that all these cell types frequently express the Wilms' tumour suppressor Wt1, which transcriptionally controls expression of Pecam-1 (CD31) and c-kit (CD117). Inducible conditional knockout of Wt1 in endothelial, haematopoietic and myeloid-derived suppressor cells is sufficient to cause regression of tumour vascularization and an enhanced immune response, leading to decreased metastasis, regression of established tumours and enhanced survival. Thus, Wt1 is an important regulator of cancer growth via modulation of tumour vascularization, immune response and metastasis formation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Progression
  • Endothelial Cells / immunology
  • Endothelial Cells / pathology
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Gene Knockout Techniques
  • Hematopoietic Stem Cells / immunology
  • Hematopoietic Stem Cells / pathology
  • Humans
  • Immunity, Innate
  • Melanoma, Experimental / blood supply
  • Melanoma, Experimental / genetics*
  • Melanoma, Experimental / immunology
  • Melanoma, Experimental / mortality
  • Mice
  • Mice, Transgenic
  • Myeloid Cells / immunology
  • Myeloid Cells / pathology
  • Neoplasm Transplantation
  • Neovascularization, Pathologic / genetics*
  • Neovascularization, Pathologic / immunology
  • Neovascularization, Pathologic / pathology
  • Platelet Endothelial Cell Adhesion Molecule-1 / genetics
  • Platelet Endothelial Cell Adhesion Molecule-1 / immunology
  • Proto-Oncogene Proteins c-kit / genetics
  • Proto-Oncogene Proteins c-kit / immunology
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Signal Transduction
  • Skin Neoplasms / blood supply
  • Skin Neoplasms / genetics*
  • Skin Neoplasms / immunology
  • Skin Neoplasms / mortality
  • Survival Analysis
  • Tumor Burden
  • Tumor Cells, Cultured
  • WT1 Proteins / antagonists & inhibitors
  • WT1 Proteins / genetics*
  • WT1 Proteins / immunology

Substances

  • Platelet Endothelial Cell Adhesion Molecule-1
  • RNA, Small Interfering
  • WT1 Proteins
  • Proto-Oncogene Proteins c-kit