The PTEN/PI3K pathway governs normal vascular development and tumor angiogenesis

  1. Koichi Hamada1,
  2. Takehiko Sasaki2,
  3. Pandelakis A. Koni4,
  4. Miyuki Natsui1,
  5. Hiroyuki Kishimoto1,
  6. Junko Sasaki1,2,
  7. Nobuyuki Yajima1,
  8. Yasuo Horie1,3,
  9. Go Hasegawa5,
  10. Makoto Naito5,
  11. Jun-ichi Miyazaki6,
  12. Toshio Suda7,
  13. Hiroshi Itoh8,
  14. Kazuwa Nakao8,
  15. Tak Wah Mak9,11,
  16. Toru Nakano10,11, and
  17. Akira Suzuki1,11,12
  1. 1Department of Molecular Biology, 2Department of Microbiology, 3Department of Gastroenterology, Akita University School of Medicine, Akita 010-8543, Japan; 4Molecular Immunology Program, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, Georgia 30912, USA; 5Department of Cellular Function, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan; 6Division of Stem Cell Regulation Research, Osaka University Graduate School of Medicine, Suita 565-0871, Japan; 7Department of Cell Differentiation, The Sakaguchi Laboratory, School of Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan; 8Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan; 9The Campbell Family Institute of Breast Cancer Research, and Departments of Immunology and Medical Biophysics, University of Toronto, Toronto M5G 2C1, Ontario, Canada; 10Department of Pathology, Medical School and Graduate School of Frontier Biosciences, Osaka University, Suita 565-0871, Japan

Abstract

PTEN is an important tumor suppressor gene. Hereditary mutation of PTEN causes tumor-susceptibility diseases such as Cowden disease. We used the Cre-loxP system to generate an endothelial cell-specific mutation of Pten (Tie2CrePten) in mice. Tie2CrePtenflox/+ mice displayed enhanced tumorigenesis due to an increase in angiogenesis driven by vascular growth factors. This effect was partially dependent on the PI3K subunits p85α and p110γ. In vitro, Tie2CrePtenflox/+ endothelial cells showed enhanced proliferation/migration. Tie2CrePtenflox/flox mice died before embryonic day 11.5 (E11.5) due to bleeding and cardiac failure caused by impaired recruitment of pericytes and vascular smooth muscle cells to blood vessels, and of cardiomyocytes to the endocardium. These phenotypes depend strongly on p110γ rather than on p85α and were associated with decreased expression of Ang-1, VCAM-1, connexin 40, and ephrinB2 but increased expression of Ang-2, VEGF-A, VEGFR1, and VEGFR2. Pten is thus indispensable for normal cardiovascular morphogenesis and post-natal angiogenesis, including tumor angiogenesis.

Keywords

Footnotes

  • Supplemental material is available at http://www.genesdev.org.

  • Article published online ahead of print. Article and publication date are at http://www.genesdev.org/cgi/doi/10.1101/gad.1308805.

  • 11 These authors contributed equally to this work.

  • 12 Corresponding author.

    12 E-MAIL suzuki{at}med.akita-u.ac.jp; FAX 81-18-884-6077.

    • Accepted June 27, 2005.
    • Received February 22, 2005.
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