PTEN controls tumor-induced angiogenesis

Mutations of the tumor suppressor PTEN, a phosphatase with specificity for 3-phosphorylated inositol phospholipids, accompany progression of brain tumors from benign to the most malignant forms. Tumor progression, particularly in aggressive and malignant tumors, is associated with the induction of angiogenesis, a process termed the angiogenic switch. Therefore, we tested whether PTEN regulates tumor progression by modulating angiogenesis. U87MG glioma cells stably reconstituted with PTEN cDNA were tested for growth in a nude mouse orthotopic brain tumor model. We observed that the reconstitution of wild-type PTEN had no effect on in vitro proliferation but dramatically decreased tumor growth in vivo and prolonged survival in mice implanted intracranially with these tumor cells. PTEN reconstitution diminished phosphorylation of AKT within the PTEN-reconstituted tumor, induced thrombospondin 1 expression, and suppressed angiogenic activity. These effects were not observed in tumors reconstituted with a lipid phosphatase inactive G129E mutant of PTEN, a result that provides evidence that the lipid phosphatase activity of PTEN regulates the angiogenic response in vivo. These data provide evidence that PTEN regulates tumor-induced angiogenesis and the progression of gliomas to a malignant phenotype via the regulation of phosphoinositide-dependent signals.

[1]  P. Bartel,et al.  Threonine phosphorylation of the MMAC1/PTEN PDZ binding domain both inhibits and stimulates PDZ binding. , 2000, Cancer research.

[2]  O. Volpert,et al.  Three distinct D-amino acid substitutions confer potent antiangiogenic activity on an inactive peptide derived from a thrombospondin-1 type 1 repeat. , 1999, Molecular pharmacology.

[3]  Carlos Cordon-Cardo,et al.  Pten is essential for embryonic development and tumour suppression , 1998, Nature Genetics.

[4]  Erwin G. Van Meir,et al.  Somatic deletion mapping on chromosome 10 and sequence analysis of PTEN/MMAC1 point to the 10q25-26 region as the primary target in low-grade and high-grade gliomas , 1998, Oncogene.

[5]  Hong Sun,et al.  PTEN/MMAC1/TEP1 suppresses the tumorigenicity and induces G1 cell cycle arrest in human glioblastoma cells. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[6]  D. Hanahan,et al.  Patterns and Emerging Mechanisms of the Angiogenic Switch during Tumorigenesis , 1996, Cell.

[7]  Eric C. Holland,et al.  Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice , 2000, Nature Genetics.

[8]  A. Koong,et al.  Loss of PTEN facilitates HIF-1-mediated gene expression. , 2000, Genes & development.

[9]  I. W. Cheney,et al.  Suppression of tumorigenicity of glioblastoma cells by adenovirus-mediated MMAC1/PTEN gene transfer. , 1998, Cancer research.

[10]  M. Ittmann,et al.  Inactivation of the PTEN tumor suppressor gene is associated with increased angiogenesis in clinically localized prostate carcinoma. , 1999, Human pathology.

[11]  T. Hunter,et al.  Protein kinases and phosphatases: The Yin and Yang of protein phosphorylation and signaling , 1995, Cell.

[12]  David W. Dawson,et al.  CD36 Mediates the In Vitro Inhibitory Effects of Thrombospondin-1 on Endothelial Cells , 1997, The Journal of cell biology.

[13]  J. Dixon,et al.  PTEN: a tumour suppressor that functions as a phospholipid phosphatase. , 1999, Trends in cell biology.

[14]  N. Sheibani.  Thrombospondin‐1, PECAM‐1, and Regulation of Angiogenesis , 2006, Histology and histopathology.

[15]  R. Hynes,et al.  Thrombospondin-1 is required for normal murine pulmonary homeostasis and its absence causes pneumonia. , 1998, The Journal of clinical investigation.

[16]  C. James,et al.  Analysis of oncogene and tumor suppressor gene alterations in pediatric malignant astrocytomas reveals reduced survival for patients with PTEN mutations. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[17]  C. Sawyers,et al.  The PTEN/MMAC1 tumor suppressor phosphatase functions as a negative regulator of the phosphoinositide 3-kinase/Akt pathway. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[18]  J. Folkman,et al.  Tumor angiogenesis: a quantitative method for histologic grading. , 1972, Journal of the National Cancer Institute.

[19]  R. Evans,et al.  Ecdysone-inducible gene expression in mammalian cells and transgenic mice. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[20]  W. Sellers,et al.  Regulation of G1 progression by the PTEN tumor suppressor protein is linked to inhibition of the phosphatidylinositol 3-kinase/Akt pathway. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[21]  J. Folkman,et al.  Tumor angiogenesis and metastasis--correlation in invasive breast carcinoma. , 1991, The New England journal of medicine.

[22]  G. Semenza,et al.  Modulation of hypoxia-inducible factor 1alpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. , 2000, Cancer research.

[23]  T. Mikkelsen,et al.  Inhibition of angiogenesis in human glioblastomas by chromosome 10 induction of thrombospondin-1. , 1996, Cancer research.

[24]  M. Myers,et al.  PTEN: sometimes taking it off can be better than putting it on. , 1997, American journal of human genetics.

[25]  W. Cavenee,et al.  The phosphoinositol phosphatase activity of PTEN mediates a serum-sensitive G1 growth arrest in glioma cells. , 1998, Cancer research.

[26]  Tomohiko Maehama,et al.  Crystal Structure of the PTEN Tumor Suppressor Implications for Its Phosphoinositide Phosphatase Activity and Membrane Association , 1999, Cell.

[27]  M. L. Le Beau,et al.  A tumor suppressor-dependent inhibitor of angiogenesis is immunologically and functionally indistinguishable from a fragment of thrombospondin. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[28]  M. Wigler,et al.  PTEN, a Putative Protein Tyrosine Phosphatase Gene Mutated in Human Brain, Breast, and Prostate Cancer , 1997, Science.

[29]  H. Wu,et al.  PTEN modulates cell cycle progression and cell survival by regulating phosphatidylinositol 3,4,5,-trisphosphate and Akt/protein kinase B signaling pathway. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[30]  C. Cordon-Cardo,et al.  Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[31]  Hong Sun,et al.  TEP1, encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor beta. , 1997, Cancer research.

[32]  P. Vogt,et al.  Phosphatidylinositol 3-kinase signaling mediates angiogenesis and expression of vascular endothelial growth factor in endothelial cells. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[33]  Jing Li,et al.  Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome , 1997, Nature Genetics.

[34]  H. Hanafusa,et al.  The tumor-suppressor activity of PTEN is regulated by its carboxyl-terminal region. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[35]  M. Wigler,et al.  The lipid phosphatase activity of PTEN is critical for its tumor supressor function. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[36]  R. McLendon,et al.  PTEN gene mutations are seen in high-grade but not in low-grade gliomas. , 1997, Cancer research.

[37]  Francisca Vazquez,et al.  Phosphorylation of the PTEN Tail Regulates Protein Stability and Function , 2000, Molecular and Cellular Biology.

[38]  Kenneth M. Yamada,et al.  Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN. , 1998, Science.

[39]  Georg Breier,et al.  Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo , 1992, Nature.

[40]  José Luis de la Pompa,et al.  Negative Regulation of PKB/Akt-Dependent Cell Survival by the Tumor Suppressor PTEN , 1998, Cell.

[41]  A. Chishti,et al.  Human Homologue of the Drosophila Discs Large Tumor Suppressor Protein Forms an Oligomer in Solution , 2000, The Journal of Biological Chemistry.

[42]  C. Ross,et al.  Evidence for regulation of the PTEN tumor suppressor by a membrane-localized multi-PDZ domain containing scaffold protein MAGI-2. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[43]  J. Folkman.  Tumor angiogenesis: therapeutic implications. , 1971, The New England journal of medicine.

[44]  Tomohiko Maehama,et al.  The Tumor Suppressor, PTEN/MMAC1, Dephosphorylates the Lipid Second Messenger, Phosphatidylinositol 3,4,5-Trisphosphate* , 1998, The Journal of Biological Chemistry.

[45]  T. Mak,et al.  High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor gene in mice , 1998, Current Biology.

[46]  W. K. Alfred Yung,et al.  Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers , 1997, Nature Genetics.

[47]  K. Dameron,et al.  Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1. , 1994, Science.

[48]  D. Cheresh,et al.  Integrin α v β 3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels , 1994, Cell.

[49]  M. Wigler,et al.  P-TEN, the tumor suppressor from human chromosome 10q23, is a dual-specificity phosphatase. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[50]  J. Adachi,et al.  Cell cycle arrest and astrocytic differentiation resulting from PTEN expression in glioma cells. , 1999, Journal of neurosurgery.

[51]  W. Cavenee,et al.  Growth suppression of glioma cells by PTEN requires a functional phosphatase catalytic domain. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[52]  M A Moses,et al.  Matrix metalloproteinase-2 is required for the switch to the angiogenic phenotype in a tumor model. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[53]  L. Cantley,et al.  New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. , 1999, Proceedings of the National Academy of Sciences of the United States of America.