PLEIOTROPHIN-- AN ANGIOGENIC SWITCH IN TUMOR PROGRESSION

Summary

Principal Investigator: THOMAS DEUEL
Abstract: The long-range goals of this research are to identify and characterize whereby pleiotrophin (PTN) and midkine (MK) signal neovascularization in tumors (i.e., "tumor angiogenesis") and to identify and exploit the sites and methods to therapeutically control pathological angiogenesis and human tumors. Both PTN and MK are highly expressed in many aggressive human tumors and cell lines from these tumors constitutively express PTN and MK, suggesting that their expression is the result of a genetically stable mutation in the transformed cell. PTN transformed cells and tumor cells in which constitutive expression of PTN or its C-terminal domain alone have been established develop highly vascular tumors in the nude mouse. Remarkably, the cells that express PTN release basic fibroblast growth factor (bFGF) to extracellular sites but non-transformed control cells do not, suggesting that bFGF release is transformation-dependent and the result of a PTN signaled pathway. Basic FGF release from transformed cells is also stipulated by PMA, suggesting that bFGF release is dependent on an activated protein kinase C (PKC) isoform. These findings may be very relevant to human tumors, since interruption of endogenous PTN signaling by a dominant negative PTN effector reverses aggressive growth of human breast cancer cells. Since there is a striking similarity of both structure and functions of PTN and MK and expression of these highly related cytokines is a feature of many aggressive and high vascularized tumors, it is mow proposed to exploit the models used to generate the Preliminary Data cited above to functionally dissect and compare the different domains of PTN and MK that lead to tumor promotion and tumor angiogenesis. The proposal seeks to define oncogenic pathways with which PTN- OR mk- "cooperates to initiate transformation and tumor promotion, to identify downstream genes and pathways which are activated by PTN or MK stimulated signaling that lead to tumor angiogenesis, to seek the factor(s) such as an activated PKC isoform or bFGF which may directly mediate PTN and MK signaled tumor angiogenesis and to define new targets in PTN and MK signaling pathways for therapies to reverse the stepwise progression of tumors in man. The results are likely to identify "angiogenic switch(s)" of potential broad importance in human tumors, advance knowledge of vasculogenesis and identify potential sites for therapeutic intervention.
Funding Period: 1999-12-20 - 2006-04-30
more information: NIH RePORT

Top Publications

  1. ncbi Pleiotrophin induces formation of functional neovasculature in vivo
    Karen L Christman
    University of California Berkeley and San Francisco Joint Bioengineering Graduate Group, USA
    Biochem Biophys Res Commun 332:1146-52. 2005
  2. ncbi Pleiotrophin, a multifunctional tumor promoter through induction of tumor angiogenesis, remodeling of the tumor microenvironment, and activation of stromal fibroblasts
    Pablo Perez-Pinera
    The Scripps Research Institute, La Jolla, California 92037, USA
    Cell Cycle 6:2877-83. 2007
  3. pmc The receptor protein tyrosine phosphatase (RPTP)beta/zeta is expressed in different subtypes of human breast cancer
    Pablo Perez-Pinera
    The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
    Biochem Biophys Res Commun 362:5-10. 2007
  4. ncbi Anaplastic lymphoma kinase is activated through the pleiotrophin/receptor protein-tyrosine phosphatase beta/zeta signaling pathway: an alternative mechanism of receptor tyrosine kinase activation
    Pablo Perez-Pinera
    Scripps Research Institute, La Jolla, California 92037, USA
    J Biol Chem 282:28683-90. 2007
  5. pmc Secretion of pleiotrophin stimulates breast cancer progression through remodeling of the tumor microenvironment
    Yunchao Chang
    Department of Molecular and Experimental Medicine and Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
    Proc Natl Acad Sci U S A 104:10888-93. 2007
  6. pmc Anaplastic lymphoma kinase is expressed in different subtypes of human breast cancer
    Pablo Perez-Pinera
    The Scripps Research Institute, La Jolla, CA 92037, USA
    Biochem Biophys Res Commun 358:399-403. 2007
  7. pmc Dominant negative pleiotrophin induces tetraploidy and aneuploidy in U87MG human glioblastoma cells
    Yunchao Chang
    Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 N Torrey Pines Rd, La Jolla, CA 92037, USA
    Biochem Biophys Res Commun 351:336-9. 2006
  8. pmc A variant of estrogen receptor-{alpha}, hER-{alpha}36: transduction of estrogen- and antiestrogen-dependent membrane-initiated mitogenic signaling
    Zhaoyi Wang
    Cancer Center, Creighton University, 2500 California Plaza, Omaha, NE 68178, USA
    Proc Natl Acad Sci U S A 103:9063-8. 2006
  9. ncbi Midkine is a potent regulator of the catecholamine biosynthesis pathway in mouse aorta
    Laura Ezquerra
    Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Rd, La Jolla, CA 92037, United States
    Life Sci 79:1049-55. 2006
  10. ncbi Identification of the angiogenesis signaling domain in pleiotrophin defines a mechanism of the angiogenic switch
    Nan Zhang
    Department of Molecular and Experimental Medicine and Cell Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
    Biochem Biophys Res Commun 343:653-8. 2006

Scientific Experts

  • Zhao Yi Wang
  • Pablo Perez-Pinera
  • Thomas F Deuel
  • Laura Ezquerra
  • Gonzalo Herradon
  • Yunchao Chang
  • James R Berenson
  • Trang Nguyen
  • Inmaculada Silos-Santiago
  • T F Deuel
  • Y Chang
  • A Astudillo
  • J Mortimer
  • Nan Zhang
  • Harold Pariser
  • Karen L Christman
  • Joanne Mortimer
  • Aurora Astudillo
  • Olivia Garcia-Suarez
  • Primitiva Menendez-Rodriguez
  • Wei Zhang
  • Masahiko Zuka
  • Jose Antonio Vega
  • Rong Zhong
  • Albert F Candia
  • Qizhi Fang
  • Hubert H Fok
  • Richard E Sievers
  • Kenneth J Colley
  • Anne J Kim
  • Randall J Lee

Detail Information

Publications15

  1. ncbi Pleiotrophin induces formation of functional neovasculature in vivo
    Karen L Christman
    University of California Berkeley and San Francisco Joint Bioengineering Graduate Group, USA
    Biochem Biophys Res Commun 332:1146-52. 2005
    ..The data suggest that PTN signals the more "complete" new blood vessel formation through its ability to stimulate different functions in different cell types not limited to the endothelial cell...
  2. ncbi Pleiotrophin, a multifunctional tumor promoter through induction of tumor angiogenesis, remodeling of the tumor microenvironment, and activation of stromal fibroblasts
    Pablo Perez-Pinera
    The Scripps Research Institute, La Jolla, California 92037, USA
    Cell Cycle 6:2877-83. 2007
    ....
  3. pmc The receptor protein tyrosine phosphatase (RPTP)beta/zeta is expressed in different subtypes of human breast cancer
    Pablo Perez-Pinera
    The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
    Biochem Biophys Res Commun 362:5-10. 2007
    ..The data suggest that the PTN/RPTPbeta/zeta signaling pathway may be constitutively activated and potentially function to constitutively activate ALK in human breast cancer...
  4. ncbi Anaplastic lymphoma kinase is activated through the pleiotrophin/receptor protein-tyrosine phosphatase beta/zeta signaling pathway: an alternative mechanism of receptor tyrosine kinase activation
    Pablo Perez-Pinera
    Scripps Research Institute, La Jolla, California 92037, USA
    J Biol Chem 282:28683-90. 2007
    ....
  5. pmc Secretion of pleiotrophin stimulates breast cancer progression through remodeling of the tumor microenvironment
    Yunchao Chang
    Department of Molecular and Experimental Medicine and Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
    Proc Natl Acad Sci U S A 104:10888-93. 2007
    ....
  6. pmc Anaplastic lymphoma kinase is expressed in different subtypes of human breast cancer
    Pablo Perez-Pinera
    The Scripps Research Institute, La Jolla, CA 92037, USA
    Biochem Biophys Res Commun 358:399-403. 2007
    ....
  7. pmc Dominant negative pleiotrophin induces tetraploidy and aneuploidy in U87MG human glioblastoma cells
    Yunchao Chang
    Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 N Torrey Pines Rd, La Jolla, CA 92037, USA
    Biochem Biophys Res Commun 351:336-9. 2006
    ....
  8. pmc A variant of estrogen receptor-{alpha}, hER-{alpha}36: transduction of estrogen- and antiestrogen-dependent membrane-initiated mitogenic signaling
    Zhaoyi Wang
    Cancer Center, Creighton University, 2500 California Plaza, Omaha, NE 68178, USA
    Proc Natl Acad Sci U S A 103:9063-8. 2006
    ....
  9. ncbi Midkine is a potent regulator of the catecholamine biosynthesis pathway in mouse aorta
    Laura Ezquerra
    Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Rd, La Jolla, CA 92037, United States
    Life Sci 79:1049-55. 2006
    ..The data also establish that norepinephrine is effectively the only catecholamine synthesized in mouse aorta...
  10. ncbi Identification of the angiogenesis signaling domain in pleiotrophin defines a mechanism of the angiogenic switch
    Nan Zhang
    Department of Molecular and Experimental Medicine and Cell Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
    Biochem Biophys Res Commun 343:653-8. 2006
    ....
  11. ncbi Identification, cloning, and expression of human estrogen receptor-alpha36, a novel variant of human estrogen receptor-alpha66
    Zhaoyi Wang
    Cancer Center, Creighton University, Omaha, NE 68178, USA
    Biochem Biophys Res Commun 336:1023-7. 2005
    ....
  12. ncbi Pleiotrophin stimulates tyrosine phosphorylation of beta-adducin through inactivation of the transmembrane receptor protein tyrosine phosphatase beta/zeta
    Harold Pariser
    Department of Molecular and Experimental Medicine, Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
    Biochem Biophys Res Commun 335:232-9. 2005
    ....
  13. ncbi Midkine regulates pleiotrophin organ-specific gene expression: evidence for transcriptional regulation and functional redundancy within the pleiotrophin/midkine developmental gene family
    Gonzalo Herradon
    Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
    Biochem Biophys Res Commun 333:714-21. 2005
    ....
  14. ncbi Midkine, a newly discovered regulator of the renin-angiotensin pathway in mouse aorta: significance of the pleiotrophin/midkine developmental gene family in angiotensin II signaling
    Laura Ezquerra
    Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
    Biochem Biophys Res Commun 333:636-43. 2005
    ....
  15. ncbi Pleiotrophin, a multifunctional angiogenic factor: mechanisms and pathways in normal and pathological angiogenesis
    Pablo Perez-Pinera
    The Scripps Research Institute, La Jolla, California 92037, USA
    Curr Opin Hematol 15:210-4. 2008
    ..This study seeks to integrate recent studies that identify new critical mechanisms through which the 136 amino acid secreted heparin-binding cytokine pleiotrophin (PTN, Ptn) stimulates both normal and pathological angiogenesis...