Plasminogen activator inhibitor-1 in tumor progression and metastasis

Summary

Principal Investigator: Yves A DeClerck
Abstract: DESCRIPTION (provided by applicant): Plasminogen activator inhibitor-1 (PAI-1) is a member of the family of endogenous serine protease inhibitors (serpins) that controls the activation of plasminogen into plasmin by tissue and urokinase type plasminogen activators (tPA and uPA, respectively). In the past, PAI-1 was considered to be anti-tumorigenic. However, in the late 1990's multiple clinical studies revealed that cancer patients whose tumors have a high content of uPA and PAI-1 have a poor rather than a favorable clinical outcome, suggesting that PAI-1 may promote rather than inhibit tumorigenesis. One explanation for the paradoxical role attributed to PAI-1 in cancer has been its pro-angiogenic function. During the past funding period of the grant, we have published two fundamental observations that further elucidate the pro-tumorigenic function of PAI-1. We first reported that PAI-1 exerts its pro-angiogenic activity in part through a novel mechanism whereby PAI-1 protects endothelial cells from Fas-mediated apoptosis through inhibition of the shedding by plasmin of a soluble mFasL pro-apoptotic fragment. Secondly, we demonstrated that PAI-1 also protects tumor cells from apoptosis, but that the mechanism is only partially dependent on plasmin and Fas. Emphasizing the role of the tumor microenvironment, we also demonstrated that stromal-derived PAI-1 compensates for a lack of tumor-derived PAI-1, and that PAI-1 contributes to the recruitment of macrophages by tumor cells. The overarching hypothesis of this application is that PAI-1 exerts its pro-tumorigenic activity through a combination of effects on endothelial cells (pro-angiogenic activity), macrophages (promotion of migration) and tumor cells (promotion of survival) that involves specific PAI-1-receptor interactions. We will test this hypothesis in vitro in several human cancer cell lines of different origins and producing variable amounts of PAI-1, and in vivo by combining genetic approaches with a pharmacologic approach. In Aim 1, we will investigate the mechanism by which the interaction between PAI-1 and one of its cell surface receptors, the low density lipoprotein receptor-like protein 1 (LRP1) signals and protects tumor cells from spontaneous and drug-induced apoptosis. In Aim 2, we will determine whether PAI-1 is necessary to allow tumors to promote angiogenesis, recruit macrophages and exit dormancy in immunodeficient PAI-1 null mice implanted with human tumor cells in which the suppression of PAI-1 expression is controlled by doxycycline. We will also investigate the effect of PAI-1 suppression on tumor initiation in PAI-1 null mice crossed with transgenic NB-Tag mice that have a 100% penetrance in neuroblastoma tumor formation. In Aim 3, we will test the effect of pharmacological inhibition of PAI-1 by newly developed small molecule inhibitors of PAI-1 in pre-clinical mouse models of tumorigenesis and tumor initiation. These studies will provide not only a better fundamental understanding of the mechanisms responsible for the pro-tumorigenic activity of PAI-1, but also a more definitive answer on the potential therapeutic value of targetin PAI-1 as part of cancer treatment strategies.
Funding Period: 2008-04-01 - 2018-04-30
more information: NIH RePORT

Top Publications

  1. pmc Plasminogen activator inhibitor-1 protects endothelial cells from FasL-mediated apoptosis
    Khalid Bajou
    Division of Hematology Oncology, Department of Pediatrics, University of Southern California and The Saban Research Institute of Childrens Hospital Los Angeles, Los Angeles, CA 90027, USA
    Cancer Cell 14:324-34. 2008
  2. pmc Synergistic activity of fenretinide and the Bcl-2 family protein inhibitor ABT-737 against human neuroblastoma
    Hua Fang
    Division of Hematology Oncology, Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
    Clin Cancer Res 17:7093-104. 2011
  3. pmc Protumorigenic activity of plasminogen activator inhibitor-1 through an antiapoptotic function
    Hua Fang
    Division of Hematology Oncology, Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
    J Natl Cancer Inst 104:1470-84. 2012

Research Grants

  1. Signaling in Inflammation, Stress, and Tumorigenesis
    GEORGE ROBERT STARK; Fiscal Year: 2013
  2. CELLULAR AND MOLECULAR MECHANISMS OF GASTROINTESTINAL CANCERS
    Lopa Mishra; Fiscal Year: 2013
  3. MPD RESEARCH CONSORTIUM
    Ronald Hoffman; Fiscal Year: 2013
  4. ROLES AND REGULATION OF P53
    Carol Prives; Fiscal Year: 2013
  5. MSKCC Center for Molecular Imaging in Cancer
    STEVEN MARK LARSON; Fiscal Year: 2013
  6. COBRE for Skeletal Health and Repair
    Qian Chen; Fiscal Year: 2013
  7. M. D. Anderson Cancer Center SPORE in Multiple Myeloma
    ROBERT ZYGMUNT ORLOWSKI; Fiscal Year: 2013
  8. Signaling and Progression in Prostate Cancer
    Dan Theodorescu; Fiscal Year: 2013
  9. Extracellular Maspin Acts as a Regulator of the Tumor Microenvironment
    Ivory Dean; Fiscal Year: 2013
  10. CHRONIC LYMPHOCYTIC LEUKEMIA RESEARCH CONSORTIUM
    Thomas J Kipps; Fiscal Year: 2013

Detail Information

Publications3

  1. pmc Plasminogen activator inhibitor-1 protects endothelial cells from FasL-mediated apoptosis
    Khalid Bajou
    Division of Hematology Oncology, Department of Pediatrics, University of Southern California and The Saban Research Institute of Childrens Hospital Los Angeles, Los Angeles, CA 90027, USA
    Cancer Cell 14:324-34. 2008
    ..We further demonstrate that plasmin cleaves FasL at Arg144-Lys145, releasing a soluble proapoptotic FasL fragment from the surface of ECs. The data provide a mechanism explaining the proangiogenic activity of PAI-1...
  2. pmc Synergistic activity of fenretinide and the Bcl-2 family protein inhibitor ABT-737 against human neuroblastoma
    Hua Fang
    Division of Hematology Oncology, Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
    Clin Cancer Res 17:7093-104. 2011
    ....
  3. pmc Protumorigenic activity of plasminogen activator inhibitor-1 through an antiapoptotic function
    Hua Fang
    Division of Hematology Oncology, Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
    J Natl Cancer Inst 104:1470-84. 2012
    ..Plasminogen activator inhibitor-1 (PAI-1) is a protease inhibitor but is paradoxically associated with poor outcomes in cancer patients. However, the mechanisms of its effects on tumor cells have not been explored...

Research Grants30

  1. Signaling in Inflammation, Stress, and Tumorigenesis
    GEORGE ROBERT STARK; Fiscal Year: 2013
    ..abstract_text> ..
  2. CELLULAR AND MOLECULAR MECHANISMS OF GASTROINTESTINAL CANCERS
    Lopa Mishra; Fiscal Year: 2013
    ..Significantly, this program promises to yield new therapies targeted at these difficult-to-treat lethal cancers at the bench, and then to translate the results rapidly into clinical care, at the bedside. ..
  3. MPD RESEARCH CONSORTIUM
    Ronald Hoffman; Fiscal Year: 2013
    ..abstract_text> ..
  4. ROLES AND REGULATION OF P53
    Carol Prives; Fiscal Year: 2013
    ..The projects are even more interdependent and interactive than before and as a result much of the proposed research cannot be done effectively without the support of this program. ..
  5. MSKCC Center for Molecular Imaging in Cancer
    STEVEN MARK LARSON; Fiscal Year: 2013
    ..In summary, we have shaped ICMIC-3 to closely adhere to the goals of PAR 09-157. ..
  6. COBRE for Skeletal Health and Repair
    Qian Chen; Fiscal Year: 2013
    ..This multidisciplinary approach is absolutely necessary to develop translational strategies for prevention and treatment of skeletal joint diseases. ..
  7. M. D. Anderson Cancer Center SPORE in Multiple Myeloma
    ROBERT ZYGMUNT ORLOWSKI; Fiscal Year: 2013
    ..abstract_text> ..
  8. Signaling and Progression in Prostate Cancer
    Dan Theodorescu; Fiscal Year: 2013
    ..The long-term objective is to translate our understanding of prostate cancer progression mechanisms into the identification of new drug targets and pre-clinical models that recapitulate key aspects of the human disease. ..
  9. Extracellular Maspin Acts as a Regulator of the Tumor Microenvironment
    Ivory Dean; Fiscal Year: 2013
    ..Specific Aim 3 is to investigate the biological consequences of extracellular maspin upon internalization. ..
  10. CHRONIC LYMPHOCYTIC LEUKEMIA RESEARCH CONSORTIUM
    Thomas J Kipps; Fiscal Year: 2013
    ..abstract_text> ..
  11. Molecular Pathogenesis of Basal-like Breast Cancer
    Richard J Baer; Fiscal Year: 2013
    ..e., metastasis, and develop strategies for therapy. ..
  12. UAB / UMN SPORE in Pancreatic Cancer
    Donald J Buchsbaum; Fiscal Year: 2013
    ..The application has strong institutional support from UAB and UMN, excellent pancreatic cancer populations and concurrence with federal guidelines. ..
  13. Mechanisms of GVHD
    Joseph H Antin; Fiscal Year: 2013
    ..Ultimately we envision an integrated genomic profile that will determine the type of GVHD prophylaxis that will be most effective. ..
  14. UNMC EPPLEY CANCER CENTER SUPPORT GRANT
    Kenneth H Cowan; Fiscal Year: 2013
    ....
  15. Role of Foxm1 in Lung Cancer Microenvironment
    TANYA KALIN; Fiscal Year: 2013
    ..Completion of the proposed studies will enable us to determine whether Foxm1 plays critical role in tumor microenvironment and whether Foxm1 is an important target for lung cancer treatment. ..
  16. Biology and Therapy of High Risk Neuroblastoma
    ROBERT CHARLES SEEGER; Fiscal Year: 2013
    ..nant.org), which includes 15 pediatric oncology institutions across the US and in Canada. ..
  17. The role of the stromal cell surface protease FAP in pancreatic cancer
    ELLEN PURE apos PURE'; Fiscal Year: 2013
    ....
  18. SPORE in Soft Tissue Sarcoma
    Samuel Singer; Fiscal Year: 2013
    ..abstract_text> ..
  19. Oklahoma Center of Biomedical Research Excellence (COBRE) in Structural Biology
    Ann H West; Fiscal Year: 2013
    ..Collectively, these specific aims are expected to increase the pace, competitiveness and success rate of structural biology research groups in Oklahoma as they seek major independent external grant support. ..
  20. Novel Molecular Therapies of Prostate Cancer
    Dario C Altieri; Fiscal Year: 2013
    ..The overarching goal is to credential novel molecular therapies for patients with advanced and metastatic prostate cancer. ..
  21. Pancreatic Tumor Micro-environment Network
    Surinder K Batra; Fiscal Year: 2013
    ..With the expertise of the involved investigators in TME, we seek to improve our understanding of the underappreciated role of tumor microenvironment in pancreatic cancer and establish potential therapeutic relevance. ..