Peroxisome Proliferator-Activated Receptor (gamma) in Lung Cancer

Summary

Principal Investigator: Raphael A Nemenoff
Abstract: DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer deaths in both men and women, with the majority of cases being classified as non-small cell lung cancer (NSCLC). Since at time of diagnosis, the majority of lung cancers are already advanced, new strategies are required to target tumor progression and metastasis. Peroxisome proliferator-activated receptor-? (PPAR?), a member of the nuclear hormone receptor superfamily of ligand-activated transcription factors, plays a critical role in adipocyte activation, but has also been implicated in a variety of cancers. During the previous funding period we demonstrated that activation of PPAR? has pleiotropic effects on human NSCLC cells, including promotion of a differentiated phenotype and inhibition of transformed growth and invasiveness. This receptor is the target of thiazolidinediones (TZDs), such as rosiglitazone and pioglitazone. Recent retrospective studies have suggested that these agents specifically reduce the risk of developing lung cancer in patients, making PPAR? an attractive target for treatment of lung cancer. Cancer progression and metastasis require complex interactions between tumor cells and the surrounding tumor microenvironment (TME). We have developed an immunocompetent mouse model for lung cancer cells progression, in which mouse lung cancer cells are injected into the lungs of syngeneic mice. These cells form a primary tumor which metastasizes to the other lobes of the lung, lymph nodes, and distant organs including liver and brain. This model allows manipulation of specific genes in either tumor cells or the TME. Using this model we have unexpectedly shown that in contrast to effects on tumor cells, systemic administration of pioglitazone accelerates tumor progression and promotes metastases. We hypothesize that these disparate effects of PPAR? activation are a result of opposing effects in tumor cells vs. the TME, with activation in tumor cells inhibiting progression and activation in cells of the TME contributing to progression. Our preliminary data indicate that pioglitazone affects the distribution of tumor-associated macrophages and may promote tumor angiogenesis. This project will use in vivo models and in vitro studies to define the contribution of PPAR? in each cell type to tumor progression and metastasis. Three specific aims are proposed. Aim 1 will examine the specific role of PPAR? activation in tumor cells on cancer progression, and define effector pathways in human and murine NSCLC cells. Aim 2 will assess the role of PPAR? in macrophages using a targeted knockout strategy. Studies will use in vitro systems to define cross-talk between cancer cells and macrophages. Aim 3 will employ a similar targeted knockout strategy to assess the role of PPAR? in endothelial cell on tumor progression in the setting of pioglitazone. Since large numbers of patients are treated with TZDs, defining the role of these agents and PPAR? on cancer progression and metastasis is of critical importance. PUBLIC HEALTH RELEVANCE: Studies indicate that activators of PPAR? can inhibit initiation of lung cancer but have conflicting roles on cancer progression and metastasis. This project will define the role for this protein both in tumor cells, macrophages, and endothelial cells using both in vivo and in vitro approaches. Understanding the cell-specific mechanisms whereby PPAR? regulates cancer progression and metastasis is critical in light of the wide-spread use of these agents, and will lead to identification of novel targets and new therapeutic approaches.
Funding Period: 2004-08-05 - 2015-11-30
more information: NIH RePORT

Top Publications

  1. ncbi Antitumorigenic effect of Wnt 7a and Fzd 9 in non-small cell lung cancer cells is mediated through ERK-5-dependent activation of peroxisome proliferator-activated receptor gamma
    Robert A Winn
    Veterans Administration Medical Center, Denver, and Department of Medicine, University of Colorado Health Sciences Center, 80220, USA
    J Biol Chem 281:26943-50. 2006
  2. pmc Knockdown of secretory phospholipase A2 IIa reduces lung cancer growth in vitro and in vivo
    Jessica A Yu
    Section of General Thoracic Surgery, Division of Cardiothoracic Surgery, Department of Surgery, University of Colorado School of Medicine, Aurora, CO, USA
    J Thorac Cardiovasc Surg 144:1185-91. 2012
  3. pmc Group IIa secretory phospholipase expression correlates with group IIa secretory phospholipase inhibition-mediated cell death in K-ras mutant lung cancer cells
    Jessica A Yu
    Division of Cardiothoracic Surgery, Department of Surgery, University of Colorado School of Medicine, Aurora, Colo 80045, USA
    J Thorac Cardiovasc Surg 144:1479-85. 2012
  4. pmc Activation of PPARγ in myeloid cells promotes lung cancer progression and metastasis
    Howard Li
    Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America
    PLoS ONE 6:e28133. 2011
  5. pmc Peroxisome proliferator-activated receptor-gamma inhibits transformed growth of non-small cell lung cancer cells through selective suppression of Snail
    Rashmi Choudhary
    Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Denver, 12700 E 19th Ave, Aurora, CO 80045, USA
    Neoplasia 12:224-34. 2010
  6. pmc Depletion of cytosolic phospholipase A2 in bone marrow-derived macrophages protects against lung cancer progression and metastasis
    Mary C M Weiser-Evans
    Division of Renal Diseases and Hypertension and Pulmonary Sciences, University of Colorado Denver, Denver, Colorado 80262, USA
    Cancer Res 69:1733-8. 2009
  7. pmc Prostacyclin prevents murine lung cancer independent of the membrane receptor by activation of peroxisomal proliferator--activated receptor gamma
    Raphael Nemenoff
    Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Health Sciences Center, Denver, CO, USA
    Cancer Prev Res (Phila) 1:349-56. 2008
  8. pmc Oncogenic K-Ras regulates proliferation and cell junctions in lung epithelial cells through induction of cyclooxygenase-2 and activation of metalloproteinase-9
    Xue Qing Wang
    Department of Medicine, University of Colorado Denver, Denver, CO 80262, USA
    Mol Biol Cell 20:791-800. 2009
  9. ncbi Antitumorigenic effects of peroxisome proliferator-activated receptor-gamma in non-small-cell lung cancer cells are mediated by suppression of cyclooxygenase-2 via inhibition of nuclear factor-kappaB
    Yvette Bren-Mattison
    Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Health Sciences Center, Box C 281, 4200 East 9th Avenue, Denver, CO 80262, USA
    Mol Pharmacol 73:709-17. 2008
  10. ncbi Peroxisome proliferator-activated receptor-gamma in lung cancer: defining specific versus "off-target" effectors
    Raphael A Nemenoff
    Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA
    J Thorac Oncol 2:989-92. 2007

Research Grants

Detail Information

Publications11

  1. ncbi Antitumorigenic effect of Wnt 7a and Fzd 9 in non-small cell lung cancer cells is mediated through ERK-5-dependent activation of peroxisome proliferator-activated receptor gamma
    Robert A Winn
    Veterans Administration Medical Center, Denver, and Department of Medicine, University of Colorado Health Sciences Center, 80220, USA
    J Biol Chem 281:26943-50. 2006
    ..These data suggest that ERK5-dependent activation of PPARgamma represents a major effector pathway mediating the anti-tumorigenic effects of Wnt 7a and Fzd 9 in NSCLC...
  2. pmc Knockdown of secretory phospholipase A2 IIa reduces lung cancer growth in vitro and in vivo
    Jessica A Yu
    Section of General Thoracic Surgery, Division of Cardiothoracic Surgery, Department of Surgery, University of Colorado School of Medicine, Aurora, CO, USA
    J Thorac Cardiovasc Surg 144:1185-91. 2012
    ..We hypothesized that knockdown of sPLA2 in lung cancer cells would reduce cell proliferation and NF-κB activity in vitro and attenuate tumor growth in vivo...
  3. pmc Group IIa secretory phospholipase expression correlates with group IIa secretory phospholipase inhibition-mediated cell death in K-ras mutant lung cancer cells
    Jessica A Yu
    Division of Cardiothoracic Surgery, Department of Surgery, University of Colorado School of Medicine, Aurora, Colo 80045, USA
    J Thorac Cardiovasc Surg 144:1479-85. 2012
    ..We hypothesize that sPLA(2)IIa modulates lung cancer cell growth in K-ras mutant cells and that sPLA(2)IIa expression in human lung tumors is increased in K-ras mutant tumors...
  4. pmc Activation of PPARγ in myeloid cells promotes lung cancer progression and metastasis
    Howard Li
    Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America
    PLoS ONE 6:e28133. 2011
    ....
  5. pmc Peroxisome proliferator-activated receptor-gamma inhibits transformed growth of non-small cell lung cancer cells through selective suppression of Snail
    Rashmi Choudhary
    Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Denver, 12700 E 19th Ave, Aurora, CO 80045, USA
    Neoplasia 12:224-34. 2010
    ..These findings suggest that selective regulation of Snail may be critical in mediating the antitumorigenic effects of PPARgamma activators...
  6. pmc Depletion of cytosolic phospholipase A2 in bone marrow-derived macrophages protects against lung cancer progression and metastasis
    Mary C M Weiser-Evans
    Division of Renal Diseases and Hypertension and Pulmonary Sciences, University of Colorado Denver, Denver, Colorado 80262, USA
    Cancer Res 69:1733-8. 2009
    ..Correspondingly, IL-6 staining was decreased in tumors grown in cPLA(2)-KO mice. These data suggest that stromal cPLA(2) plays a critical role in tumor progression by altering tumor-macrophage interactions and cytokine production...
  7. pmc Prostacyclin prevents murine lung cancer independent of the membrane receptor by activation of peroxisomal proliferator--activated receptor gamma
    Raphael Nemenoff
    Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Health Sciences Center, Denver, CO, USA
    Cancer Prev Res (Phila) 1:349-56. 2008
    ..This reduction was not enhanced by administration of supplemental iloprost. These studies indicate that PPARgamma is a critical target for prostacyclin-mediated lung cancer chemoprevention and may also have therapeutic activity...
  8. pmc Oncogenic K-Ras regulates proliferation and cell junctions in lung epithelial cells through induction of cyclooxygenase-2 and activation of metalloproteinase-9
    Xue Qing Wang
    Department of Medicine, University of Colorado Denver, Denver, CO 80262, USA
    Mol Biol Cell 20:791-800. 2009
    ....
  9. ncbi Antitumorigenic effects of peroxisome proliferator-activated receptor-gamma in non-small-cell lung cancer cells are mediated by suppression of cyclooxygenase-2 via inhibition of nuclear factor-kappaB
    Yvette Bren-Mattison
    Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Health Sciences Center, Box C 281, 4200 East 9th Avenue, Denver, CO 80262, USA
    Mol Pharmacol 73:709-17. 2008
    ..These data indicate that high levels of PGE(2) as a result of elevated COX-2 expression are critical for promoting lung tumorigenesis and that the antitumorigenic effects of PPARgamma are mediated in part through blocking this pathway...
  10. ncbi Peroxisome proliferator-activated receptor-gamma in lung cancer: defining specific versus "off-target" effectors
    Raphael A Nemenoff
    Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA
    J Thorac Oncol 2:989-92. 2007
    ..This review examines these pathways with a specific focus on the role of TZDs and PPAR gamma in lung cancer...
  11. pmc Eicosanoid profiling in an orthotopic model of lung cancer progression by mass spectrometry demonstrates selective production of leukotrienes by inflammatory cells of the microenvironment
    Joanna M Poczobutt
    Department of Medicine, University of Colorado Denver, Aurora, Colorado, United States of America
    PLoS ONE 8:e79633. 2013
    ....

Research Grants30

  1. PPAR gamma Agonists for Lung Cancer Chemoprevention
    Robert Keith; Fiscal Year: 2013
    ..Our results will lead to a better understanding of the early stages of lung cancer and may lead to future human chemoprevention trials. ..
  2. Leukocyte Biomarkers for Predicting Human Breast Cancer Outcomes
    LAURA J VAN 'T VEER; Fiscal Year: 2013
    ..of outcomes in human breast cancer with leukocyte transcriptomes and novel leukocyte biomarkers;and Project 3 will drive translation of leukocyte biomarkers into clinically applicable diagnostic and therapeutic probes ..