PHEOCHROMOCYTOMAS FROM NEUROFIBROMATOSIS KNOCKOUT MICE

Summary

Principal Investigator: Arthur Tischler
Abstract: Endocrine tumors of the adrenal medulla are known as pheochromocytomas. These tumors are rare in humans, as in most other species, except in patients with hereditary endocrine or neurocutaneous tumor syndromes. Pheochromocytomas are developmentally related to neuroblastomas, which are common adrenal medullary neoplasms, and pheochromocytoma cells can undergo neuronal differentiation. However, an important difference between the endocrine and neuronal phenotype is that the latter is associated with inability to express phenylethanolamine N-methyltransferase (PNMT), the enzyme that synthesizes epinephrine. There are currently no human pheochromocytoma cell lines, and other lines are not adequate models for studying PNMT regulation because they are noradrenergic, and express little or no PNMT. Pheochromocytomas occur with increased frequency in patients with neurofibromatosis type 1, a neurocutaneous syndrome characterized by loss or defective function of neurofibromin, the protein encoded by the tumor suppressor gene NF1. Neurofibromin is a GTPase-activating protein that can regulate the activity of ras proteins in intracellular signalling. However, neurofibromin can inhibit ras-dependent tumor growth independently of its GTPase activity. Transplantable pheochromocytoma tumors and cell lines have now been developed from neurofibromatosis knockout mice. Mouse pheochromocytoma (MPC) cells show spontaneous or growth factor- induced neuronal differentiation in culture similarly to their human counterparts and express PNMT in vivo and in vitro. These tumors have clear relevance to human disease. They are a valuable new tool for studying signalling pathways in adrenal medullary neoplasms, and are a unique model for studying regulation of PNMT expression. The proposed studies will develop and utilize this model with the long-term objective of determining mechanisms responsible for development and progression of adrenal medullary tumors and for regulating tumor cell phenotype. The Specific Aims are: (1) to establish lines of MPC cells characterized with respect to basal expression of PNMT. (2) To establish conditions that promote PNMT expression or neuronal differentiation in MPC cells and test the hypothesis that neuronal differentiation causes loss of PNMT expression. (3) To use MPC cells to test the hypothesis that PNMT expression is determined by an interplay of silencing and positively-acting transcription factors, such that silencing predominates both in noradrenergic pheochromocytomas and in pheochromocytomas that have undergone neuronal differentiation. (4) To determine the status of neurofibromin in MPC cells and test the hypothesis that abnormal regulation of ras activity is responsible for neuronal differentiation in this model.
Funding Period: 1999-04-23 - 2004-03-31
more information: NIH RePORT

Top Publications

  1. ncbi ErbB-2 induces bilateral adrenal pheochromocytoma formation in mice
    Edwin W Lai
    Lombardi Cancer Comprehensive Center, Department of Oncology, Georgetown University Medical Center, Washington, DC 20057, USA
    Cell Cycle 6:1946-50. 2007
  2. ncbi GDNF-induced leukemia inhibitory factor can mediate differentiation via the MEK/ERK pathway in pheochromocytoma cells derived from nf1-heterozygous knockout mice
    Jong In Park
    The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
    Exp Cell Res 303:79-88. 2005
  3. pmc Noninvasive monitoring of a murine model of metastatic pheochromocytoma: a comparison of contrast-enhanced microCT and nonenhanced MRI
    Lucia Martiniova
    Reproductive and Adult Endocrinology Program, National Institutes of Child Health and Human Development, Bethesda, Maryland 20892 1109, USA
    J Magn Reson Imaging 29:685-91. 2009
  4. pmc Characterization of an animal model of aggressive metastatic pheochromocytoma linked to a specific gene signature
    Lucia Martiniova
    Section on Medical Neuroendocrinology, Reproductive and Adult Endocrinology Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development NIH, 10 Center Drive MSC 1109, Bethesda, MD 20892 1109, USA
    Clin Exp Metastasis 26:239-50. 2009
  5. ncbi Adrenergic differentiation and Ret expression in rat pheochromocytomas
    James F Powers
    Department of Pathology, Tufts New England Medical Center, Boston, MA 02111, USA
    Endocr Pathol 19:9-16. 2008
  6. ncbi Metastasis-associated gene expression profile of liver and subcutaneous lesions derived from mouse pheochromocytoma cells
    Shoichiro Ohta
    Reproductive Biology and Medicine Branch, National Institute of Child Health and Human Development, Bethesda, Maryland 20892 1109, USA
    Mol Carcinog 47:245-51. 2008
  7. ncbi Animal models of pheochromocytoma including NIH initial experience
    Shoichiro Ohta
    Reproductive Biology and Medicine Branch, National Institute of Child Health and Human Development, NIH, Building 10, CRC, Room 1E 3141, 10 Center Drive MSC 1109, Bethesda, MD 20892 1109, USA
    Ann N Y Acad Sci 1073:300-5. 2006
  8. pmc MicroCT for high-resolution imaging of ectopic pheochromocytoma tumors in the liver of nude mice
    Shoichiro Ohta
    Reproductive Biology and Medicine Branch, National Institute of Child Health and Human Development, Bethesda, MD 20892 1109, USA
    Int J Cancer 119:2236-41. 2006
  9. ncbi Nicotine stimulates expression of the PNMT gene through a novel promoter sequence
    Marian J Evinger
    Department of Pediatrics, Stony Brook University, Stony Brook, NY 11794, USA
    J Mol Neurosci 26:39-55. 2005
  10. ncbi Microarray-based comparative genomic hybridization of pheochromocytoma cell lines from neurofibromatosis knockout mice reveals genetic alterations similar to those in human pheochromocytomas
    James F Powers
    Department of Pathology, Tufts New England Medical Center, Boston, MA 02111, USA
    Cancer Genet Cytogenet 159:27-31. 2005

Scientific Experts

  • J F Powers
  • Jong In Park
  • Marian J Evinger
  • Edwin W Lai
  • Karel Pacak
  • Shoichiro Ohta
  • Lucia Martiniova
  • Arthur S Tischler
  • John C Morris
  • Richard Kvetnansky
  • Irina A Lubensky
  • Mones Abu-Asab
  • Daniel Schimel
  • Salvatore Alesci
  • Shun Ichiro Taniguchi
  • Marcelino Bernardo
  • David Thomasson
  • Abdel G Elkahloun
  • Daniel C Solis
  • Peter L Choyke
  • Andrea Wickremasinghe
  • Thanh Truc Huynh
  • Shiromi M Perera
  • Melanie S Kotys
  • Jan Ruzicka
  • Maria J Merino
  • Jeffery E Green
  • Hiroshi Yazawa
  • Richard Zhang
  • Wai Yee Chan
  • Morihiro Watanabe
  • Paul Sirajuddin
  • Alan L Y Pang
  • Caroline Cromelin
  • Kristen L Picard
  • Olga C Rodriguez
  • Chris Albanese
  • Michael P Lisanti
  • Stanley T Fricke
  • Maral Aventian
  • Susannah Cleary
  • Douglas A Bakan
  • Brenda Klaunberg

Detail Information

Publications13

  1. ncbi ErbB-2 induces bilateral adrenal pheochromocytoma formation in mice
    Edwin W Lai
    Lombardi Cancer Comprehensive Center, Department of Oncology, Georgetown University Medical Center, Washington, DC 20057, USA
    Cell Cycle 6:1946-50. 2007
    ..These data establish that increased ErbB-2 growth factor receptor signaling in the adrenal medulla can lead to PCC through combined influences on Pten, AKT andcyclin D1...
  2. ncbi GDNF-induced leukemia inhibitory factor can mediate differentiation via the MEK/ERK pathway in pheochromocytoma cells derived from nf1-heterozygous knockout mice
    Jong In Park
    The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
    Exp Cell Res 303:79-88. 2005
    ..Our findings suggest that LIF may be utilized for signaling mediated by GDNF and may be important in the pathobiology of neuroendocrine tumors...
  3. pmc Noninvasive monitoring of a murine model of metastatic pheochromocytoma: a comparison of contrast-enhanced microCT and nonenhanced MRI
    Lucia Martiniova
    Reproductive and Adult Endocrinology Program, National Institutes of Child Health and Human Development, Bethesda, Maryland 20892 1109, USA
    J Magn Reson Imaging 29:685-91. 2009
    ..However, the choice of imaging modality is still evolving...
  4. pmc Characterization of an animal model of aggressive metastatic pheochromocytoma linked to a specific gene signature
    Lucia Martiniova
    Section on Medical Neuroendocrinology, Reproductive and Adult Endocrinology Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development NIH, 10 Center Drive MSC 1109, Bethesda, MD 20892 1109, USA
    Clin Exp Metastasis 26:239-50. 2009
    ..Microarray gene expression comparison and quantitative real-time PCR of these more aggressive cells to the MPC-parental cell line identified genes that may be important for the metastatic process...
  5. ncbi Adrenergic differentiation and Ret expression in rat pheochromocytomas
    James F Powers
    Department of Pathology, Tufts New England Medical Center, Boston, MA 02111, USA
    Endocr Pathol 19:9-16. 2008
    ..Loss of p27(Kip1) does not appear to account for the high frequency of pheochromocytomas in commonly utilized rat strains...
  6. ncbi Metastasis-associated gene expression profile of liver and subcutaneous lesions derived from mouse pheochromocytoma cells
    Shoichiro Ohta
    Reproductive Biology and Medicine Branch, National Institute of Child Health and Human Development, Bethesda, Maryland 20892 1109, USA
    Mol Carcinog 47:245-51. 2008
    ....
  7. ncbi Animal models of pheochromocytoma including NIH initial experience
    Shoichiro Ohta
    Reproductive Biology and Medicine Branch, National Institute of Child Health and Human Development, NIH, Building 10, CRC, Room 1E 3141, 10 Center Drive MSC 1109, Bethesda, MD 20892 1109, USA
    Ann N Y Acad Sci 1073:300-5. 2006
    ..This and alternative animal models of metastatic pheochromocytoma are promising avenues in preclinical studies to evaluate new therapeutic approaches for malignant pheochromocytoma...
  8. pmc MicroCT for high-resolution imaging of ectopic pheochromocytoma tumors in the liver of nude mice
    Shoichiro Ohta
    Reproductive Biology and Medicine Branch, National Institute of Child Health and Human Development, Bethesda, MD 20892 1109, USA
    Int J Cancer 119:2236-41. 2006
    ..35 mm as early as 4 weeks after the injection of the tumor cells. This model may be useful for in vivo studies of tumor biology and for development of new strategies to treat metastatic pheochromocytoma...
  9. ncbi Nicotine stimulates expression of the PNMT gene through a novel promoter sequence
    Marian J Evinger
    Department of Pediatrics, Stony Brook University, Stony Brook, NY 11794, USA
    J Mol Neurosci 26:39-55. 2005
    ..Thus, nicotinic cholinergic stimuli appear to regulate expression of the epinephrine-synthesizing gene PNMT through a previously uncharacterized regulatory element...
  10. ncbi Microarray-based comparative genomic hybridization of pheochromocytoma cell lines from neurofibromatosis knockout mice reveals genetic alterations similar to those in human pheochromocytomas
    James F Powers
    Department of Pathology, Tufts New England Medical Center, Boston, MA 02111, USA
    Cancer Genet Cytogenet 159:27-31. 2005
    ..Additional changes that may be specific to this model included complete or partial gains of chromosome 12 as seen in 3 of the 4 lines analyzed by array CGH...
  11. ncbi High prevalence of herpes simplex virus DNA in temporal arteritis biopsy specimens
    James F Powers
    Department of Pathology, Tufts New England Medical Center, Boston, MA 02111, USA
    Am J Clin Pathol 123:261-4. 2005
    ..Analysis of 10 renal artery samples from age-matched control subjects using the same assay showed no detectable HSV DNA. We conclude that detectable HSV DNA is correlated with histologically confirmed GCA in this patient population...
  12. ncbi Up-regulation of ret by reserpine in the adult rat adrenal medulla
    J F Powers
    Department of Pathology, Tufts New England Medical Center, Tufts University School of Medicine, Boston, MA 02111, USA
    Neuroscience 132:605-12. 2005
    ..Our findings suggest potential utility of the rat model for studying the roles of ret in the adrenal medulla and the mechanisms of its involvement in MEN 2 and other pheochromocytoma syndromes...
  13. ncbi RET expression and neuron-like differentiation of pheochromocytoma and normal chromaffin cells
    J F Powers
    Department of Pathology, Tufts Medical Center, Boston, MA 02111, USA
    Horm Metab Res 41:710-4. 2009
    ..Whether wild-type RET contributes to tumor development or is merely a lineage marker for cells at various stages of neuronal differentiation may vary, with other tumor characteristics...