The von HippeI-Lindau (VHL) syndrome is a hereditary disease that is characterized by the development of highly vascularized tumors. Its underlying genetic defect is in the VHL tumor suppressor gene. The VHL mutant therefore represents an excellent system for studying the tumor-induced angiogenesis. We have identified an evolutionarily conserved novel mutational mechanism that leads to FGF receptor (FGFR) over-accumulation on the cell surface in VHL mutants. This phenomenon is observed in Drosophila, in the malignant renal cell carcinoma (RCC) culture, and likely in the human microvascular endothelial cells (HMVECs). It was also noted that the over-accumulated FGFR leads to aberrant cell migration and induction of Ets1 activity, whose function has been linked to metastasis and angiogenesis. We have previously found that the function of VHL is likely mediated by another tumor suppressor gene nm23. Based on these preliminary data, a novel intracellular mechanism is proposed that underlies the FGFR accumulation phenotype in VHL and nm23 mutations (as in human VHL disease patients and in Drosophila developmental mutant) and how this aberrant signaling event, via Ets1, can modulate cell motility during angiogenesis. We will utilize in vitro and in vivo model systems and employ cross-species comparative studies to dissect the signaling mechanisms.
Aim 1 will dissect the vesicle transport pathway that results in FGFR over-accumulation.
Aim 2 will analyze the role of VHL, FGFR, and Ets1 in modulating angiogenesis, employing a 3-dimensional co-culture system.
Aim 3 will examine the novel function of VHL in relation to Nm23.
Aim 4 will employ knockout mice to test the hypothesis that VHL heterozygous mutation in endothelial cells in the VHL disease patients play an important role in the disease' highly vascularized tumorigenic characteristics.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA109860-01
Application #
6827684
Study Section
Special Emphasis Panel (ZRG1-TME (01))
Program Officer
Sussman, Daniel J
Project Start
2004-07-01
Project End
2009-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
1
Fiscal Year
2004
Total Cost
$299,300
Indirect Cost
Name
Medical University of South Carolina
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
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Kuo, Chan-Yen; Lin, Chih-Hung; Hsu, Tien (2017) VHL Inactivation in Precancerous Kidney Cells Induces an Inflammatory Response via ER Stress-Activated IRE1? Signaling. Cancer Res 77:3406-3416
Bader, Hannah L; Hsu, Tien (2016) Inactivation of the tumor suppressor gene von Hippel-Lindau (VHL) in granulocytes contributes to development of liver hemangiomas in a mouse model. BMC Cancer 16:797
Pritchett, T L; Bader, H L; Henderson, J et al. (2015) Conditional inactivation of the mouse von Hippel-Lindau tumor suppressor gene results in wide-spread hyperplastic, inflammatory and fibrotic lesions in the kidney. Oncogene 34:2631-9
Lin, Chih-Hung; Dammai, Vincent; Adryan, Boris et al. (2015) Interaction between Nm23 and the tumor suppressor VHL. Naunyn Schmiedebergs Arch Pharmacol 388:143-52
Ignesti, Marilena; Barraco, Marilena; Nallamothu, Gouthami et al. (2014) Notch signaling during development requires the function of awd, the Drosophila homolog of human metastasis suppressor gene Nm23. BMC Biol 12:12
Liby, Tiera A; Spyropoulos, Perry; Buff Lindner, Haley et al. (2012) Akt3 controls vascular endothelial growth factor secretion and angiogenesis in ovarian cancer cells. Int J Cancer 130:532-43
Hsu, T (2012) Complex cellular functions of the von Hippel-Lindau tumor suppressor gene: insights from model organisms. Oncogene 31:2247-57
Bader, Hannah L; Hsu, Tien (2012) Systemic VHL gene functions and the VHL disease. FEBS Lett 586:1562-9
Hsu, Tien (2011) NME genes in epithelial morphogenesis. Naunyn Schmiedebergs Arch Pharmacol 384:363-72

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