Tumor cells depend on angiogenesis to proliferate, survive, and metastasize. Therefore, targeted disruption of the tumor blood vessels might be beneficial for treatment of patients with cancer. Head and neck squamous cell carcinomas (HNSCC) are highly vascularized and present high risk for metastatic dissemination. These features suggest that there is an active interplay between HNSCC tumor cells and the neovascular endothelial cells that line the tumor's blood vessels. There is solid information about angiogenic factors secreted by HNSCC cells, and the consequences of these factors for the pathobiology of head and neck tumors. However, very little is known about the molecules that the tumor-associated endothelial cells secrete, the signaling pathways that regulate the synthesis of these molecules, and the consequences of endothelial cell-derived molecules to HNSCC gene expression profile and metastatic behavior. We have recently demonstrated that tumor cell-derived vascular endothelial growth factor (VEGF) induces expression of Bcl-2 in endothelial cells, and that Bcl-2 overexpression is sufficient to enhance HNSCC tumor growth and microvessel density. Interestingly, endothelial cells that overexpress Bcl-2 become more angiogenic, and secrete high levels of the pro-angiogenic CXC chemokines interteukin (IL-8), and growth related oncogene GRO-alpha. The broad long-term goal of this research is to understand the molecular interplay between neovascular endothelial cells and squamous cell carcinoma cells. The objectives of this application are to study the signaling transduction pathway mediated by Bcl-2 that results in upregulation of IL-8 and GRO-alpha expression in endothelial cells, and to evaluate the influence of endothelial cell-derived IL-8 and GRO-alpha on HNSCC gene expression profile, metastasis, and tumor microvascular density. We designed experiments to evaluate the role of NF-kappaB in Bcl-2-induced pro-angiogenic signaling events. Functional genomics studies will be performed to identify and begin characterization of endothelial ceil-induced HNSCC gene expression profiles, and their function in tumor cell invasion and metastasis. And the role of endothelial cell-derived IL-8 and GRO-alpha in tumor angiogenesis (autocrine pathway) will be studied with oligonucleotide microarrays, capiltary tube assay, and the SCID Mouse Model of Human Angiogenesis. The knowledge generated here will enhance our understanding about the molecular interplay between neovascular endothelial cells and HNSCC, and may suggest novel therapeutic targets for the treatment of patients with head and neck cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE015948-03
Application #
6990537
Study Section
Special Emphasis Panel (ZDE1-PZ (15))
Program Officer
Shirazi, Yasaman
Project Start
2004-03-01
Project End
2009-01-31
Budget Start
2006-02-01
Budget End
2007-01-31
Support Year
3
Fiscal Year
2006
Total Cost
$373,511
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Dentistry
Type
Schools of Dentistry
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Zeitlin, Benjamin D; Nör, Jacques E (2011) Small-molecule inhibitors reveal a new function for Bcl-2 as a proangiogenic signaling molecule. Curr Top Microbiol Immunol 348:115-37
Hegen, Anja; Blois, Anna; Tiron, Crina E et al. (2011) Efficient in vivo vascularization of tissue-engineering scaffolds. J Tissue Eng Regen Med 5:e52-62
Krishnamurthy, Sudha; Dong, Zhihong; Vodopyanov, Dmitry et al. (2010) Endothelial cell-initiated signaling promotes the survival and self-renewal of cancer stem cells. Cancer Res 70:9969-78
Zhang, Z; Neiva, K G; Lingen, M W et al. (2010) VEGF-dependent tumor angiogenesis requires inverse and reciprocal regulation of VEGFR1 and VEGFR2. Cell Death Differ 17:499-512

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