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.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
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Special Emphasis Panel (ZDE1-PZ (15))
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Shirazi, Yasaman
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University of Michigan Ann Arbor
Schools of Dentistry
Ann Arbor
United States
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Krishnamurthy, Sudha; Nör, Jacques E (2013) Orosphere assay: a method for propagation of head and neck cancer stem cells. Head Neck 35:1015-21
Ritchie, Kathryn E; Nör, Jacques E (2013) Perivascular stem cell niche in head and neck cancer. Cancer Lett 338:41-6
Gomes, Fausto Gueths; Nedel, Fernanda; Alves, Alessandro Menna et al. (2013) Tumor angiogenesis and lymphangiogenesis: tumor/endothelial crosstalk and cellular/microenvironmental signaling mechanisms. Life Sci 92:101-7
Imai, Atsushi; Zeitlin, Benjamin D; Visioli, Fernanda et al. (2012) Metronomic dosing of BH3 mimetic small molecule yields robust antiangiogenic and antitumor effects. Cancer Res 72:716-25
Zeitlin, Benjamin D; Dong, Zhihong; Nör, Jacques E (2012) RAIN-Droplet: a novel 3D in vitro angiogenesis model. Lab Invest 92:988-98
Tarquinio, Sandra B C; Zhang, Zhaocheng; Neiva, Kathleen G et al. (2012) Endothelial cell Bcl-2 and lymph node metastasis in patients with oral squamous cell carcinoma. J Oral Pathol Med 41:124-30
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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