Head and neck squamous cell carcinoma is an aggressive epithelial malignancy that has a poor five-year survival. This is due, in part, to the development of multiple primary tumors throughout the mucosa of these patients. Therefore, the use of chemopreventive strategies must be included to completely treat this disease. Retinoic acid has been the most successful chemopreventive agent against the development of new squamous cell carcinomas. The mechanisms by which retinoic acid works in a chemopreventive setting remain unclear. Recent work by this lab suggests that retinoic acid's chemopreventive effects may be partly due to its ability to make endothelial cells refractory to the inducers of angiogenesis. However, the specific molecular mechanism by which endothelial cells become refractory is unknown. The hypothesis underlying this work is that one or more members of the retinoic acid receptor (RAR) family directly participate in rendering endothelial cells refractory to inducers of angiogenesis. The goal is to determine which RARs are responsible for causing this altered response of endothelial cells. This investigator proposes to carefully determine the profile of functional RARs expressed in endothelial cells, using both Northern and Western blots, as well as electromobility shift assays (EMSA). Receptor specific ligands will then be used in in vitro and in vivo angiogenesis assays to determine which subset of expressed receptors are required for altering the ability of endothelial cells to respond to inducers of angiogenesis. Finally, the Principal Investigator proposes to transduce human microvascular endothelial cells with retroviral vectors containing either dominant negative, wild type, or chimeric RARs. These cells will then be tested in vitro for their ability to migrate towards various angiogenic substances as well as purified angiogenic factors in the presence or absence of various retinoid compounds. The transduced cells will also be implanted into mice and their ability to incorporate into newly forming blood vessels in vivo in the presence or absence of retinoids determined. These studies should advance our understanding of the biologic and molecular mechanisms by which one can modify the angiogenic response which plays a critical role in a large array of both pathologic and physiologic conditions, including the development of new primary oral squamous cell carcinomas.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
7R01DE012322-07
Application #
6735414
Study Section
Oral Biology and Medicine Subcommittee 1 (OBM)
Program Officer
Shirazi, Yasaman
Project Start
1998-06-01
Project End
2005-05-31
Budget Start
2002-10-15
Budget End
2005-05-31
Support Year
7
Fiscal Year
2002
Total Cost
$110,588
Indirect Cost
Name
University of Chicago
Department
Pathology
Type
Schools of Medicine
DUNS #
225410919
City
Chicago
State
IL
Country
United States
Zip Code
60637
Lingen, Mark W; Szabo, Eva (2012) Validation of LOH profiles for assessing oral cancer risk. Cancer Prev Res (Phila) 5:1075-7
Zhou, Guolin; Hasina, Rifat; Wroblewski, Kristen et al. (2010) Dual inhibition of vascular endothelial growth factor receptor and epidermal growth factor receptor is an effective chemopreventive strategy in the mouse 4-NQO model of oral carcinogenesis. Cancer Prev Res (Phila) 3:1493-502
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
Seiwert, Tanguy Y; Jagadeeswaran, Ramasamy; Faoro, Leonardo et al. (2009) The MET receptor tyrosine kinase is a potential novel therapeutic target for head and neck squamous cell carcinoma. Cancer Res 69:3021-31
Cohen, Ezra E W; Zhu, Hongyan; Lingen, Mark W et al. (2009) A feed-forward loop involving protein kinase Calpha and microRNAs regulates tumor cell cycle. Cancer Res 69:65-74
Hasina, Rifat; Martin, Leslie E; Kasza, Kristen et al. (2009) ABT-510 is an effective chemopreventive agent in the mouse 4-nitroquinoline 1-oxide model of oral carcinogenesis. Cancer Prev Res (Phila) 2:385-93
Hasina, Rifat; Whipple, Mark E; Martin, Leslie E et al. (2008) Angiogenic heterogeneity in head and neck squamous cell carcinoma: biological and therapeutic implications. Lab Invest 88:342-53
Nickoloff, Brian J; Lingen, Mark W; Chang, Bey-Dih et al. (2004) Tumor suppressor maspin is up-regulated during keratinocyte senescence, exerting a paracrine antiangiogenic activity. Cancer Res 64:2956-61
Kuo, Winston Patrick; Jenssen, Tor-Kristian; Park, Peter J et al. (2002) Gene expression levels in different stages of progression in oral squamous cell carcinoma. Proc AMIA Symp :415-9
Todd, Randy; Lingen, Mark W; Kuo, Winston P (2002) Gene expression profiling using laser capture microdissection. Expert Rev Mol Diagn 2:497-507