Oral squamous cell carcinoma (SCC) cells infiltrate into adjacent tissues, degrading basement membranes and extracellular matrix, and display unregulated growth. In contrast to normal mucosa where epithelial proliferation is highly regulated and is restricted to the basal cell layer, SCC cells proliferate rapidly throughout the suprabasal cell layers. Furthermore, the survival and growth of normal epithelial cells require signals generated by integrin-matrix interactions, and the detachment induced apoptosis (anoikis) is followed by induction of terminal differentiation. However, suprabasal oral SCC cells in vivo are devoid of integrin engagement generally escape apoptosis and are able to survive and proliferate. We have identified a novel mechanism by which oral SCC cells enhance their survival through formation of intracellular adhesions in a process we have called """"""""synoikis"""""""". The goal of the proposed research is to define the importance of both matrix and cell-cell adhesion in regulating survival and growth of oral SCC cells. The following specific aims will be addressed: 1) Determine how loss of integrin-ECM adhesion initiates anoikis. 2), Define the molecular basis of cell-cell adhesion-dependent survival in synoikis. 3). Determine how cell adhesion activates growth factor receptors. These studies will help expand our understanding, at the molecular level, of the mechanisms through which cell adhesion regulates survival and uncontrolled intratumoral growth of oral cancer and provide the biological basis for discovery of new therapeutic strategies targeted to this debilitating disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE011436-12
Application #
7157635
Study Section
Oral Biology and Medicine Subcommittee 1 (OBM)
Program Officer
Shirazi, Yasaman
Project Start
1995-04-01
Project End
2008-12-31
Budget Start
2007-01-01
Budget End
2007-12-31
Support Year
12
Fiscal Year
2007
Total Cost
$307,051
Indirect Cost
Name
University of California San Francisco
Department
Anatomy/Cell Biology
Type
Schools of Dentistry
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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Humtsoe, J O; Kramer, R H (2010) Differential epidermal growth factor receptor signaling regulates anchorage-independent growth by modulation of the PI3K/AKT pathway. Oncogene 29:1214-26
Ishikawa, Tohru; Kramer, Randall H (2010) Sdc1 negatively modulates carcinoma cell motility and invasion. Exp Cell Res 316:951-65
Zuo, Jianhong; Ishikawa, Tohru; Boutros, Shadi et al. (2010) Bcl-2 overexpression induces a partial epithelial to mesenchymal transition and promotes squamous carcinoma cell invasion and metastasis. Mol Cancer Res 8:170-82
Onishi, Akiko; Chen, Qianming; Humtsoe, Joseph O et al. (2008) STAT3 signaling is induced by intercellular adhesion in squamous cell carcinoma cells. Exp Cell Res 314:377-86
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Shen, Xiaodong; Kramer, Randall H (2004) Adhesion-mediated squamous cell carcinoma survival through ligand-independent activation of epidermal growth factor receptor. Am J Pathol 165:1315-29
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Vizirianakis, Ioannis S; Chen, Yao-Qi; Kantak, Seema S et al. (2002) Dominant-negative E-cadherin alters adhesion and reverses contact inhibition of growth in breast carcinoma cells. Int J Oncol 21:135-44

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