Growing evidence indicates that tumor development and progression of experimental skin squamous cell carcinoma (SCC) induced by chemical carcinogens and promoters, are a consequence of genetic lesions that include not only abnormalities in known oncogenes and tumor suppressor genes but also the overexpression of cell cycle related genes (CCRG) such as cyclin D1. In the present proposal, we intend to study a group of human SCC's of the oral cavity that have a strong etiological linkage with alcohol and tobacco consumption and also harbor similar abnormalities in cyclin D1. The principal objective of this proposal is to demonstrate alterations in CCRGs expression that contribute to tumor development and progression and investigate the mechanism underlying the increased level of CCRG protein expression. The hypothesis to be tested in this application is that increased expression of multiple G1 cyclins and their respective Cdk's can be used as markers of poor prognosis in human head and neck SCC's, and that this occurs in most cases without gene amplification mechanisms such as increased half-life of the protein. In order to achieve this we plan to: a) detect changes in G1/S cyclins, and their respective cyclin dependent kinases in oral cancer and its precursors, b) utilize an extensive epidemiological data bank at our disposal to evaluate the role of CCRG abnormalities in oral cancer as function of tobacco-alcohol consumption as well as dietary habits and family-clinical history, c) confirm in a large series of human lesions that CCRG overexpression could be used as marker of tumor progression and poor prognosis, d) determine which component of the invasive/metastatic cascade is implicated in this process of tumor progression and e) investigate in selected SCC cell lines systems which CCRGs are the most significant in inducing enhancement of the malignant phenotype, and which are the basic mechanisms behind the overexpression of CCRGs in SCC cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA071539-02
Application #
2668049
Study Section
Chemical Pathology Study Section (CPA)
Program Officer
Okano, Paul
Project Start
1997-05-15
Project End
2002-02-28
Budget Start
1998-03-01
Budget End
1999-02-28
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Fox Chase Cancer Center
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19111
Mahloogi, Haleh; Gonzalez-Guerrico, Anatilde M; Lopez De Cicco, Ricardo et al. (2003) Overexpression of the calcium sensor visinin-like protein-1 leads to a cAMP-mediated decrease of in vivo and in vitro growth and invasiveness of squamous cell carcinoma cells. Cancer Res 63:4997-5004
Mercapide, Javier; Zhang, Shi Yu; Fan, Xing et al. (2002) CCND1- and ERBB2-gene deregulation and PTEN mutation analyses in invasive lobular carcinoma of the breast. Mol Carcinog 35:6-12
Liu, Shao Chen; Bassi, Daniel E; Zhang, Shi Yu et al. (2002) Overexpression of cyclin D2 is associated with increased in vivo invasiveness of human squamous carcinoma cells. Mol Carcinog 34:131-9
Liu, S C; Zhang, S Y; Babb, J S et al. (2001) Image cytometry of cyclin D1: a prognostic marker for head and neck squamous cell carcinomas. Cancer Epidemiol Biomarkers Prev 10:455-9
Salter, E R; Tichansky, D; Furth, E E et al. (2001) Tumor-associated antigen expression and growth requirements predict tumorigenesis in squamous cell carcinoma. In Vitro Cell Dev Biol Anim 37:530-5
Liu, S C; Klein-Szanto, A J (2000) Markers of proliferation in normal and leukoplakic oral epithelia. Oral Oncol 36:145-51
Zhang, S Y; Liu, S C; Johnson, D G et al. (2000) E2F-1 gene transfer enhances invasiveness of human head and neck carcinoma cell lines. Cancer Res 60:5972-6
Zhang, S Y; Liu, S C; Al-Saleem, L F et al. (2000) E2F-1: a proliferative marker of breast neoplasia. Cancer Epidemiol Biomarkers Prev 9:395-401
Liu, S C; Hu, Y; Sauter, E R et al. (1999) Image analysis of p53 and cyclin D1 expression in premalignant lesions of the oral mucosa. Anal Quant Cytol Histol 21:166-73
Liu, S C; Sauter, E R; Clapper, M L et al. (1998) Markers of cell proliferation in normal epithelia and dysplastic leukoplakias of the oral cavity. Cancer Epidemiol Biomarkers Prev 7:597-603