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Mark W. Lingen, D.D.S., Ph.D.Basic and Translational Research Focused on Tumor Angiogenesis, Tumor Suppressor Gene Biology and Molecular DiagnosticsResearch SummaryMy laboratory is actively involved in a number of facets of cancer research. Tumor angiogenesis is a long-standing interest of ours and this area of research represents the majority of the lab’s NIH funding. Within this dynamic area of investigation, we are pursuing the hypothesis that inhibitors of angiogenesis may be useful in a chemoprevention setting, using head and neck squamous cell carcinoma (HNSCC) as a model. Despite advances in treatment, the five-year survival for HNSCC has not changed in the last 50 years. This poor outcome is due to a number of variables including multiple primary tumors. Therefore, it is essential to supplement early detection with effective prevention strategies. The expression of the angiogenic phenotype is both a very early and an essential step in the development of HNSCC, making it an attractive target for cancer prevention. The long-term goal of this work is to develop novel, nontoxic chemopreventive strategies for HNSCC that are based upon the inhibition of angiogenesis, which would be of dramatic clinical benefit to large numbers of patients who are at tremendous risk for developing multiple lesions throughout their upper aerodigestive tract.In addition, we are pursuing molecularly-based diagnostic protocols for HNSCC. Current diagnostic techniques for premalignant disease, based upon histologic recognition of nuclear and cellular atypia, are relatively poor predictors of ultimate clinical outcome. Since morphological or cytological changes may occur late in the process of transformation, histologically benign-appearing lesions may have malignant potential. Therefore, methods for detecting molecularly pre-malignant lesions at an earlier stage are required. The long-term goal of this work is to define a profile of molecular markers of premalignancy for HNSCC. The hypothesis underlying this work is that specific gene/protein expression patterns between normal, reactive, and dysplastic oral mucosa will be distinctly different. Upon the identification of a subset of genes that can be used as potential biomarkers capable of predicting progression to dysplasia, a large-scale prospective analysis will be initiated in order to validate their potential utility for molecular diagnostics. The confirmation of such biomarkers will provide us with the ability to detect premalignant lesions at a much earlier stage, which should markedly increase our ability to detect, prevent and treat this devastating disease. Finally, my lab has recently cloned a novel tumor suppressor gene (NOL7) whose expression is lost in cervical cancer (CC). NOL7 is a nucleolar protein whose gene is located at the 6p23 locus, and demonstrates LOH in 40% of CC. Re-introduction of NOL7 into CC cells lines suppresses tumor growth by 95%. The induction of tumor dormancy correlated with an angiogenic switch caused by a decreased production of vascular endothelial growth factor (VEGF) and an increase in the production of the angiogenesis inhibitor thrombospondin-1 (TSP-1). These data suggest that NOL7 may function as a tumor suppressor gene in part by modulating the expression of the angiogenic phenotype. A number of basic cell and molecular projects to expand on our findings are underway in the lab.
Selected PapersLingen MW, Chang K-W, Pelzer HJ, Kies MS, Mittal BB, Solt DB, and McMurray SJ. (2000). Overexpression of p53 in squamous cell carcinoma of the tongue in young patients with no known risk factors is not associated with mutations in exons 5-9. Head & Neck, 22:328-335. Kini AR, Peterson LC, Tallman MS, Lingen MW. (2001). All-trans retinoic acid (ATRA) inhibits vascular endothelial growth factor (VEGF)-mediated angiogenesis in acute promyelocytic leukemia (APL). Blood, 97:3919-3924. Liss C, Fekete MJ, Hasina R, Lam CD, Lingen MW. (2001). Characterization of a paracrine loop for the expression of the angiogenic phenotype in head and neck cancer. International Journal of Cancer, 93:781-785. Liss C, Fekete MJ, Hasina R, Lingen MW. (2002). Retinoic acid modulates the ability of macrophages to participate in the induction of the angiogenic phenotype in head and neck squamous cell carcinoma. International Journal of Cancer Research, 100: 283-289. Cline EI, Bicciato S, DiBello C, Lingen MW. (2002). Prediction of in vivo synergistic anti-angiogenic activity by gene expression profiling. Cancer Research, 62:7143-7148. Hasina R, Hulett K, Bicciato S, Petruzzelli G, Lingen
MW. (2003). Plasminogen
Activator Inhibitor-2: A Molecular Biomarker for Head and Neck Cancer
Progression. Cancer Research, 63:555-559. Hasina R, Fekete MJ, Martin L, Qi X-M, Brigaudeau C,
Pramanik R, Edith I. Cline, Coignet L, Lingen MW. (2006). NOL7 is a
Nucleolar
Candidate Tumor Supressor Gene in Cervical Cancer that Modulates the
Angiogenic Phenotype. Oncogene, 25:588-598. |
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