Distinct Effects of Genetic and Chronologic Aging on Oral Carcinogenesis

Telomere length decreases with age which may be a predisposing factor for tumor formation in epithelial tissues. However the histopathologic spectrum of tumors arising in genetically vs. chronologically aged animal models only partially overlaps. Hypothesis: Oral cancer arising in genetically vs. chronologically aged mice exhibits distinct genotypic and phenotypic differences. Objectives: To characterize the phenotypic and genetic differences of oral cancer arising in late generation telomerase null mutant (Terc-/-) and chronologically aged mice. Methods: One month old Terc+/+, one month old first generation (G1) Terc-/-, one month old fifth generation (G5) Terc-/-, and 1 year old Terc+/+ mice (C57Bl6 background) were orally dosed twice weekly with 25 ug dimethylbenzanthracene to induce squamous cell carcinomas (SCC). Tumors were harvested for histopathologic and gene expression analyses when euthanasia criteria were achieved for each mouse. Results: One year old Terc+/+ mice developed oral SCC significantly earlier than 1 month old Terc+/+ or Terc-/- mice (18 vs. 22 wks, p<0.03). Primary tumors in 1 year old Terc+/+ mice were less vascularized than those in 1 month old Terc+/+ and Terc-/- animals and developed large areas of necrosis. However, vascular endothelial growth factor expression was not significantly different in primary tumors from these groups of mice. Tumor bearing 1 year old Terc+/+ and G1 Terc-/- mice exhibited significantly decreased cervical lymph node metastasis compared to 1 month old Terc+/+ or G5 Terc-/- mice (1.8, 2.5, 4.1, and 3.5 positive nodes/mouse respectively; p<0.01). Immunohistochemical studies of oral SCC in the mouse revealed gene expression changes similar to those found in the human disease. We also demonstrated distinct patterns of gene expression which correlated with metastasis, loss of telomerase activity, and chronologic aging. Conclusions: Aging produces distinct phenotypic and gene expression changes in oral SCC not found in tumors from genetically aged mice. NIH grant DE14283