Biological and Oncogenic Properties of p53-Deficient Salivary Gland Epithelial Cells with Particular Emphasis on Stromal-Epithelial Interactions in Tumorigenesis

Abstract

Objective: To understand the salivary gland pathobiology, we established an immortalized duct/basal cell line (MSE) from the submandibular glands of p53-deficient mice. Methods: A variety of culture assays and xenograft experiments were conducted. Cellular characteristics were analyzed using histological, immunohistochemical, ultrastructural, and molecular techniques. Results: Inoculation of a mixture of MSE and Matrigel reconstructed polarized ducts whereas cotransplantation of MSE with both Matrigel and NIH3T3 (3T3) cells developed mixed tumors of adenoma and sarcoma. A daughter adenoma line (MSA) showed some transformed phenotype in vitro, but was marginally tumorigenic in vivo. Notably, pleomorphic adenoma gene 1 (PLAG1) was expressed in MSA but not in MSE. As compared with MSE, MSA showed higher levels of insulin-like growth factor-I receptor (IGF-IR). Interestingly, 3T3 sarcoma secreted insulin-like growth factor-II (IGF-II), while MSA did not. Conclusion: The intrinsic tumorigenic programs of p53 null salivary epithelium are promoted by 3T3 sarcoma-derived IGF-IIin a paracrine manner through overexpression of PLAG1 and IGF-IR.