Biological and oncogenic properties of p53-deficient salivary gland epithelial cells with particular emphasis on stromal-epithelial interactions in tumorigenesis.
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.


CONCLUSIONS
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.
Obara
Kumi
K
Department of Pathology, Tsurumi University School of Dental Medicine, Yokohama, Japan.
Ide
Fumio
F
Mishima
Kenji
K
Inoue
Hiroko
H
Yamada
Hiroyuki
H
Hayashi
Yoshio
Y
Saito
Ichiro
I
D008949:Adenoma, Pleomorphic / Q000378:metabolism / Q000473:pathology; D000818:Animals; D015153:Blotting, Western; D002450:Cell Communication / Q000502:physiology*; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D003094:Collagen; D004268:DNA-Binding Proteins / Q000378:metabolism; D004338:Drug Combinations; D004847:Epithelial Cells / Q000378:metabolism*; D005260:Female; D007150:Immunohistochemistry; D007797:Laminin; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D009374:Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology; D011509:Proteoglycans; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012468:Salivary Gland Neoplasms / Q000378:metabolism / Q000473:pathology; D012469:Salivary Glands / Q000378:metabolism* / Q000648:ultrastructure; D012509:Sarcoma / Q000378:metabolism / Q000473:pathology; D017154:Stromal Cells / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency*
D004268:DNA-Binding Proteins; D004338:Drug Combinations; D007797:Laminin; C491264:Plag1 protein, mouse; D011509:Proteoglycans; D016159:Tumor Suppressor Protein p53; C059485:matrigel; D003094:Collagen; D017526:Receptor, IGF Type 1