Neuroendocrine (ne) cell hyperplasia and non-ne tumors in transgenic mice with v-ha-ras driven by the calcitonin promoter
Ras mediated signalling can play a role in ME cell differentiation: transfection of v-Ha-ras into cultured NE tumor cells induces NE cell or non-NE features. We have generated transgenic mice with v-Ha-ras driven by the neural/NE-specific cjdcitonin/calcitonin gene-related peptide (CGRP) promoter. 5 "RASCAL" transgenic mouse lineages have been derived; transgene expression is strongest in thyroid and lung. Morphometric analyses of CGRP immunostained lung tissues from 23 RASCALs and 20 normal littermates demonstrated pulmonary NE cell hyperplasia, with a 3X increase in the mean number of CGRP-positive ecus per cm. of airway epithelium in RASCALs as compared to normals (65 ±17 versus 23 ±9, p = 0.04); 3 of these RASCALs had profound NE cell hyperplasia with >100 CGRP+ cells/cm. At autopsy of over 500 mice, 7 primary lung tumors were detected. 6 of these tumors were in RASCALs. Immunostaining demonstrated the type n cell marker SP-C in 4/6 tumors, the Clara cell specific antigen CC10 in 1/6, and the NE cell marker PGP9.5 in 1/6; 4/6 of the tumors were also mucin positive. Only one normal littermate had a microadenoma. Over 75% of mice also develop medullary thyroid (NE) carcinomas, 10% of which have both follicular (non-NE) and NE differentiation. In conclusion, in some animals, v-Ha-ras expression may occur in a bipotential stem cell which leads to both ME and non-NE epithelial cell hyperplasia or neoplasia.
Sunday, ME; Mu, Q; Fishman, M; Hatzis, D
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