Abstract
We initiated a transgenic model for primary pulmonary neuroendocrine cell (PNEC) hyperplasia/neoplasia using v-Ha-ras driven by the neural/neuroendocrine (NE)-specific calcitonin promoter (rascal). Previously, we showed that nitrosamine treated rodents develop PNEC hyperplasia but non-NE lung tumors, with variable outcomes presumably reflecting ras activation in multiple cell lineages. Interestingly, all rascal transgenic mouse lineages develop hyperplasias of NE and non-NE cells but mostly non-NE lung carcinomas, with rascal mRNA in differentiated PNECs and tumor cells. Analyses of embryonic lung demonstrate rascal mRNA in undifferentiated epithelium, consistent with expression in a common pluripotent precursor cell. These unexpected observations indicate that v-Ha-ras can lead to both NE and non-NE hyperplasia/neoplasia in vivo, opening new avenues for studies of lung carcinogenesis.
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Abbreviations
- CGRP:
-
calcitonin gene-related peptide
- H&E:
-
hematoxylin and eosin
- MTC:
-
medullary carcinoma of the thyroid
- NE:
-
neuroendocrine
- NSCLC:
-
non-small cell lung carcinoma
- PBS:
-
phosphate-buffered saline
- PGP9.5:
-
protein gene product 9.5
- PNEC:
-
pulmonary NE cell
- RT – PCR:
-
reverse transcription polymerase chain reaction
- SCLC:
-
small cell carcinoma of the lung
- Tag:
-
SV40 large T antigen
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Acknowledgements
The authors would like to thank Dr Mark Fishman for the v-Ha-ras construct, Dr Mark Swanson and DNX for generation of the five rascal transgenic founders, and Hai Dong in the Brigham and Women's Hospital Pathology laboratory for assistance with cutting thin sections. We acknowledge the technical assistance of Dr Donald Johnston. This work was supported in part by NIH grants #RO1-HL44984 and -HL50045 (ME Sunday); production of the rascal transgenic mice at DNX was supported by the National Institute of Child Health and Human Development contract NO1-HD02911.
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Sunday, M., Haley, K., Sikorski, K. et al. Calcitonin driven v-Ha-ras induces multilineage pulmonary epithelial hyperplasias and neoplasms. Oncogene 18, 4336–4347 (1999). https://doi.org/10.1038/sj.onc.1202810
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DOI: https://doi.org/10.1038/sj.onc.1202810
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