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  • Original Paper
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Calcitonin driven v-Ha-ras induces multilineage pulmonary epithelial hyperplasias and neoplasms

Oncogene volume 18, pages 4336–4347 (1999)Cite this article

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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  1. Children's Hospital, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, Massachusetts, USA

    Mary E Sunday, Kathleen J Haley, Kristan Sikorski, Sherry A Graham, Rodica L Emanuel, Fan Zhang, QiQi Mu, Aliakbar Shahsafaei & Dimitrios Hatzis

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  1. Mary E Sunday
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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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