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Human Bronchial Epithelial Cells Transformed by the c-raf-1 and c-myc Protooncogenes Induce Multidifferentiated Carcinomas in Nude Mice: A Model for Lung Carcinogenesis

Laboratory of Human Carcinogenesis [A. M. A. P., D. M., E. S., C. C. H.] and Laboratory of Biology [P. E. B.], National Cancer Institute, NIH, Bethesda, Maryland 20892; Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland 21201 [R. T. J., B. F. T.]; and Department of Pathology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111 [A. J. P. K.]

We have previously described the neoplastic transformation of immortalized human bronchial epithelial cells (BEAS-2B) by the combination of the c-raf-1 and c-myc protooncogenes and the concomitant induction of neuron-specific enolase mRNA expression (A. Pfeifer et al., Proc. Natl. Acad. Sci. USA, 86: 10075–10079, 1989). In this paper we describe the morphological, biochemical, and immunohistochemical characteristics of the primary c-raf-1/c-myc tumors, xenografts of these tumors, and tumors that originated from cell lines of the primary neoplasm. The tumors were morphologically characterized by the appearance of desmosomes and tonofilaments, microvilli, and dense core granules representing markers of squamous, glandular, and neuroendocrine differentiation, respectively. A total of 11 of 13 tumors were positive by immunohistochemical techniques for neuron-specific enolase, serotonin (nine of 13), and calcitonin (six of 13). Keratins were expressed in 11 of 13 tumors, and while specific keratins (K5, K7, K16/K17) decreased, there was an increase of vimentin in the tumor cells. Gastrin-releasing peptide immunoreactivity was detectable in a small number of tumors (five of 13). BEAS-2B cells transfected with the c-raf-1 and c-myc protooncogenes and cell lines established from the primary tumors expressed major histocompatibility Class II antigen which has been found on small cell lung carcinoma cells. The tumors induced by the c-raf-1 and c-myc protooncogenes resemble the multidifferentiated phenotype of small cell lung cancer frequently detected in vivo and present a defined model to study the relation between molecular markers, phenotypical appearance, and response to chemotherapeutic agents and radiation.

¹ Present address: Centre de Recherche Nestle, Vers-Chez-LeBlanc, 1000 Lausanne 26, Switzerland.

² Present address: Biological Sciences, University of Dundee, Dundee DD5 4DU, Scotland, United Kingdom.

³ Present address: Frederick Cancer Research Development Center, P. O. Box B, Seventh St., Frederick, MD 21701.

⁴ To whom requests for reprints should be addressed, at Laboratory of Human Carcinogenesis, National Cancer Institute, NIH, Bldg. 37, Room 2C05, Bethesda, MD 20892.

Received 12/10/90. Accepted 4/25/91.

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