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NSP-encoded Reticulons Are Neuroendocrine Markers of a Novel Category in Human Lung Cancer Diagnosis¹

Laboratory for Molecular Oncology, Center for Human Genetics, University of Leuven, Herestraat 49 [H. J. K. v. d. V., A. J. M. R., W. J. M. V. d. V.], and Department of Histochemistry and Cytochemistry, University of Leuven, Minderbroedersstraat 12 [T. A. D. R.], B-3000 Leuven, Belgium, and Department of Molecular Cell Biology and Genetics, University of Limburg, Maastricht, the Netherlands [N. H. M. S., J. L. V. B., F. C. S. R.]

The NSP gene was recently shown to constitute the prototype of a novel gene family, to be selectively transcribed in neural and endocrine cells, and to encode three overlapping proteins, NSP-A, NSP-B, and NSP-C. These proteins were collectively designated reticulons, because they were found to be anchored to membranes of the endoplasmic reticulum through their common carboxy-terminal regions. The goal of the present study was to determine whether the reticulons might be used as markers for neuroendocrine differentiation in human lung tumors. Therefore, the tissue distribution of the NSP-A protein was studied and expression in human lung tumors was evaluated. Immunohistochemical analysis of normal tissues with monoclonal antibodies specifically recognizing the NSP-A protein indicated that NSP-A exhibits a distinct neuroendocrine distribution pattern since it was found to be expressed in a variety of cells with an established neuroendocrine phenotype but not in cells lacking such features. Results with specimens of a wide variety of primary human tumors provided further support for this claim. Immunohistochemical analysis of primary lung carcinomas revealed that NSP-A was readily detectable in small cell lung carcinoma (SCLCs) (8 of 12) and carcinoid tumors of the lung (3 of 3) but not in nonneuroendocrine non-SCLCs (0 of 10). In 13 of 27 non-SCLCs expressing the neural cell adhesion molecule and/or neurofilament proteins, however, NSP-A was found to be expressed. Northern blot analysis of human lung carcinoma cell lines revealed expression of NSP-A- and/or NSP-C-encoding mRNAs in all 18 SCLC cell lines that were studied, except one; however, no expression of these mRNAs could be detected in any of the 11 non-SCLC cell lines tested. The NSP transcript encoding NSP-B was found only in SCLC cell line NCI-H82. In conclusion, the results of our studies suggest that, in lung tumor cells, expression of NSP-A and most likely also NSP-C is restricted to cells with a neuroendocrine phenotype.

¹ This work was supported in part by the Nationaal Fonds voor Wetenschappelijk Onderzoek (NFWO), the Dutch Cancer Foundation (Project IKL90-09), and the Geconcerteerde Onderzoekacties 1992–1996. This text presents results of the Belgian Programme on Interuniversity Poles of Attraction initiated by the Belgian State, Prime Minister's Office, Science Policy Programming. The scientific responsibility is assumed by its authors. H. J. K. v. d. V. is a Research Assistant of the National Fund for Scientific Research (Belgium).

² To whom correspondence should be addressed.

Received 3/23/94. Accepted 6/22/94.

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