HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Accepted manuscript (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Engelmann, D. Articles by Pützer, B. PubMed PubMed Citation Articles by Engelmann, D. Articles by Pützer, B.

D Engelmann, Vectorology and Experimental Gene Therapie, University of Rostock, Rostock, Germany
D Koczan, Institute of Immunology, University of Rostock, Rostock, Germany
P Ricken, Vectorology and Experimental Gene Therapie, University of Rostock, Rostock, Germany
U Rimpler, Vectorology and Experimental Gene Therapie, University of Rostock, Rostock, Germany
J Pahnke, Neurology, University of Rostock, Rostock, Germany
Z Li, Vectorology and Experimental Gene Therapie, University of Rostock, Rostock, Germany
B Pützer, Vectorology and Experimental Gene Therapie, University of Rostock, Rostock, 18055, Germany

Correspondence: Brigitte Pützer, Email: brigitte.puetzer{at}med.uni-rostock.de

Abstract

Activating mutations in the RET proto-oncogene are responsible for occurence of multiple endocrine neoplasia (MEN) type 2A and 2B, and familial medullary thyroid carcinoma (FMTC). A striking genotype-phenotype correlation between the mutated RET codon and clinical manifestation implies that tumorigenesis is conditioned by the type of mutation. We investigated gene expression profiles between and within distinct MEN2 subtypes through whole-genome microarray analysis in xenograft tumors induced by NIH-3T3 cells transformed with defined RET-MEN2A (C609Y, C634R), MEN2B (A883F, M918T) and FMTC (Y791F) mutations. Expression profiling identified a statistically significant modification of 1494 genes, 628 down- and 866 upregulated in MEN2B compared to MEN2A/FMTC tumors. In contrast, no obvious alterations were observed among individual MEN2B and MEN2A type mutations, or between MEN2A and FMTC. Functional clustering of differential genes revealed RET-MEN2B specific upregulation of genes associated with novel growth and survival pathways. Intriguingly, RET-MEN2A/FMTC specific tumors were characterized by a considerable number of genes involved in the host antitumor immune response via stimulation of natural killer/T cell proliferation, migration and cytotoxicity, which were completely absent in RET-MEN2B related cancers. QPCR on tumors versus cultured NIH-RET cell lines demonstrated that they are largely attributed to the host innate immune system, whereas expression of CX3CL1 involved in leukocyte recruitment is exclusively RET-MEN2A/FMTC-tumor cell dependent. In correlation, massive inflammatory infiltrates were apparent only in tumors carrying MEN type 2A/FMTC mutations, suggesting that RET-MEN2B receptors specifically counteract immune infiltration by preventing chemokine expression, which may contribute to the different clinical outcome of both subtypes.