Abstract
BackgroundA large fraction of murine tumors induced by transgenic expression of SV40 large T antigen (SV40 TAg) exhibits a neuroendocrine phenotype. It is unclear whether SV40 TAg induces the neuroendocrine phenotype by preferential transformation of progenitor cells committed to the neuroendocrine lineage or by transcriptional activation of neuroendocrine genes.Methodology/Principal FindingsTo address this question we analyzed CEA424-SV40 TAg-transgenic mice that develop spontaneous tumors in the antral stomach region. Immunohistology revealed expression of the neuroendocrine marker chromogranin A in tumor cells. By ELISA an 18-fold higher level of serotonin could be detected in the blood of tumor-bearing mice in comparison to nontransgenic littermates. Transcriptome analyses of antral tumors combined with gene set enrichment analysis showed significant enrichment of genes considered relevant for human neuroendocrine tumor biology. This neuroendocrine gene signature was also expressed in 424GC, a cell line derived from a CEA424-SV40 TAg tumor, indicating that the tumor cells exhibit a similar neuroendocrine phenotype also in vitro. Treatment of 424GC cells with SV40 TAg-specific siRNA downregulated expression of the neuroendocrine gene signature.Conclusions/SignificanceSV40 TAg thus appears to directly induce a neuroendocrine gene signature in gastric carcinomas of CEA424-SV40 TAg-transgenic mice. This might explain the high incidence of neuroendocrine tumors in other murine SV40 TAg tumor models. Since the oncogenic effect of SV40 TAg is caused by inactivation of the tumor suppressor proteins p53 and RB1 and loss of function of these proteins is commonly observed in human neuroendocrine tumors, a similar mechanism might cause neuroendocrine phenotypes in human tumors.
Highlights
A number of different strategies have been adopted to create transgenic murine tumor models which mirror human malignant disease
At day 30 (d30), CEA424SV40 TAg-transgenic mice exhibit small multifocal tumor lesions in the pyloric region of the antrum (Figure 1 H, inset) which grow exponentially leading to extended tumors at an age of 90 days which infiltrate into the duodenum and cause death within a further 2–3 weeks probably by pyloric stenosis (Figure 1 D)
A substantial fraction of the most highly expressed and most strongly upregulated genes comprised genes characteristic for the neuroendocrine lineage, e.g. genes encoding chromogranin B (Chgb), secretin (Sct), glucagon (Gcg), secretogranin II (Scg2) and tryptophan hydroxylase (Tph1) (Figure 1 A–C; Table S2). This finding was substantiated using gene set enrichment analyses (GSEA) by comparing the d90 tumor versus normal tissue ranked gene list with a list of 399 genes preferentially expressed after transdifferentiation of ATP4B-expressing gastric preparietal progenitor cells, without neuroendocrine features, into locally invasive or metastatic neuroendocrine tumor cells in gastric tumors of Atp4b promoter-SV40 TAg-transgenic mice (Table 5 in [4])
Summary
A number of different strategies have been adopted to create transgenic murine tumor models which mirror human malignant disease. Inactivation of the RB proteins leads to loss of suppression of a family of E2F transcription factors which in turn induce expression of cell cycle-promoting genes. The majority of SV40 TAg-induced tumors exhibit a neuroendocrine phenotype [4,5,6,7,8,9]. A large fraction of murine tumors induced by transgenic expression of SV40 large T antigen (SV40 TAg) exhibits a neuroendocrine phenotype. It is unclear whether SV40 TAg induces the neuroendocrine phenotype by preferential transformation of progenitor cells committed to the neuroendocrine lineage or by transcriptional activation of neuroendocrine genes
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