However, these mice develop tumors only after a prolonged latency period ( 9), which suggests that islet tissues must acquire additional sequential mutations to cooperate with Men1 mutation for progression to PanNET. Transgenic mouse models with conditional deletion of Men1 in pancreatic islet cells develop PanNETs. Mice with heterozygous Men1 deletion develop a spectrum of endocrine tumors, including pancreatic islet tumors, similar to that observed in human patients carrying germline mutant alleles ( 8). Among these aberrations, somatic inactivation of MEN1, a tumor suppressor gene that acts as a nuclear scaffold to modulate chromatin structure and selectively regulate gene transcription, is among the most common events in the initiation of PanNETs ( 5, 7). Recent studies analyzing the genomic landscape of PanNETs show that key genes regulating mTOR signaling, histone modifications, telomere length, and DNA damage are targets for mutations in PanNET tissues ( 5, 6). A statistically significant increase in the incidence of PanNETs has been reported in past decades ( 2), coinciding with new insights about molecular and cell signaling pathways underlying tumor progression ( 3, 4). Pancreatic neuroendocrine tumors (PanNETs) are neoplasms arising from specialized islet cells within the pancreas, conferring a median overall survival of 3.6 years based on estimates for tumors diagnosed between 19 ( 1). This work will refocus attention on new strategies to inhibit TS activity for PanNET treatment. In summary, elevated hTS directly participates in promoting PanNET tumorigenesis with reduced survival in Men1-mutant background. In addition, we analyzed the survival of 88 patients with PanNETs and observed that high TS protein expression independently predicted worse clinical outcomes. We showed that elevated hTS in Men1-deleted tumor cells enhanced cell proliferation, deregulated cell cycle kinetics, and was associated with a higher frequency of somatic mutations, DNA damage, and genomic instability. We also observed a decrease in overall survival of hTS/Men1 +/– and hTS/Men1 –/– mice as compared with control mice.
We demonstrated that increased hTS expression was associated with earlier tumor onset and accelerated PanNET development in comparison with control Men1 –/– and Men1 +/ ΔN3-8 mice.
To study the causal impact of elevated TS levels in PanNETs, we generated a mouse model with elevated human TS (hTS) and conditional inactivation of the Men1 gene in pancreatic islet cells ( hTS/Men1 –/–). We previously showed that elevated TS exhibits properties of an oncogene and promotes pancreatic neuroendocrine tumors (PanNETs) with a long latency. Clinical studies of cancer patients have shown that overexpression or amplification of thymidylate synthase (TS) correlates with a worse clinical outcome.
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