Heterogeneity in signaling pathways of gastroenteropancreatic neuroendocrine tumors: a critical look at notch signaling pathway

Abstract

The molecular pathogenesis of gastroenteropancreatic neuroendocrine tumors is largely unknown. We hypothesize that gastroenteropancreatic neuroendocrine tumors are heterogeneous with regard to these signaling pathways and these differences could have a significant impact on the outcome of clinical trials. We selected 120 well-differentiated neuroendocrine tumors including tumors originating in pancreas (n ¼ 74), ileum (n ¼ 31), and rectum (n ¼ 15). Immunohistochemistry was performed on tissue microarrays using the following antibodies: NOTCH1, HES1, HEY1, pIGF1R, and FGF2. Gene profiling study was performed by using human genome U133A 2.0 array and data were analyzed. The gene profiling results were selectively confirmed by using quantitative reverse-transcription PCR. Initial immunohistochemical analysis showed NOTCH1 was uniformly expressed in rectal neuroendocrine tumors (100%), a subset of pancreatic neuroendocrine tumors (34%), and negative in ileal neuroendocrine tumors. Similarly, a downstream target of NOTCH1, HES1 was preferentially expressed in rectal neuroendocrine tumors (64%), a subset of pancreatic neuroendocrine tumors (10%), and uniformly negative in ileal neuroendocrine tumors. Messenger RNAs for NOTCH1, HES1, and HEY1 were 2.32-, 2.44-, and 2.39-folds, respectively, higher in rectal neuroendocrine tumors as compared with ileal neuroendocrine tumors. Global gene expression profiling showed 95 genes were differentially expressed in small intestinal vs rectal neuroendocrine tumors, with changes as high as 50-fold. These genes were concentrated in several signal transduction pathways including cancer endocrine pathway and cell growth/proliferation pathway. The differential expression of selected genes including ISL LIM homeobox 1, cathepsin B, glucagon, and tryptophan hydroxylase 1 were confirmed by qPCR and immunohistochemistry. Our results confirm the heterogeneity in signaling pathways of gastroenteropancreatic neuroendocrine tumors. NOTCH1 inhibitors are unlikely to provide benefit in ileal neuroendocrine tumors; conversely, their efficacy in rectal neuroendocrine tumors needs further study. Further analysis of signaling pathways is critical for designing clinical trials in gastroenteropancreatic neuroendocrine tumors.

Notch1 Activation Up-Regulates Pancreatic and Duodenal Homeobox-1

“…These data further support the concept that Notch1 activation up-regulates PDX-1 expression and that Notch1 activation may contribute to the overexpression of PDX-1 in PNETs. Notch1 has been reported to be expressed in PNET with accompanied expression of HES1, a downstream target of Notch1 [57]. Our studies showed that the majority of human PNET specimens expressed NICD in correlation with PDX-1 overexpression.…”

Goblet cell carcinoids of the appendix: Tumor biology, mutations and management strategies

“…However Notch signaling also appears to have a tumor suppressor role in gastrointestinal, thyroid and pulmonary neuroendocrine tumors[42,48,49]. In another recent study of 31 ileal carcinoids, Notch signaling was uniformly absent in ileal neuroendocrine tumors suggestive of loss of tumor suppressive role[50]. Is the loss of Notch signaling, the driving mutation and occurs after the first stem cell division at the level of transit amplifying cells with subsequent progeny showing dysfunction?…”

Notch1-Hes1 signalling axis in the tumourigenesis of biliary neuroendocrine tumours

“…However, this histogenesis of NET is not common in any NETs. Wang et al 20 reported that gastroenteropancreatic NETs were heterogeneous with regard to the Notch1-HES1 signalling pathway; Notch1 and Hes1 were preferentially expressed in rectal NETs and a subset of pancreatic NETs, but uniformly negative in ileal NETs, indicating the heterogeneity in signalling pathways of gastroenteropancreatic NETs. Moreover, in the developing endoderm, disruption of Notch-Hes1 signalling results in precocious endocrine differentiation in the pancreas.…”