Heterogeneity in signaling pathways of gastroenteropancreatic neuroendocrine tumors: a critical look at notch signaling pathway.
Summary of "Heterogeneity in signaling pathways of gastroenteropancreatic neuroendocrine tumors: a critical look at notch signaling pathway."
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=74), ileum (n=31), and rectum (n=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.Modern Pathology advance online publication, 24 August 2012; doi:10.1038/modpathol.2012.143.
Affiliation
Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
Journal Details
This article was published in the following journal.
Name: Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc
ISSN: 1530-0285
Pages:
Links
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/22918166
- DOI: http://dx.doi.org/10.1038/modpathol.2012.143
Medical and Biotech [MESH] Definitions
Neuroendocrine Tumors
Tumors whose cells possess secretory granules and originate from the neuroectoderm, i.e., the cells of the ectoblast or epiblast that program the neuroendocrine system. Common properties across most neuroendocrine tumors include ectopic hormone production (often via APUD CELLS), the presence of tumor-associated antigens, and isozyme composition.
Carcinoma, Neuroendocrine
A group of carcinomas which share a characteristic morphology, often being composed of clusters and trabecular sheets of round "blue cells", granular chromatin, and an attenuated rim of poorly demarcated cytoplasm. Neuroendocrine tumors include carcinoids, small ("oat") cell carcinomas, medullary carcinoma of the thyroid, Merkel cell tumor, cutaneous neuroendocrine carcinoma, pancreatic islet cell tumors, and pheochromocytoma. Neurosecretory granules are found within the tumor cells. (Segen, Dictionary of Modern Medicine, 1992)
Synaptophysin
A 38-kDa integral membrane glycoprotein of the presynaptic vesicles in neuron and neuroendocrine cells. It is expressed by a variety of normal and neoplastic neuroendocrine cells and is therefore used as an immunocytochemical marker for neuroendocrine differentiation in various tumors. In ALZHEIMER DISEASE and other dementing disorders, there is an important synapse loss due in part to a decrease of synaptophysin in the presynaptic vesicles.
Smad Proteins, Inhibitory
A sub-family of smad proteins that inhibit cell signaling by RECEPTOR-REGULATED SMAD PROTEINS. They form autoinhibitory feedback loops in the TGF-BETA signaling pathway and mediate signaling cross-talk with other signaling pathways
Casein Kinase Ialpha
A casein kinase I isoenzyme that plays a role in intracellular signaling pathways including the CELL CYCLE, membrane trafficking, and RNA processing. In DROSOPHILA casein kinase Ialpha has been in regulation of Hedghog and Wingless signaling pathways. Multiple isoforms of casein kinase Ialpha exist and are due ALTERNATIVE SPLICING.
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