Ligand-dependent Notch signaling is involved in tumor initiation and tumor maintenance in pancreatic cancer
| Autor: | Xing Fan, William Matsui, Georg Feldmann, Yue Ming Li, Anirban Maitra, Charles G. Eberhart, Jan Bart M. Koorstra, G. Johan A. Offerhaus, Clark M. Henderson, Michael Mullendore |
|---|---|
| Přispěvatelé: | Pathology |
| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
Cancer Research
medicine.medical_specialty Pancreatic disease Notch signaling pathway Tumor initiation Biology Ligands Article RNA interference Internal medicine Pancreatic cancer Cell Line Tumor medicine Humans Receptor Notch2 Enzyme Inhibitors Receptor Notch1 Cell Proliferation Receptors Notch Cell growth Gene Amplification Intracellular Signaling Peptides and Proteins Cancer Membrane Proteins Aldehyde Dehydrogenase medicine.disease Pancreatic Neoplasms Endocrinology Oncology Mutation Cancer research Intercellular Signaling Peptides and Proteins Signal transduction Amyloid Precursor Protein Secretases Jagged-2 Protein Signal Transduction |
| Zdroj: | Clinical cancer research, 15(7), 2291-2301. American Association for Cancer Research Inc. |
| ISSN: | 1078-0432 |
| Popis: | Purpose: Aberrant activation of the Notch signaling pathway is commonly observed in human pancreatic cancer, although the mechanism(s) for this activation has not been elucidated. Experimental Design: A panel of 20 human pancreatic cancer cell lines was profiled for the expression of Notch pathway-related ligands, receptors, and target genes. Disruption of intracellular Notch signaling, either genetically by RNA interference targeting NOTCH1 or pharmacologically by means of the γ-secretase inhibitor GSI-18, was used for assessing requirement of Notch signaling in pancreatic cancer initiation and maintenance. Results: Striking overexpression of Notch ligand transcripts was detectable in the vast majority of pancreatic cancer cell lines, most prominently JAGGED2 (18 of 20 cases, 90%) and DLL4 (10 of 20 cases, 50%). In two cell lines, genomic amplification of the DLL3 locus was observed, mirrored by overexpression of DLL3 transcripts. In contrast, coding region mutations of NOTCH1 or NOTCH2 were not observed. Genetic and pharmacologic inhibition of Notch signaling mitigated anchorage-independent growth in pancreatic cancer cells, confirming that sustained Notch activation is a requirement for pancreatic cancer maintenance. Further, transient pretreatment of pancreatic cancer cells with GSI-18 resulted in depletion in the proportion of tumor-initiating aldehyde dehydrogenase–expressing subpopulation and was associated with inhibition of colony formation in vitro and xenograft engraftment in vivo, underscoring a requirement for the Notch-dependent aldehyde dehydrogenase–expressing cells in pancreatic cancer initiation. Conclusions: Our studies confirm that Notch activation is almost always ligand dependent in pancreatic cancer, and inhibition of Notch signaling is a promising therapeutic strategy in this malignancy. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|