Notch Signaling Contributes to Lung Cancer Clonogenic Capacity In Vitro but May Be Circumvented in Tumorigenesis In Vivo
- 1 December 2011
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Molecular Cancer Research
- Vol. 9 (12), 1746-1754
- https://doi.org/10.1158/1541-7786.mcr-11-0286
Abstract
The Notch signaling pathway is a critical embryonic developmental regulatory pathway that has been implicated in oncogenesis. In non–small cell lung cancer (NSCLC), recent evidence suggests that Notch signaling may contribute to maintenance of a cancer stem or progenitor cell compartment required for tumorigenesis. We explored whether intact Notch signaling is required for NSCLC clonogenic and tumorigenic potential in vitro and in vivo using a series of genetically modified model systems. In keeping with previous observations, we find that Notch3 in particular is upregulated in human lung cancer lines and that downregulation of Notch signaling using a selective γ-secretase inhibitor (MRK-003) is associated with decreased proliferation and clonogenic capacity in vitro. We show that this phenotype is rescued with the expression of NICD3, a constitutively active cleaved form of Notch3 not affected by γ-secretase inhibition. Using an inducible LSL-KRASG12D model of lung cancer in vivo, we show a transient upregulation of Notch pathway activity in early tumor precursor lesions. However, a more rigorous test of the requirement for Notch signaling in lung oncogenesis, crossing the LSL-KRASG12D mouse model with a transgenic with a similarly inducible global dominant-negative suppressor of Notch activity, LSL-DNMAML (dominant-negative mastermind-like), reveals no evidence of Notch pathway requirement for lung tumor initiation or growth in vivo. Distinct Notch family members may have different and potentially opposing activities in oncogenesis, and targeted inhibition of individual Notch family members may be a more effective anticancer strategy than global pathway suppression. Mol Cancer Res; 9(12); 1746–54. ©2011 AACR.Other Versions
This publication has 53 references indexed in Scilit:
- A novel tumour-suppressor function for the Notch pathway in myeloid leukaemiaNature, 2011
- NOTCH1 and NOTCH3 Coordinate Esophageal Squamous Differentiation Through a CSL-Dependent Transcriptional NetworkGastroenterology, 2010
- Notch Signaling in Solid TumorsCurrent Topics in Developmental Biology, 2010
- Notch: The Past, the Present, and the FuturePublished by Elsevier BV ,2010
- Notch3 cooperates with the EGFR pathway to modulate apoptosis through the induction of bimOncogene, 2009
- The Canonical Notch Signaling Pathway: Unfolding the Activation MechanismCell, 2009
- Ha-Ras transformation of MCF10A cells leads to repression of Singleminded-2s through NOTCH and C/EBPβOncogene, 2009
- Notch tumor suppressor functionOncogene, 2008
- Prospective identification of tumorigenic breast cancer cellsProceedings of the National Academy of Sciences of the United States of America, 2003
- Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cellNature Medicine, 1997