Notch Pathway Activity Identifies Cells with Cancer Stem Cell―like Properties and Correlates with Worse Survival in Lung Adenocarcinoma

• Published in: Clinical cancer research Vol. 19; no. 8; pp. 1972 - 1980
• Main Authors: HASSAN, Khaled A, LUO WANG, KORKAYA, Hasan, GUOAN CHEN, MAILLARD, Ivan, BEER, David G, KALEMKERIAN, Gregory P, WICHA, Max S
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.04.2013
• Subjects: Adenocarcinoma - drug therapy; Adenocarcinoma - genetics; Adenocarcinoma - pathology; Animals; Antineoplastic agents; Apoptosis - drug effects; Apoptosis - genetics; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; Biological and medical sciences; Cell Cycle - drug effects; Cell Cycle - genetics; Cell Line, Tumor; Cyclic S-Oxides - pharmacology; Flow Cytometry; Gene Expression Regulation, Neoplastic; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Medical sciences; Mice; Mice, Inbred NOD; Mice, Nude; Mice, SCID; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Multivariate Analysis; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Pharmacology. Drug treatments; Pneumology; Protein Isoforms - antagonists & inhibitors; Protein Isoforms - genetics; Protein Isoforms - metabolism; Receptors, Notch - antagonists & inhibitors; Receptors, Notch - genetics; Receptors, Notch - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction - drug effects; Signal Transduction - genetics; Thiadiazoles - pharmacology; Transcription Factor HES-1; Tumors; Tumors of the respiratory system and mediastinum; Xenograft Model Antitumor Assays; Lung disease; Notch receptor; Respiratory disease; Lung cancer; Stem cell; Malignant tumor; Bronchopulmonary adenocarcinoma; In vitro; Survival; Biological activity; Bronchopulmonary; Cell signaling; Bronchus disease; Tumor cell; Cancer
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-12-0370

The cancer stem cell theory postulates that tumors contain a subset of cells with stem cell properties of self-renewal, differentiation, and tumor initiation. The purpose of this study is to determine the role of Notch activity in identifying lung cancer stem cells. We investigated the role of Notch activity in lung adenocarcinoma using a Notch GFP reporter construct and a γ-secretase inhibitor (GSI), which inhibits Notch pathway activity. Transduction of lung cancer cells with Notch GFP reporter construct identified a subset of cells with high Notch activity (GFP-bright). GFP-bright cells had the ability to form more tumor spheres in serum-free media and were able to generate both GFP-bright and GFP-dim (lower Notch activity) cell populations. GFP-bright cells were resistant to chemotherapy and were tumorigenic in serial xenotransplantation assays. Tumor xenografts of mice treated with GSI had decreased expression of downstream effectors of Notch pathway and failed to regenerate tumors upon reimplantation in NOD/SCID mice. Using multivariate analysis, we detected a statistically significant correlation between poor clinical outcome and Notch activity (reflected in increased Notch ligand expression or decreased expression of the negative modulators), in a group of 443 patients with lung adenocarcinoma. This correlation was further confirmed in an independent group of 89 patients with adenocarcinoma in which Hes-1 overexpression correlated with poor overall survival. Notch activity can identify lung cancer stem cell-like population and its inhibition may be an appropriate target for treating lung adenocarcinoma.