Abstract
Progression of non-small-cell lung cancer (NSCLC) to metastasis is poorly understood. Two genetic approaches were used to evaluate the role of adherens junctions in a C-RAF driven mouse model for NSCLC: conditional ablation of the cdh1 gene and expression of dominant-negative (dn) E-cadherin. Disruption of E-cadherin caused massive formation of intratumoral vessels that was reversible in the early phase of induction. Vascularized tumors grew more rapidly, developed invasive fronts, and gave rise to micrometastasis. beta-catenin was identified as a critical effector of E-cadherin disruption leading to upregulation of VEGF-A and VEGF-C. In vivo, lung tumor cells with disrupted E-cadherin expressed beta-catenin target genes normally found in other endodermal lineages suggesting that reprogramming may be involved in metastatic progression.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adenocarcinoma / etiology
-
Adenocarcinoma / metabolism
-
Adenocarcinoma / secondary*
-
Adenoma / etiology
-
Adenoma / pathology
-
Adherens Junctions
-
Animals
-
Antigens, CD
-
Apoptosis
-
Biomarkers / metabolism
-
Cadherins / genetics
-
Cadherins / metabolism*
-
Carcinoma, Non-Small-Cell Lung / etiology
-
Carcinoma, Non-Small-Cell Lung / metabolism
-
Carcinoma, Non-Small-Cell Lung / secondary*
-
Cell Adhesion*
-
Cells, Cultured
-
Disease Progression
-
Endoderm / metabolism
-
Endothelium, Vascular / cytology
-
Endothelium, Vascular / metabolism
-
Endothelium, Vascular / pathology
-
Fluorescent Antibody Technique
-
Genes, Dominant
-
Immunoblotting
-
Immunoprecipitation
-
In Situ Nick-End Labeling
-
Luciferases / metabolism
-
Lung Neoplasms / blood supply*
-
Lung Neoplasms / metabolism
-
Lung Neoplasms / pathology
-
Mice
-
Mice, Knockout
-
Mice, Transgenic
-
Neoplasm Invasiveness
-
Neovascularization, Pathologic / pathology*
-
Proto-Oncogene Proteins c-raf / genetics
-
Proto-Oncogene Proteins c-raf / physiology*
-
RNA, Messenger / genetics
-
RNA, Messenger / metabolism
-
Reverse Transcriptase Polymerase Chain Reaction
-
Signal Transduction
-
Vascular Endothelial Growth Factor A / genetics
-
Vascular Endothelial Growth Factor A / metabolism
-
beta Catenin / genetics
-
beta Catenin / metabolism
Substances
-
Antigens, CD
-
Biomarkers
-
CDH1 protein, human
-
Cadherins
-
RNA, Messenger
-
Vascular Endothelial Growth Factor A
-
beta Catenin
-
vascular endothelial growth factor A, mouse
-
Luciferases
-
Proto-Oncogene Proteins c-raf