Disruption of tumor cell adhesion promotes angiogenic switch and progression to micrometastasis in RAF-driven murine lung cancer.
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.
Ceteci
Fatih
F
Institut für Medizinische Strahlenkunde und Zellforschung, Universität Würzburg, Versbacher Strasse 5, 97078, Würzburg, Germany.
Ceteci
Semra
S
Karreman
Christiaan
C
Kramer
Boris W
BW
Asan
Esther
E
Götz
Rudolf
R
Rapp
Ulf R
UR
D000230:Adenocarcinoma / Q000209:etiology / Q000378:metabolism / Q000556:secondary*; D000236:Adenoma / Q000209:etiology / Q000473:pathology; D022005:Adherens Junctions; D000818:Animals; D015703:Antigens, CD; D017209:Apoptosis; D015415:Biomarkers / Q000378:metabolism; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000209:etiology / Q000378:metabolism / Q000556:secondary*; D002448:Cell Adhesion; D002478:Cells, Cultured; D018450:Disease Progression; D004707:Endoderm / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D005455:Fluorescent Antibody Technique; D005799:Genes, Dominant; D015151:Immunoblotting; D047468:Immunoprecipitation; D020287:In Situ Nick-End Labeling; D008156:Luciferases / Q000378:metabolism; D008175:Lung Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000473:pathology*; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
D015703:Antigens, CD; D015415:Biomarkers; C513384:CDH1 protein, human; D015820:Cadherins; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D051176:beta Catenin; C467480:vascular endothelial growth factor A, mouse; D008156:Luciferases; D019908:Proto-Oncogene Proteins c-raf