title: Epithelial-to-mesenchymal transition in the development and progression of adenocarcinoma and squamous cell carcinoma of the lung.
abstract: Epithelial-to-mesenchymal transition is a process in which cells undergo a developmental switch from an epithelial to a mesenchymal phenotype. We investigated the role of this phenomenon in the pathogenesis and progression of adenocarcinoma and squamous cell carcinoma of the lung. Archived tissue from primary tumors (n=325), brain metastases (n=48) and adjacent bronchial epithelial specimens (n=192) were analyzed for immunohistochemical expression by image analysis of E-cadherin, N-cadherin, integrin-alpha v beta 6, vimentin, and matrix metalloproteinase-9. The findings were compared with the patients' clinicopathologic features. High expression of the epithelial-to-mesenchymal transition phenotype (low E-cadherin and high N-cadherin, integrin-alpha v beta 6, vimentin, and matrix metalloproteinase-9) was found in most lung tumors examined, and the expression pattern varied according to the tumor histologic type. Low E-cadherin membrane and high N-cadherin cytoplasmic expression were significantly more common in squamous cell carcinoma than in adenocarcinoma (P=0.002 and 0.005, respectively). Dysplastic lesions had significantly lower expression of the epithelial-to-mesenchymal transition phenotype than the squamous cell carcinomas, and integrin-alpha v beta 6 membrane expression increased stepwise according to the histopathologic severity. Brain metastases had decreased epithelial-to-mesenchymal transition expression compared with primary tumors. Brain metastases had significantly lower integrin-alpha v beta 6 membrane (P=0.04), N-cadherin membrane, and cytoplasm (P<0.0002) expression than the primary tumors. The epithelial-to-mesenchymal transition phenotype is commonly expressed in primary squamous cell carcinoma and adenocarcinoma of the lung; this expression occurs early in the pathogenesis of squamous cell carcinoma. Brain metastases showed characteristics of reversed mesenchymal-to-epithelial transition. Our findings suggest that epithelial-to-mesenchymal transition is a potential target for lung cancer chemoprevention and therapy.
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA.
authors.forename: Ludmila
authors.initials: L
authors.lastname: Prudkin
authors.forename: Diane D
authors.initials: DD
authors.lastname: Liu
authors.forename: Natalie C
authors.initials: NC
authors.lastname: Ozburn
authors.forename: Menghong
authors.initials: M
authors.lastname: Sun
authors.forename: Carmen
authors.initials: C
authors.lastname: Behrens
authors.forename: Ximing
authors.initials: X
authors.lastname: Tang
authors.forename: Kathlynn C
authors.initials: KC
authors.lastname: Brown
authors.forename: B Nebiyou
authors.initials: BN
authors.lastname: Bekele
authors.forename: Cesar
authors.initials: C
authors.lastname: Moran
authors.forename: Ignacio I
authors.initials: II
authors.lastname: Wistuba
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D000951:Antigens, Neoplasm / Q000096:biosynthesis; D014408:Biomarkers, Tumor / Q000032:analysis; D001932:Brain Neoplasms / Q000378:metabolism / Q000556:secondary; D015820:Cadherins / Q000096:biosynthesis; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation / Q000502:physiology*; D018450:Disease Progression; D004847:Epithelial Cells / Q000473:pathology*; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D016023:Integrins / Q000096:biosynthesis; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D008648:Mesoderm / Q000473:pathology*; D009367:Neoplasm Staging; D010641:Phenotype; D046888:Tissue Array Analysis; D014746:Vimentin / Q000096:biosynthesis
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D015820:Cadherins; D016023:Integrins; D014746:Vimentin; C073878:integrin alphavbeta6; D020780:Matrix Metalloproteinase 9