Epithelial-to-mesenchymal transition in the development and progression of adenocarcinoma and squamous cell carcinoma of the lung

Ludmila Prudkin, Diane D Liu, Natalie C Ozburn, Menghong Sun, Carmen Behrens, Ximing Tang, Kathlynn C Brown, B Nebiyou Bekele, Cesar Moran, Ignacio I Wistuba, Ludmila Prudkin, Diane D Liu, Natalie C Ozburn, Menghong Sun, Carmen Behrens, Ximing Tang, Kathlynn C Brown, B Nebiyou Bekele, Cesar Moran, Ignacio I Wistuba

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.

Figures

Figure 1
Figure 1
Representative microphotographs of immunohistochemical expression of epithelial-to-mesenchymal transition markers in tissue specimens of primary adenocarcinoma and squamous cell carcinoma. Tumor cells show membrane immunostaining for E-cadherin and integrin-αvβ6, membrane and cytoplasm staining for N-cadherin, and cytoplasm staining for vimentin and MMP-9.
Figure 2
Figure 2
Scores of membrane and cytoplasm immunohistochemical expression of epithelial-to-mesenchymal transition markers in normal and reactive epithelia compared with those in primary tumors. The number of samples is indicated for each histologic group and marker. P values comparing normal epithelial and tumor histologic types are shown for all comparisons.
Figure 3
Figure 3
Scores for membrane immunohistochemical expression of E-cadherin, N-cadherin, and integrin-αvβ6 in bronchial respiratory epithelial lesions related to the pathogenesis of squamous cell carcinoma of the lung: normal and reactive epithelium, squamous preneoplasia (dysplasias and carcinoma in situ), and primary squamous cell carcinoma. The number of samples is indicated for each histologic group and marker. Significant P values for comparisons between each group are shown. For each marker, representative microphotographs of immunohistochemical expression in tissue specimens of bronchial epithelium with normal, squamous dysplasia, and carcinoma in situ are shown. For E-cadherin, decreased membrane immunostaining was found with increased histologic severity. The opposite phenomenon is shown for cytoplasm N-cadherin and membrane integrin-αvβ6 expression.

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