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1.
BMC Cancer ; 12: 35, 2012 Jan 24.
Article in English | MEDLINE | ID: mdl-22273460

ABSTRACT

BACKGROUND: Several stromal cell subtypes including macrophages contribute to tumor progression by inducing epithelial-mesenchymal transition (EMT) at the invasive front, a mechanism also linked to metastasis. Tumor associated macrophages (TAM) reside mainly at the invasive front but they also infiltrate tumors and in this process they mainly assume a tumor promoting phenotype. In this study, we asked if TAMs also regulate EMT intratumorally. We found that TAMs through TGF-ß signaling and activation of the ß-catenin pathway can induce EMT in intratumoral cancer cells. METHODS: We depleted macrophages in F9-teratocarcinoma bearing mice using clodronate-liposomes and analyzed the tumors for correlations between gene and protein expression of EMT-associated and macrophage markers. The functional relationship between TAMs and EMT was characterized in vitro in the murine F9 and mammary gland NMuMG cells, using a conditioned medium culture approach. The clinical relevance of our findings was evaluated on a tissue microarray cohort representing 491 patients with non-small cell lung cancer (NSCLC). RESULTS: Gene expression analysis of F9-teratocarcinomas revealed a positive correlation between TAM-densities and mesenchymal marker expression. Moreover, immunohistochemistry showed that TAMs cluster with EMT phenotype cells in the tumors. In vitro, long term exposure of F9-and NMuMG-cells to macrophage-conditioned medium led to decreased expression of the epithelial adhesion protein E-cadherin, activation of the EMT-mediating ß-catenin pathway, increased expression of mesenchymal markers and an invasive phenotype. In a candidate based screen, macrophage-derived TGF-ß was identified as the main inducer of this EMT-associated phenotype. Lastly, immunohistochemical analysis of NSCLC patient samples identified a positive correlation between intratumoral macrophage densities, EMT markers, intraepithelial TGF-ß levels and tumor grade. CONCLUSIONS: Data presented here identify a novel role for macrophages in EMT-promoted tumor progression. The observation that TAMs cluster with intra-epithelial fibroblastoid cells suggests that the role of macrophages in tumor-EMT extends beyond the invasive front. As macrophage infiltration and pronounced EMT tumor phenotype correlate with increased grade in NSCLC patients, we propose that TAMs also promote tumor progression by inducing EMT locally in tumors.


Subject(s)
Epithelial-Mesenchymal Transition , Macrophages/pathology , Teratocarcinoma/pathology , Adenocarcinoma/metabolism , Adenocarcinoma/pathology , Animals , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line, Tumor , Disease Progression , Epithelial-Mesenchymal Transition/drug effects , Humans , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Macrophages/physiology , Mice , Neoplasm Invasiveness/pathology , Teratocarcinoma/genetics , Teratocarcinoma/metabolism , Transforming Growth Factor beta/metabolism , Transforming Growth Factor beta/pharmacology
2.
Mol Cancer ; 10: 127, 2011 Oct 10.
Article in English | MEDLINE | ID: mdl-21985405

ABSTRACT

BACKGROUND: The L1 cell adhesion molecule (L1CAM) is potentially involved in epithelial-mesenchymal transition (EMT). EMT marker expression is of prognostic significance in non-small cell lung cancer (NSCLC). The relevance of L1CAM for NSCLC is unclear. We investigated the protein expression of L1CAM in a cohort of NSCLC patients. L1CAM protein expression was correlated with clinico-pathological parameters including survival and markers of epithelial-mesenchymal transition. RESULTS: L1CAM protein expression was found in 25% of squamous cell carcinomas and 24% of adenocarcinomas and correlated with blood vessel invasion and metastasis (p < 0.05). L1CAM was an independent predictor of survival in a multivariate analysis including pT, pN, and pM category, and tumor differentiation grade. L1CAM expression positively correlated with vimentin, beta-catenin, and slug, but inversely with E-cadherin (all p-values < 0.05). E-cadherin expression was higher in the tumor center than in the tumor periphery, whereas L1CAM and vimentin were expressed at the tumor-stroma interface. In L1CAM-negative A549 cells the L1CAM expression was upregulated and matrigel invasion was increased after stimulation with TGF-beta1. In L1CAM-positive SK-LU-1 and SK-LC-LL cells matrigel invasion was decreased after L1CAM siRNA knockdown. CONCLUSIONS: A subset of NSCLCs with vessel tropism and increased metastasis aberrantly expresses L1CAM. L1CAM is a novel prognostic marker for NSCLCs that is upregulated by EMT induction and appears to be instrumental for enhanced cell invasion.


Subject(s)
Adenocarcinoma/metabolism , Biomarkers, Tumor/metabolism , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Squamous Cell/metabolism , Lung Neoplasms/metabolism , Neural Cell Adhesion Molecule L1/metabolism , Adenocarcinoma/mortality , Adenocarcinoma/pathology , Aged , Biomarkers, Tumor/genetics , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Squamous Cell/mortality , Carcinoma, Squamous Cell/pathology , Cell Line, Tumor , Epithelial-Mesenchymal Transition , Female , Gene Knockdown Techniques , Humans , Kaplan-Meier Estimate , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Male , Middle Aged , Multivariate Analysis , Neoplasm Invasiveness , Neural Cell Adhesion Molecule L1/genetics , Prognosis , RNA Interference
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