Journal Article

Prognostic gene-expression signature of carcinoma-associated fibroblasts in non-small cell lung cancer

Zhu, Chang-Qi, Bandarchi, Bizhan, Der, Sandy, Strumpf, Dan, Panchal, Devang, Jurisica, Igor, Yun, James J, Ibrahimov, Emin, Barczyk, Malgorzata, Pintilie, Melania, Leung, Lisa, Ramnarine, Varune Rohan, Shepherd, Frances A, To, Christine, Tsao, Ming-Sound, Navab, Roya, Radulovich, Nikolina

2011

Overview

The tumor microenvironment strongly influences cancer development, progression, and metastasis. The role of carcinoma-associated fibroblasts (CAFs) in these processes and their clinical impact has not been studied systematically in non-small cell lung carcinoma (NSCLC). We established primary cultures of CAFs and matched normal fibroblasts (NFs) from 15 resected NSCLC. We demonstrate that CAFs have greater ability than NFs to enhance the tumorigenicity of lung cancer cell lines. Microarray gene-expression analysis of the 15 matched CAF and NF cell lines identified 46 differentially expressed genes, encoding for proteins that are significantly enriched for extracellular proteins regulated by the TGF-β signaling pathway. We have identified a subset of 11 genes (13 probe sets) that formed a prognostic gene-expression signature, which was validated in multiple independent NSCLC microarray datasets. Functional annotation using protein-protein interaction analyses of these and published cancer stroma-associated gene-expression changes revealed prominent involvement of the focal adhesion and MAPK signaling pathways. Fourteen (30%) of the 46 genes also were differentially expressed in laser-capture-microdissected corresponding primary tumor stroma compared with the matched normal lung. Six of these 14 genes could be induced by TGF-β1 in NF. The results establish the prognostic impact of CAF-associated gene-expression changes in NSCLC patients.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Adenocarcinoma / adhesion / Animals / Biological Sciences / Cancer / Carcinoma, Non-Small-Cell Lung - metabolism / Carcinoma, Non-Small-Cell Lung - mortality / Carcinoma, Non-Small-Cell Lung - pathology / Cell culture / Cell Line, Transformed / data collection / Datasets / Disease-Free Survival / Female / Fibroblasts / Fibroblasts - metabolism / Fibroblasts - pathology / Gene expression / Gene Expression Profiling / gene expression regulation / Gene Expression Regulation, Neoplastic / Genes / Humans / Lung - metabolism / Lung - pathology / Lung cancer / Lung neoplasms / Lung Neoplasms - metabolism / Lung Neoplasms - mortality / Lung Neoplasms - pathology / Lungs / Male / Metastasis / Mice / Mice, SCID / microarray technology / mitogen-activated protein kinase / Neoplasm Proteins - biosynthesis / Non small cell lung carcinoma / Oligonucleotide Array Sequence Analysis / patients / protein-protein interactions / Proteins / Signal Transduction / Signatures / Survival Rate / transforming growth factor beta 1 / Tumors