title: Prognostic gene-expression signature of carcinoma-associated fibroblasts in non-small cell lung cancer.
abstract: 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.
authors.affiliation: The Campbell Family Institute for Cancer Research, Ontario Cancer Institute at Princess Margaret Hospital, University Health Network, Toronto, ON, Canada.
authors.forename: Roya
authors.initials: R
authors.lastname: Navab
authors.forename: Dan
authors.initials: D
authors.lastname: Strumpf
authors.forename: Bizhan
authors.initials: B
authors.lastname: Bandarchi
authors.forename: Chang-Qi
authors.initials: CQ
authors.lastname: Zhu
authors.forename: Melania
authors.initials: M
authors.lastname: Pintilie
authors.forename: Varune Rohan
authors.initials: VR
authors.lastname: Ramnarine
authors.forename: Emin
authors.initials: E
authors.lastname: Ibrahimov
authors.forename: Nikolina
authors.initials: N
authors.lastname: Radulovich
authors.forename: Lisa
authors.initials: L
authors.lastname: Leung
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Barczyk
authors.forename: Devang
authors.initials: D
authors.lastname: Panchal
authors.forename: Christine
authors.initials: C
authors.lastname: To
authors.forename: James J
authors.initials: JJ
authors.lastname: Yun
authors.forename: Sandy
authors.initials: S
authors.lastname: Der
authors.forename: Frances A
authors.initials: FA
authors.lastname: Shepherd
authors.forename: Igor
authors.initials: I
authors.lastname: Jurisica
authors.forename: Ming-Sound
authors.initials: MS
authors.lastname: Tsao
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D002461:Cell Line, Transformed; D018572:Disease-Free Survival; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D020411:Oligonucleotide Array Sequence Analysis; D015398:Signal Transduction; D015996:Survival Rate
chemical_list: D009363:Neoplasm Proteins