title: Cross-species functional analysis of cancer-associated fibroblasts identifies a critical role for CLCF1 and IL-6 in non-small cell lung cancer in vivo.
abstract: Cancer-associated fibroblasts (CAF) have been reported to support tumor progression by a variety of mechanisms. However, their role in the progression of non-small cell lung cancer (NSCLC) remains poorly defined. In addition, the extent to which specific proteins secreted by CAFs contribute directly to tumor growth is unclear. To study the role of CAFs in NSCLCs, a cross-species functional characterization of mouse and human lung CAFs was conducted. CAFs supported the growth of lung cancer cells in vivo by secretion of soluble factors that directly stimulate the growth of tumor cells. Gene expression analysis comparing normal mouse lung fibroblasts and mouse lung CAFs identified multiple genes that correlate with the CAF phenotype. A gene signature of secreted genes upregulated in CAFs was an independent marker of poor survival in patients with NSCLC. This secreted gene signature was upregulated in normal lung fibroblasts after long-term exposure to tumor cells, showing that lung fibroblasts are "educated" by tumor cells to acquire a CAF-like phenotype. Functional studies identified important roles for CLCF1-CNTFR and interleukin (IL)-6-IL-6R signaling in promoting growth of NSCLCs. This study identifies novel soluble factors contributing to the CAF protumorigenic phenotype in NSCLCs and suggests new avenues for the development of therapeutic strategies.
authors.affiliation: AutCancer Biology Program, Division of Hematology/Oncology, Department of Pediatrics, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Silvestre
authors.initials: S
authors.lastname: Vicent
authors.forename: Leanne C
authors.initials: LC
authors.lastname: Sayles
authors.forename: Dedeepya
authors.initials: D
authors.lastname: Vaka
authors.forename: Purvesh
authors.initials: P
authors.lastname: Khatri
authors.forename: Olivier
authors.initials: O
authors.lastname: Gevaert
authors.forename: Ron
authors.initials: R
authors.lastname: Chen
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Zheng
authors.forename: Anna K
authors.initials: AK
authors.lastname: Gillespie
authors.forename: Nicole
authors.initials: N
authors.lastname: Clarke
authors.forename: Yue
authors.initials: Y
authors.lastname: Xu
authors.forename: Joseph
authors.initials: J
authors.lastname: Shrager
authors.forename: Chuong D
authors.initials: CD
authors.lastname: Hoang
authors.forename: Sylvia
authors.initials: S
authors.lastname: Plevritis
authors.forename: Atul J
authors.initials: AJ
authors.lastname: Butte
authors.forename: E Alejandro
authors.initials: EA
authors.lastname: Sweet-Cordero
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology / Q000473:pathology; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000276:immunology* / Q000473:pathology*; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D005347:Fibroblasts / Q000276:immunology* / Q000473:pathology*; D006801:Humans; D015850:Interleukin-6 / Q000276:immunology*; D008175:Lung Neoplasms / Q000276:immunology* / Q000473:pathology*; D051379:Mice; D013045:Species Specificity; D017154:Stromal Cells / Q000276:immunology / Q000473:pathology; D014183:Transplantation, Heterologous
chemical_list: D015850:Interleukin-6