Functional Heterogeneity of Cancer-Associated Fibroblasts From Human Colon Tumors Shows Specific Prognostic Gene Expression Signature
Menée in vitro et sur 142 échantillons tumoraux prélevés sur des patients atteints d'un cancer du côlon, cette étude identifie une signature qui, basée sur l'expression de 4 gènes dans des fibroblastes associés au cancer, permet d'identifier les patients à haut risque de récidive
Purpose:Cancer-associated fibroblasts (CAFs) actively participate in reciprocal communication with tumor cells and with other cell types in the microenvironment, contributing to a tumor-permissive neighborhood and promoting tumor progression. The aim of this study is the characterization of how CAFs from primary human colon tumors promote migration of colon cancer cells.
Experimental Design: Primary CAF cultures from 15 primary human colon tumors were established. Their enrichment in CAFs was evaluated by the expression of various epithelial and myofibroblast specific markers. Co-culture assays of primary CAFs with different colon tumor cells were performed to evaluate pro-migratory CAF-derived effects on cancer cells. Gene expression profiles were developed to further investigate CAF characteristics.
Results:Co-culture assays showed significant differences in fibroblast-derived paracrine pro-migratory effects on cancer cells. Moreover, association between CAFs' pro-migratory effects on cancer cells and classical fibroblast activation or stemness markers was observed. CAF gene expression profiles were analyzed by microarray to identify deregulated genes in different pro-migratory CAFs. The gene expression signature, derived from the most pro-tumorogenic CAFs, was identified. Interestingly, this "CAF signature" showed a remarkable prognostic value for the clinical outcome of colon cancer patients. Moreover, this prognostic value was validated in an independent series of 142 colon cancer patients, by RT-qPCR, with a set of four genes included in the "CAF signature".
Conclusions:In summary, these studies demonstrate for the first time the heterogeneity of primary CAFs' effect on colon cancer cell migration. A CAF gene expression signature able to classify colon cancer patients into high- and low-risk groups was identified.
Clinical Cancer Research , résumé, 2013