Functional heterogeneity of cancer-associated fibroblasts from human colon tumors shows specific prognostic gene expression signature.
OBJECTIVE
Cancer-associated fibroblasts (CAF) 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.


METHODS
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. Coculture assays of primary CAFs with different colon tumor cells were performed to evaluate promigratory CAF-derived effects on cancer cells. Gene expression profiles were developed to further investigate CAF characteristics.


RESULTS
Coculture assays showed significant differences in fibroblast-derived paracrine promigratory effects on cancer cells. Moreover, the association between CAFs' promigratory effects on cancer cells and classic fibroblast activation or stemness markers was observed. CAF gene expression profiles were analyzed by microarray to identify deregulated genes in different promigratory CAFs. The gene expression signature, derived from the most protumorogenic CAFs, was identified. Interestingly, this "CAF signature" showed a remarkable prognostic value for the clinical outcome of patients with colon cancer. Moreover, this prognostic value was validated in an independent series of 142 patients with colon cancer, by quantitative real-time PCR (qRT-PCR), with a set of four genes included in the "CAF signature."


CONCLUSIONS
In summary, these studies show for the first time the heterogeneity of primary CAFs' effect on colon cancer cell migration. A CAF gene expression signature able to classify patients with colon cancer into high- and low-risk groups was identified.
Authors' Affiliations: Departments of Medical Oncology and Pathology, Hospital Universitario Puerta de Hierro Majadahonda, Majadahonda; Functional Proteomics Laboratory, Centro de Investigaciones Biológicas (CIB-CSIC), Madrid; Programa de Recerca en Càncer, IMIM-Hospital del Mar, Barcelona, Spain; and Department of Genetic Engineering and Biotechnology, University of Dhaka, Dhaka, Bangladesh.
Mercedes
M
Herrera
Abul B M M K
AB
Islam
Alberto
A
Herrera
Paloma
P
Martín
Vanesa
V
García
Javier
J
Silva
Jose M
JM
Garcia
Clara
C
Salas
Ignacio
I
Casal
Antonio García
AG
de Herreros
Félix
F
Bonilla
Cristina
C
Peña
D015415:Biomarkers / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D016000:Cluster Analysis; D018920:Coculture Techniques; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D019899:Paracrine Communication; D010641:Phenotype; D011379:Prognosis; D059467:Transcriptome
D015415:Biomarkers