Differences between CAFs and their paired NCF from adjacent colonic mucosa reveal functional heterogeneity of CAFs, providing prognostic information.
Little is known about the difference in gene expression between carcinoma-associated fibroblasts (CAFs) and paired normal colonic fibroblasts (NCFs) in colorectal cancer. Paired CAFs and NCFs were isolated from eight primary human colorectal carcinoma specimens. In culture conditions, soluble factors secreted by CAFs in the conditioned media increased clonogenicity and migration of epithelial cancer cells lines to a greater extent than did NCF. In vivo, CAFs were more competent as tumour growth enhancers than paired NCFs when co-inoculated with colorectal cell lines. Gene expression analysis of microarrays of CAF and paired NCF populations enabled us to identify 108 deregulated genes (38 upregulated and 70 downregulated genes). Most of those genes are fibroblast-specific. This has been validated in silico in dataset GSE39396 and by qPCR in selected genes. GSEA analysis revealed a differential transcriptomic profile of CAFs, mainly involving the Wnt signallingsignalling pathway, focal adhesion and cell cycle. Both deregulated genes and biological processes involved depicted a considerable degree of overlap with deregulated genes reported in breast, lung, oesophagus and prostate CAFs. These observations suggest that similar transcriptomic programs may be active in the transition from normal fibroblast in adjacent tissues to CAFs, independently of their anatomic demarcation. Additionally NCF already depicted an activated pattern associated with inflammation. The deregulated genes signature score seemed to correlate with CAF tumour promoter abilities in vitro, suggesting a high degree of heterogeneity between CAFs, and it has also prognostic value in two independent datasets. Further characterization of the roles these biomarkers play in cancer will reveal how CAFs provide cancer cells with a suitable microenvironment and may help in the development of new therapeutic targets for cancer treatment.
Translational Research Laboratory, Catalan Institute of Oncology, IDIBELL, L'Hospitalet de Llobregat, 08908 Catalonia, Spain.
Mireia
M
Berdiel-Acer
Biomarkers and Susceptibility Unit, Cancer Prevention and Monitoring Programme, Catalan Institute of Oncology, IDIBELL, L'Hospitalet de Llobregat, Catalonia, Spain.
Rebeca
R
Sanz-Pamplona
Oncology Programme, Institute for Research in Biomedicine IRB, Barcelona, Catalonia, Spain.
Alexandre
A
Calon
Biomarkers and Susceptibility Unit, Cancer Prevention and Monitoring Programme, Catalan Institute of Oncology, IDIBELL, L'Hospitalet de Llobregat, Catalonia, Spain.
Daniel
D
Cuadras
Biomarkers and Susceptibility Unit, Cancer Prevention and Monitoring Programme, Catalan Institute of Oncology, IDIBELL, L'Hospitalet de Llobregat, Catalonia, Spain.
Antoni
A
Berenguer
Pathology Department, Hospital Universitari de Bellvitge, IDIBELL, L'Hospitalet de Llobregat, Catalonia, Spain.
Xavier
X
Sanjuan
Pathology Department, Hospital Universitari de Bellvitge, IDIBELL, L'Hospitalet de Llobregat, Catalonia, Spain.
Maria José
MJ
Paules
Medical Oncology Department, Catalan Institute of Oncology, IDIBELL, L'Hospitalet de Llobregat, Catalonia, Spain.
Ramon
R
Salazar
Biomarkers and Susceptibility Unit, Cancer Prevention and Monitoring Programme, Catalan Institute of Oncology, IDIBELL, L'Hospitalet de Llobregat, Catalonia, Spain.
Victor
V
Moreno
Oncology Programme, Institute for Research in Biomedicine IRB, Barcelona, Catalonia, Spain.
Eduard
E
Batlle
Translational Research Laboratory, Catalan Institute of Oncology, IDIBELL, L'Hospitalet de Llobregat, 08908 Catalonia, Spain.
Alberto
A
Villanueva
Translational Research Laboratory, Catalan Institute of Oncology, IDIBELL, L'Hospitalet de Llobregat, 08908 Catalonia, Spain. Electronic address: dgmollevi@iconcologia.net.
David G
DG
Molleví
D000818:Animals; D002478:Cells, Cultured; D003106:Colon / Q000378:metabolism / Q000473:pathology*; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008819:Mice, Nude; D011379:Prognosis
Biomarker; Carcinoma-associated fibroblasts; Colorectal; Microenvironment; Stroma