Cancer associated fibroblasts and their prognostic role in colorectal cancer: review and meta-analysis

Silvia Mihaela Ilie¹LAURENTIA GALES^2,3Ana Maria Musina⁴Kevin Rouet^4*Alexandra Elena Stefan^1,5*Mara Simona Belceanu⁶Anda Stefania Trandafir²Constantin Guillaume⁷Aurélie Bertaut⁷Ikram Charifi,⁷Adel Cueff⁷Valentin Derangère⁸Francois Ghiringhelli^10,9

• ¹Centre Georges François Leclerc, Dijon, France
• ²Medical Oncology, Institute of Oncology Alexandru Trestioreanu, Bucarest, Romania
• ³Universitatea de Medicina si Farmacie Carol Davila din Bucuresti Facultatea de Medicina, Bucharest, Romania
• ⁴Regional Institute of Oncology, Iasi, Romania
• ⁵Institute of Oncology Alexandru Trestioreanu, Bucarest, Romania
• ⁶Institute of Oncology Alexandru Trestioreanu, Bucarest, Romania
• ⁷Unit of Methodology and Biostatistics, Centre Georges François Leclerc, Dijon, France
• ⁸Platform of Transfer in Biological Oncology, Centre Georges François Leclerc, Dijon, France
• ⁹Cancer Early Phase Trial Unit, Centre Georges François Leclerc, Dijon, France
• ¹⁰Universite Bourgogne Europe, Dijon, France

Background: Cancer-associated fibroblasts (CAFs) are a component of the tumor microenvironment, influencing tumor behavior and progression. This meta-analysis aims to describe the prognostic value of CAFs biomarkers in colorectal cancer (CRC). Methods: A systematic search of the existing literature was performed in Medline and Embase, on CAF immunohistochemical (IHC) biomarkers and their association with disease-free (DFS) and overall survival (OS). The selection of studies was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and Population, Intervention, Comparator, Outcome criteria. The quality of included articles was assessed using the Newcastle Ottawa Scale. Results: A total of 3535 records were identified, of which 84 were selected for the qualitative review and 59 (N=15,396 patients) were included in the final meta-analysis. In general, CAF biomarker expression was associated with poor prognosis, with high heterogeneity among studies. Significant results for DFS were found for cluster of differentiation (CD)163, matrix metalloproteinase 9 (MMP-9) and tenascin C. The following markers were significantly associated with OS: CD163, MMP-9, periostin and vimentin. Conclusion: Several CAF IHC biomarkers, particularly CD 163, MMP-9 periostin and vimentin significantly associated with prognosis in CRC, could be proposed as surrogates for phenotypical characterization of the tumor microenvironment.