High Expression of FAP in Colorectal Cancer Is Associated With Angiogenesis and Immunoregulation Processes

Mairene Coto-Llerena; Caner Ercan; Venkatesh Kancherla; Stephanie Taha-Mehlitz; Serenella Eppenberger-Castori; Savas D Soysal; Charlotte K Y Ng; Martin Bolli; Markus von Flüe; Guillaume P Nicolas; Luigi M Terracciano; Melpomeni Fani; Salvatore Piscuoglio

doi:10.3389/fonc.2020.00979

High Expression of FAP in Colorectal Cancer Is Associated With Angiogenesis and Immunoregulation Processes

Front Oncol. 2020 Jul 8:10:979. doi: 10.3389/fonc.2020.00979. eCollection 2020.

Authors

Affiliations

¹ Institute of Pathology and Medical Genetics, University Hospital Basel, Basel, Switzerland.
² Visceral Surgery Research Laboratory, Department of Biomedicine, University of Basel, Basel, Switzerland.
³ Department of Visceral Surgery, Clarunis University Centre for Gastrointestinal and Liver Diseases, St. Clara Hospital and University Hospital Basel, Basel, Switzerland.
⁴ Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland.
⁵ Division of Nuclear Medicine, University Hospital Basel, Basel, Switzerland.
⁶ Division of Radiopharmaceutical Chemistry, University Hospital Basel, University of Basel, Basel, Switzerland.

Abstract

Fibroblast activation protein α (FAP) plays an important role in tissue remodeling and helps tumor cells invade surrounding tissue. We sought to investigate FAP as a prognostic molecular marker in colorectal cancer (CRC) using immunohistochemical and transcriptomic data. FAP expression and clinicopathological information were obtained from The Cancer Genome Atlas data set. The association of FAP expression and tissue cellular heterogeneity landscape was explored using the xCell method. We evaluated FAP protein expression in a cohort of 92 CRCs and 19 non-tumoral tissues. We observed that FAP was upregulated in tumors both at the mRNA and protein levels, and its expression was associated with advanced stages, poor survival, and consensus molecular subtype 4. FAP expression was also associated with angiogenesis and collagen degradation. We observed an enrichment in immune-cell process-related genes associated with FAP overexpression. Colorectal cancers with high FAP expression display an inflamed phenotype enriched for macrophages and monocytes. Those tumors showed enrichment for regulatory T cell populations and depletion of T_H1 and natural killer T cells, pointing to an immunosuppressive environment. Colorectal cancers with high levels of stromal FAP are associated with aggressive disease progression and survival. Our results suggest that FAP plays additional roles in tumor progression such as modulation of angiogenesis and immunoregulation in the tumor microenvironment.

Keywords: FAP; cancer-associated fibroblast; colorectal cancer; gene expression; immunohistochemistry.