Broadening Drug Design and Targets to Tumor Microenvironment? Cancer-Associated Fibroblast Marker Expression in Cancers and Relevance for Survival Outcomes.

Abstract

Solid tumors have complex biology and structure comprising cancer cells, stromal cells, and the extracellular matrix. While most therapeutics target the cancer cells, recent data suggest that cancer cell behavior and response to treatment are markedly influenced by the tumor microenvironment (TME). In particular, the cancer-associated fibroblasts (CAFs) are the most abundant stromal cells, and play a significant contextual role in shaping tumor initiation, progression, and metastasis. CAFs have therefore emerged as part of the next-generation cancer drug design and discovery innovation strategy. We report here new findings on differential expression and prognostic significance of CAF markers in several cancers. We utilized two publicly available resources: The Cancer Genomic Atlas and Gene Expression Profiling Interactive Analysis. We examined the expression of CAF markers, ACTA2, S100A4, platelet-derived growth factor receptor-beta [PDGFR-β], CD10, and fibroblast activation protein-alpha (FAP-α), in tumor tissues versus the adjacent normal tissues. We found that CAF markers were differentially expressed in various different tumors such as colon, breast, and esophageal cancers and melanoma. No CAF marker is expressed in the same pattern in all cancers, however. Importantly, we report that patients with colon adenocarcinoma and esophageal carcinoma expressing high FAP-α and CD10, respectively, had significantly shorter overall survival, compared with those with low levels of these CAF markers (p < 0.05). We call for continued research on TME biology and clinical evaluation of the CAF markers ACTA2, S100A4, PDGFR-β, CD10, and FAP-α in relation to prognosis of solid cancers in large population samples. An effective cancer drug design and discovery roadmap in the 21st century ought to be broadly framed, and include molecular targets informed by both cancer cell and TME variations.