Prognostic value of the immunohistochemical detection of cancer‐associated fibroblasts in oral cancer: A systematic review and meta‐analysis

Abstract

AIM:To perform a meta-analysis to assess whether the presence of cancer-associated fibroblasts (CAF) is a prognostic marker of oral squamous cell carcinomas (OSCC). METHODS:Immunohistochemical studies assessing the prognostic relevance of CAF (alpha smooth muscle actin (α-SMA)-positive fibroblasts) in patients with OSCC were systematically reviewed using Cochrane, Lilacs, PubMed, Scopus and Web of Science databases. The outcomes assessed were overall survival (OS) and disease-free survival (DFS). The meta-analysis was performed using the random and fixed effects model with adjusted hazard ratio (HR) and 95% confidence intervals (95% CI) as effect measures. The methodological quality of the included studies was assessed using the Meta-Analysis of Statistics Assessment and Review Instrument (MAStARI) tool and the evidence quality was assessed by the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) system. RESULTS:The presence of high levels of CAF in the stroma of OSCC predicted shortened time to DFS (HR= 3.32, 95% CI: 2.09-5.26, p<0.00001) and an overall decrease in survival (HR: 2.16, 95% CI: 1.60-2.92, p<0.00001). Moreover, high presence of CAF was frequently reported in association with parameters that worsen the prognosis in OSCC, including advanced disease stage (TNM classification), recurrence, tumor grade, depth of invasion, vascular, lymphatic and neural invasion and extranodal metastatic spread. CONCLUSION:The presence of CAF, as assessed by α-SMA-positive fibroblasts in the stroma, indicates poor prognosis in patients with OSCC.

Prognostic impact of tumour–stroma ratio in early‐stage oral tongue cancers

“…Vascular endothelial growth factor and other growth factors such as epidermal growth factor are derived from stromal cells and endothelial cells, and promote tumour angiogenesis, which enhances tumour growth, survival, and metastasis . In OTSCC, CAFs identified by the use of α‐smooth muscle actin have been reported as key players in tumour progression, and they serve as an important prognostic marker in oral cancers, including all stages of OTSCC . In addition, stromal compounds, such as activin A, tenascin‐C, and fibronectin, have shown prognostic power in OTSCC .…”

Heat shock factor 1 in cancer‐associated fibroblasts is a potential prognostic factor and drives progression of oral squamous cell carcinoma

“…Evidence has shown that the close communication between TME and cancer cells contributes to invasion and metastasis in tumors . As the key component of the TME, CAFs are important regulators of tumor growth, angiogenesis, invasion, metastasis, and poor prognosis in many malignancies . Recently, HSF1 expression in CAFs has attracted substantial attention regarding its role in tumor progression.…”

“…Recently, activated CAFs have been thought to be characterized by the expression of α‐SMA, FSP‐1, FAP, fibronectin and Vimentin . Of note, increased infiltration of CAFs in tumor stroma is correlated with poor prognosis in many malignancies, including breast cancer, colorectal cancer and oral cancer …”

Clinicopathological significance of chemokine receptor (CCR1, CCR3, CCR4, CCR5, CCR7 and CXCR4) expression in head and neck squamous cell carcinomas

“…Additionally, treatment and prognosis of HNSCC are proposed according to the TNM stage, but nevertheless it has been observed that patients with the same TNM receiving similar therapeutic approaches have different evolution, evidencing that TNM is not always effective and new prognostic markers (adjuvants for TNM) are imperative in HNSCC. The aggressive features of HNSCC are dependent on the interactions between neoplastic cells and tumour microenvironment components . Neoplastic cells are in permanent interaction with the microenvironment and cells of the connective tissue, such as cancer‐associated fibroblasts (CAF) and immune cells.…”