Cancer-Associated Fibroblast Density, Prognostic Characteristics, and Recurrence in Head and Neck Squamous Cell Carcinoma: A Meta-Analysis

Abstract

IntroductionThe progression and clinical course of head and neck squamous cell carcinoma (HNSCC) relies on complex interactions between cancer and stromal cells in the tumor microenvironment (TME). Among the most abundant of these stromal cells are cancer-associated fibroblasts (CAFs). While their contribution to tumor progression is widely acknowledged, and various CAF-targeted treatments are under development, the relationship between CAF density and the clinicopathologic course of HNSCC has not been clearly defined. Here we examine the published evidence investigating the relationship of cancer-associated fibroblasts to local recurrence and indicators of prognostic significance in HNSCC.MethodsWe conducted a meta-analysis of existing publications that compare the relationship between CAF density, local recurrence, and clinically significant pathologic criteria of disease development (T stage, nodal positivity, clinical stage, vascular invasion, perineural invasion, Ki67 expression, and differentiation). Thirteen studies met the selection criteria, providing a total study population of 926 patients. Forest plots and risk ratios were generated to illustrate overall relationships.ResultsHigher CAF density within the tumor microenvironment is associated with advanced T stage, nodal infiltration, clinical stage, vascular invasion, perineural invasion, Ki67 expression, and differentiation (p <0.05). High CAF density is also associated with increased rates of local recurrence (p <0.001).ConclusionsAcross multiple studies, increased CAF density is correlated with histopathological criteria of poor prognosis in HNSCC. These findings highlight that CAFs may play a pivotal role in HNSCC development and progression. Staining for CAFs may represent a valuable addition to current pathologic analysis and help to guide prognosis and treatment. Understanding the mechanisms by which CAFs reciprocally interact with cancer cells will be crucial for optimization of TME-focused treatment of HNSCC.

Cancer-Associated Fibroblasts: Implications for Cancer Therapy

“…This is a consequence of fibroblast activation and enhanced deposition of ECM [ 165 ]. Indeed, an enrichment in αSMA-positive fibroblasts can be found in chemo and radiotherapy treated tumours [ 158 , 166 ] and stromal signatures are often associated with a worse outcome regarding disease free survival [ 166 , 167 , 168 , 169 ]. High amounts of ECM can then activate pro-survival pathways in cancer cells and impair the response to radiotherapy as well as to chemotherapy, in an integrin β1-dependent manner [ 87 , 88 , 170 , 171 , 172 ].…”

Signaling pathways in cancer-associated fibroblasts and targeted therapy for cancer

“…Cancer-associated fibroblasts (CAFs), as the major components of TME, have been extensively explored and are known to be involved in diverse cellular processes, including cell differentiation, proliferation, and stemness; extracellular matrix (ECM) remodeling; and cell migration and apoptosis, all of which can exert critical roles in tumor biological behaviors, including tumorigenesis, tumor growth, energy metabolism, tumor immunity, angiogenesis, tumor progression, recurrence, and metastasis. 9 – 11 The biological activities of CAFs are mediated by various intracellular and extracellular factors, especially those in signaling pathways closely related to cancer progression, which might be targeted for anticancer therapy. Since CAFs exert molecular and functional heterogeneity in different cancers and even in different stages of the same type of tumor and because of the specific crosstalk between CAFs and cancer cells, 12 any therapeutic strategies developed should exploit the specificity and diversity of CAFs to optimize treatment efficacy for targeted therapy.…”

Metastasis Risk Assessment Using BAG2 Expression by Cancer-Associated Fibroblast and Tumor Cells in Patients with Breast Cancer

“…Interactions between the tumor and the CAFs play an important role in tumor progression in several solid cancers [ 15 , 16 , 17 , 18 ]. Across multiple studies, increasing CAF density or activated oncogenic signaling pathways in CAFs are found to be associated with poor prognosis in head and neck, oral, gastric, hepatocellular, and esophageal cancers [ 15 , 16 , 17 , 18 ]. Activated CAF may enhance metastasis, directly or indirectly, by releasing growth factors and cytokines to stimulate growth and epithelial-mesenchymal transition [ 19 , 20 , 21 ].…”

“…Interactions between the tumor and the CAFs play an important role in tumor progression in several solid cancers [15][16][17][18]. Across multiple studies, increasing CAF density or activated oncogenic signaling pathways in CAFs are found to be associated with poor prognosis in head and neck, oral, gastric, hepatocellular, and esophageal cancers [15][16][17][18].…”