Aims: This study assessed the expression and clinical relevance of cancer-asssociated fibroblast (CAF)-related biomarkers in brain metastasis (BM). Moreover, molecular characterization of patient-derived primary CAFs and normal fibroblasts (NFs) was performed. Methods: Sixty-eight patients with BM from various primary cancer types were selected. Immunohistochemistry (IHC) and immunofluorescence (IF) staining were performed to evaluate the expression of various CAF-related biomarkers. CAFs and NFs were isolated from fresh tissues. Results: Various CAF-related biomarkers were expressed in CAFs in BMs of different primary cancers. However, only PDGFR-β, α-SMA, and collagen type I were associated with BM size. PDGFR-β and α-SMA were associated with BM recurrence after resection. PDGFR-β was associated with recurrence-free survival (RFS). Interestingly, high expression of PDGFR-β and α-SMA was found in the patients with previous chemotherapy or radiotherapy for primary cancer. In primary cell culture, PDGFR-β and α-SMA were expressed at higher levels in patient-derived CAFs than in NFs or cancer cells. The origins of CAF in BM were presumed to be pericytes of blood vessels, circulating endothelial progenitor cells, or transformed astrocytes of the peritumoral glial stroma. Conclusion: Our results suggest that high expression of CAF-related biomarkers, particularly PDGFR-β and α-SMA, is associated with poor prognosis and recurrence in patients with BM. With the elucidation of the role and origins of CAF in the tumor microenvironment, CAF can be a new imperative target for BM immunotherapy.
Keywords: Alpha-smooth muscle actin; Brain metastasis; Cancer-associated fibroblasts; Platelet-derived growth factor receptor-beta; Tumor microenvironment.
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