Different Expression and Clinical Implications of Cancer-Associated Fibroblast (CAF) Markers in Brain Metastases

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-13, alpha-SMA, and collagen type I were associated with BM size. PDGFR-13 and alpha-SMA were associated with BM recurrence after resection. PDGFR-13 was associated with recurrence-free survival (RFS). Interestingly, high expression of PDGFR-13 and alpha-SMA was found in the patients with previous chemotherapy or radiotherapy for primary cancer. In primary cell culture, PDGFR-13 and alpha-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-13 and alpha-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.

Automated summary

This study evaluated the expression and clinical relevance of cancer-associated fibroblast (CAF)-related biomarkers in brain metastasis and characterized patient-derived primary CAFs and normal fibroblasts. Various CAF-related biomarkers were expressed in brain metastasis of different primary cancers. PDGFR-13 and alpha-SMA were associated with tumor size and recurrence after resection. High expression of PDGFR-13 and alpha-SMA was found in patients with previous chemotherapy or radiotherapy. In primary cell culture, PDGFR-13 and alpha-SMA were expressed at higher levels in patient-derived CAFs than in normal fibroblasts or cancer cells. The origins of CAF in brain metastasis were presumed to be pericytes of blood vessels, circulating endothelial progenitor cells, or transformed astrocytes of the peritumoral glial stroma. Overall, high expression of CAF-related biomarkers, particularly PDGFR-13 and alpha-SMA, is associated with poor prognosis and recurrence in patients with brain metastasis.