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J Cancer 2023; 14(3):464-479. doi:10.7150/jca.80115 This issue Cite

Research Paper

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

Md Rashedunnabi Akanda^1,4*, Eun-Jung Ahn^2*, Yeong Jin Kim², S M Abdus Salam¹, Myung-Giun Noh¹, Sung Sun Kim¹, Tae-Young Jung², In-Young Kim², Chang-Hyun Kim³, Kyung-Hwa Lee^1,5✉, Kyung-Sub Moon^2✉

1. Department of Pathology, Chonnam National University Research Institute of Medical Science, Chonnam National University Hwasun Hospital and Medical School, Hwasun, Jeollanam-do, South Korea.
2. Department of Neurosurgery, Chonnam National University Research Institute of Medical Science, Chonnam National University Hwasun Hospital and Medical School, Hwasun, Jeollanam-do, South Korea.
3. Department of Surgery, Chonnam National University Research Institute of Medical Science, Chonnam National University Hwasun Hospital and Medical School, Hwasun, Jeollanam-do, South Korea.
4. Department of Pharmacology and Toxicology, Sylhet Agricultural University, Sylhet, Bangladesh.
5. BioMedical Sciences Graduate Program (BMSGP), Chonnam National University, Hwasun Jeollanam-do, South Korea.
* There authors share first authorship.

✉ Corresponding authors: Kyung-Sub Moon, Department of Neurosurgery, Chonnam National University Research Institute of Medical Science, Chonnam National University Hwasun Hospital and Medical School, 322 Seoyang-ro, Hwasun-eup, Hwasun-gun, Jeollanam-do, 58128, South Korea. Tel.: +82-61-379-7666, / Fax: +82-61-379-7673, E-mail: moonksac.kr. Kyung-Hwa Lee, Department of Pathology, Chonnam National University Research Institute of Medical Science, Chonnam National University Hwasun Hospital and Medical School, 322 Seoyang-ro, Hwasun-eup, Hwasun-gun, Jeollanam-do, 58128, South Korea. Tel.: +82-61-379-7050, / Fax: +82-61-379-7099, E-mail: mdkayleeac.kr More

Abstract

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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