Mitsuhashi Atsushi, Nishioka Yasuhiko
Department of Respiratory Medicine and Rheumatology, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan.
Department of Community Medicine for Rheumatology, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan.
Cancer Sci. 2025 Jan;116(1):21-28. doi: 10.1111/cas.16385. Epub 2024 Nov 4.
Fibrocytes were identified as bone marrow-derived myeloid cells that also have fibroblast-like phenotypes, such as ECM production and differentiation to myofibroblasts. Although fibrocytes are known to contribute to various types of tissue fibrosis, their functions in the tumor microenvironment are unclear. We focused on fibrocytes as pivotal regulators of tumor progression. Our previous studies have indicated that fibrocytes induce angiogenesis and cancer stem cell-like phenotypes by secreting various growth factors. In contrast, immune checkpoint inhibitor (ICI)-treated fibrocytes demonstrated antigen-presenting capacity and enhanced antitumor T cell proliferation. Taken together, these findings indicate that fibrocytes have multiple effects on tumor progression. However, the detailed phenotypes of fibrocytes have not been fully elucidated because the isolation of distinct fibrocyte clusters has not been achieved without culturing in ECM-coated conditions or intracellular staining of ECM. The development of single-cell analyses partially resolves these problems. Single-cell RNA sequences in CD45 immune cells from tumor tissue identified ECM-expressing myeloid-like cells as distinct fibrocyte clusters. In addition, these findings enabled the isolation of tumor-infiltrating fibrocytes as CD45CD34 cells. These tumor-infiltrating fibrocytes demonstrated both antigen-presenting ability and differentiation into myofibroblast-like cancer-associated fibroblasts. Considering these functions of fibrocytes in tumor progression, molecular-targeting agents for the migration, activity, and differentiation of fibrocytes are promising therapeutic strategies. Furthermore, identification of specific cell surface markers and master regulators of fibrocytes will advance novel fibrocyte-targeting therapies. In this review, we discuss the multiple roles of tumor-infiltrating fibrocytes and novel cancer therapeutic strategies.
纤维细胞被鉴定为源自骨髓的髓样细胞，它们还具有成纤维细胞样表型，如细胞外基质（ECM）的产生以及向肌成纤维细胞的分化。尽管已知纤维细胞会导致各种类型的组织纤维化，但其在肿瘤微环境中的功能尚不清楚。我们将纤维细胞作为肿瘤进展的关键调节因子进行研究。我们之前的研究表明，纤维细胞通过分泌各种生长因子诱导血管生成和癌症干细胞样表型。相反，经免疫检查点抑制剂（ICI）处理的纤维细胞表现出抗原呈递能力，并增强了抗肿瘤T细胞增殖。综上所述，这些发现表明纤维细胞对肿瘤进展具有多种影响。然而，由于在未进行细胞外基质包被条件下培养或对细胞外基质进行细胞内染色的情况下，尚未实现分离不同的纤维细胞簇，因此纤维细胞的详细表型尚未完全阐明。单细胞分析的发展部分解决了这些问题。对肿瘤组织中CD45免疫细胞进行的单细胞RNA测序将表达细胞外基质的髓样样细胞鉴定为不同的纤维细胞簇。此外，这些发现使得能够将肿瘤浸润性纤维细胞分离为CD45⁺CD34⁺细胞。这些肿瘤浸润性纤维细胞既表现出抗原呈递能力，又能分化为肌成纤维细胞样癌症相关成纤维细胞。考虑到纤维细胞在肿瘤进展中的这些功能，针对纤维细胞迁移、活性和分化的分子靶向药物是很有前景的治疗策略。此外，鉴定纤维细胞的特异性细胞表面标志物和主调节因子将推动新型纤维细胞靶向治疗的发展。在这篇综述中，我们讨论了肿瘤浸润性纤维细胞的多种作用以及新型癌症治疗策略。
