Tumor Cells-Derived FGF-2 Promotes Lymphangiogenesis as a Prognostic Marker in OSCC

IF 2.3 3区医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE

Journal of Oral Pathology & Medicine Pub Date : 2025-08-05 DOI:10.1111/jop.70019

Jia Kang, Aoming Cheng, Guanzheng Chen, Lin Zhu, Zhengxue Han, Qiaoshi Xu

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引用次数: 0

Abstract

Background

The “cold” tumor microenvironment of oral squamous cell carcinoma (OSCC), where tumor-associated lymphatic vessels play a critical role in the transport of immune cells, is associated with a poor prognosis. However, the effect of tumor-induced lymphangiogenesis on CD8+ T cell infiltration and its role in the formation of the tumor immune microenvironment remain unclear.

Methods

We analyzed the prognostic significance of several lymphangiogenesis factors in OSCC with The Cancer Genome Atlas dataset, and confirmed the impact of fibroblast growth factor-2 (FGF-2) on prognosis in tissue specimens. Subsequently, we investigated the effects of FGF-2 on the proliferation, migration, and tube formation capacities of lymphatic endothelial cells, and CD8+ T cell infiltration through in vivo and in vitro experiments. Survival analysis was performed by Kaplan–Meier analysis and log-rank tests. The hazard ratio was calculated by Cox proportional hazards model.

Results

Patients with high FGF-2 levels and increased numbers of peritumoral lymphatic vessels were associated with a worse prognosis. Furthermore, we demonstrated that tumor cell-derived FGF-2 promoted lymphangiogenesis by regulating the FGFR1/PTEN/AKT axis and increased the secretion of CXCL9 to recruit and egress CD8+ T cells via neo-lymphatic vessels. PD-166866, an inhibitor of FGFR1, suppressed lymphangiogenesis and the secretion of CXCL9 to increase CD8+ T cell infiltration and inhibit tumor progression.

Conclusions

Our data suggest that FGF-2 is a significant prognostic factor that induces lymphangiogenesis and affects intratumoral CD8+ T cells, contributing to the formation of a “cold” tumor microenvironment in OSCC. FGF-2/FGFR1 could serve as an effective target for improving the prognosis of OSCC.

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肿瘤细胞来源的FGF-2促进淋巴管生成作为OSCC的预后标志物。

背景：口腔鳞状细胞癌（OSCC）的“冷”肿瘤微环境与预后不良有关，肿瘤相关淋巴管在免疫细胞的运输中起着关键作用。然而，肿瘤诱导的淋巴管生成对CD8+ T细胞浸润的影响及其在肿瘤免疫微环境形成中的作用尚不清楚。方法：利用the Cancer Genome Atlas数据集分析几种淋巴管生成因子在OSCC中的预后意义，并在组织标本中证实成纤维细胞生长因子-2 （FGF-2）对预后的影响。随后，我们通过体内和体外实验研究了FGF-2对淋巴内皮细胞增殖、迁移和成管能力以及CD8+ T细胞浸润的影响。生存分析采用Kaplan-Meier分析和log-rank检验。采用Cox比例风险模型计算风险比。结果：高FGF-2水平和瘤周淋巴管数量增加的患者预后较差。此外，我们证明肿瘤细胞来源的FGF-2通过调节FGFR1/PTEN/AKT轴促进淋巴管生成，并增加CXCL9的分泌，通过新淋巴管招募和输出CD8+ T细胞。PD-166866是FGFR1的抑制剂，可抑制淋巴管生成和CXCL9的分泌，从而增加CD8+ T细胞浸润，抑制肿瘤进展。结论：我们的数据表明，FGF-2是一个重要的预后因子，可诱导淋巴管生成并影响肿瘤内CD8+ T细胞，促进OSCC“冷”肿瘤微环境的形成。FGF-2/FGFR1可作为改善OSCC预后的有效靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Oral Pathology & Medicine 医学-病理学

CiteScore

5.90

自引率

6.10%

发文量

121

审稿时长

4-8 weeks

期刊介绍： The aim of the Journal of Oral Pathology & Medicine is to publish manuscripts of high scientific quality representing original clinical, diagnostic or experimental work in oral pathology and oral medicine. Papers advancing the science or practice of these disciplines will be welcomed, especially those which bring new knowledge and observations from the application of techniques within the spheres of light and electron microscopy, tissue and organ culture, immunology, histochemistry and immunocytochemistry, microbiology, genetics and biochemistry.