Zhao Jingjing, Li Yahui, Huang Yingying, Su Peng, Nie Fujiao, Yang Pishan, Yang Chengzhe
Department of Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, China.
Department of Oral and Maxillofacial Surgery, Qilu Hospital of Shandong University, Jinan, China.
J Cell Physiol. 2025 Jan;240(1):e31498. doi: 10.1002/jcp.31498. Epub 2024 Dec 5.
Cancer associated fibroblasts (CAFs) are the predominant stromal cell-type in the solid tumor microenvironment, originating from various cell types and playing a crucial role in promoting tumor progression and metastasis The generation of CAFs is influenced by complex factors secreted by tumor cells, with particular emphasis on transforming growth factor-β (TGF-β). However, it remains largely unknown whether growth/differentiation factor-15 (GDF15), as a member of the TGF-β superfamily, exerts similar effects to TGF-β in oral squamous cell carcinoma (OSCC). In this study, we investigated the impact of GDF15 derived from tumor cells on CAF transformation and elucidated the underlying mechanisms. Exogenous GDF15 and OSCC cells induced the transformation of bone marrow mesenchymal stem cells (BMSCs) and human gingival fibroblasts (HGFs) into CAFs, as evidenced by α-smooth muscle actin (α-SMA) as a phenotypic marker and TGF-β, interleukin 6 (IL-6), and vascular endothelial-derived growth factor (VEGF) as functional markers. Conversely, knockdown of GDF15 in OSCC cells reversed CAF transformation. Mechanistically, extracellular signal-regulated kinases 1/2(ERK1/2) pathway was associated with GDF15-mediated promotion of CAF transformation. Furthermore, OSCC-induced CAFs enhanced migration and invasion abilities of OSCC cells; but this pro-cancer effect was abolished upon knockdown of GDF15 in OSCC cells. Subcutaneous coinjection of OSCC cells with BMSCs or HGFs into mice revealed the promoted tumor growth along with increased expression levels of α-SMA and Ki67 compared with alone OSCC cells injection; these effects were attenuated when GDF15 was knocked down in OSCC cells. Collectively, our findings suggest that tumor-derived GDF15 contributes to the progression of OSCC by promoting CAF transformation through activation of the ERK1/2 pathway.
癌症相关成纤维细胞（CAFs）是实体瘤微环境中主要的基质细胞类型，起源于多种细胞类型，在促进肿瘤进展和转移中起关键作用。CAFs的产生受肿瘤细胞分泌的复杂因子影响，尤其着重于转化生长因子-β（TGF-β）。然而，作为TGF-β超家族成员的生长/分化因子-15（GDF15）在口腔鳞状细胞癌（OSCC）中是否发挥与TGF-β类似的作用，在很大程度上仍不清楚。在本研究中，我们研究了肿瘤细胞来源的GDF15对CAF转化的影响，并阐明了其潜在机制。外源性GDF15和OSCC细胞诱导骨髓间充质干细胞（BMSCs）和人牙龈成纤维细胞（HGFs）转化为CAFs，以α-平滑肌肌动蛋白（α-SMA）作为表型标志物，TGF-β、白细胞介素6（IL-6）和血管内皮生长因子（VEGF）作为功能标志物可证明这一点。相反，在OSCC细胞中敲低GDF15可逆转CAF转化。机制上，细胞外信号调节激酶1/2（ERK1/2）通路与GDF15介导的CAF转化促进作用相关。此外，OSCC诱导的CAFs增强了OSCC细胞的迁移和侵袭能力；但在OSCC细胞中敲低GDF15后，这种促癌作用被消除。将OSCC细胞与BMSCs或HGFs皮下共注射到小鼠体内，与单独注射OSCC细胞相比，显示出肿瘤生长加速，同时α-SMA和Ki67的表达水平增加；当在OSCC细胞中敲低GDF15时，这些作用减弱。总的来说，我们的研究结果表明，肿瘤来源的GDF15通过激活ERK1/2通路促进CAF转化，从而有助于OSCC的进展。
