RANK in cancer-associated fibroblasts: A valuable prognostic determinant for metastasis in early-stage breast cancer patients.

IF 4.6 Q2 MATERIALS SCIENCE, BIOMATERIALS
María Belén Giorello, Francisco Raúl Borzone, María Florencia Mora, María Del Rosario Padin, Alejandra Wernicke, Vivian Labovsky, Norma Alejandra Chasseing
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Abstract

Background: The molecular system of receptor activator of nuclear factor kappa-β (RANK) and its ligand (RANKL) plays a role in a variety of physiological and pathological processes. These encompass the regulation of bone metabolism, mammary gland development, immune function, as well as their involvement and tumorigenesis. Nevertheless, limited knowledge exists regarding their function within the tumor microenvironment.

Methods and results: We explored the significance of RANK expression in cancer-associated fibroblasts (CAFs) as a prognostic biomarker in early breast cancer patients (BCPs) by immunohistochemistry. Results reveal a significant correlation between high RANK expression in CAFs and an increased risk of metastasis (p= 0.006), shorter metastasis-free survival (MFS) [p= 0.007, OR (95%CI) = 2.290 (1.259-4.156)], and lower overall survival (OS) [p= 0.004, OR (95%CI) = 2.469 (1.343-4.541)]. Upon analyzing the phenotype of CD34(-) CAFs isolated from primary tumors in BCPs, we observed co-expression of RANK with CD105 marker by immunofluorescence and flow cytometry, characteristic of mesenchymal stem/stromal cells (MSCs), suggesting the possible cellular origin. Also RANKL-RANK system increase the OCT-4, SOX-2 and DKK-1 (dickkopf 1) gene expression in CD34(-) CAFs by RT-PCR. Moreover, this system plays a crucial role in the migration of these CD34(-) CAFs.

Conclusions: These results support the clinical relevance of RANK in CAFs and propose its potential as a future therapeutic target in the treatment of early BCPs.

癌症相关成纤维细胞中的 RANK:早期乳腺癌患者转移的重要预后决定因素。
背景:核因子卡帕β受体激活剂(RANK)及其配体(RANKL)分子系统在多种生理和病理过程中发挥作用。这些过程包括调节骨代谢、乳腺发育、免疫功能以及参与肿瘤发生。然而,人们对它们在肿瘤微环境中的功能了解有限:我们通过免疫组化方法探讨了癌症相关成纤维细胞(CAFs)中 RANK 表达作为早期乳腺癌患者(BCPs)预后生物标志物的意义。结果显示,CAFs中RANK高表达与转移风险增加(p= 0.006)、无转移生存期(MFS)缩短[p= 0.007,OR(95%CI)= 2.290(1.259-4.156)]和总生存期(OS)降低[p= 0.004,OR(95%CI)= 2.469(1.343-4.541)]之间存在明显相关性。在分析从BCPs原发性肿瘤中分离出的CD34(-)CAFs的表型时,我们通过免疫荧光和流式细胞术观察到RANK与CD105标记物共同表达,这是间质干细胞/基质细胞(MSCs)的特征,表明其可能来源于细胞。RANKL-RANK系统还通过RT-PCR技术增加了CD34(-)CAFs中OCT-4、SOX-2和DKK-1(dickkopf 1)基因的表达。此外,该系统在这些 CD34(-)CAFs 的迁移过程中起着至关重要的作用:这些结果支持了 RANK 在 CAFs 中的临床意义,并提出了其作为治疗早期 BCPs 的未来治疗靶点的潜力。
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
ACS Applied Bio Materials
ACS Applied Bio Materials Chemistry-Chemistry (all)
CiteScore
9.40
自引率
2.10%
发文量
464
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