Laboratorio de Inmunohematología, Instituto de Biología y Medicina Experimental (IBYME), Fundación IBYME, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina.
Departamento de Anatomía Patológica, Hospital Italiano, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina.
Cancer Biomark. 2024;41(2):115-132. doi: 10.3233/CBM-230523.
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.
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.
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.
核因子 κB 受体激活剂（RANK）及其配体（RANKL）的分子系统在多种生理和病理过程中发挥作用。这些过程包括骨代谢、乳腺发育、免疫功能的调节，以及它们的参与和肿瘤发生。然而，关于它们在肿瘤微环境中的功能，我们的了解有限。
我们通过免疫组织化学法探讨了 RANK 在癌症相关成纤维细胞（CAFs）中的表达作为早期乳腺癌患者（BCP）的预后生物标志物的意义。结果表明，CAFs 中 RANK 的高表达与转移风险增加显著相关（p=0.006），无转移生存（MFS）较短[ p=0.007，OR（95%CI）=2.290（1.259-4.156）]，总生存（OS）较低[ p=0.004，OR（95%CI）=2.469（1.343-4.541）]。在分析 BCP 原发肿瘤中分离的 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 标志物的共表达，这是间充质干细胞（MSCs）的特征，表明可能的细胞起源。此外，RANKL-RANK 系统通过 RT-PCR 增加 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 的迁移中起着至关重要的作用。
这些结果支持 RANK 在 CAFs 中的临床相关性，并提出其作为早期 BCP 治疗未来治疗靶点的潜力。
