Istituto per l'Endocrinologia e l'Oncologia Sperimentale "G. Salvatore" (IEOS), CNR, Naples, Italy.
Istituto di Biostrutture e Bioimmagini, CNR, Naples, Italy.
Theranostics. 2018 Oct 6;8(18):5178-5199. doi: 10.7150/thno.27798. eCollection 2018.
While the overall mortality for breast cancer has recently declined, management of triple-negative breast cancer (TNBC) is still challenging because of its aggressive clinical behavior and the lack of targeted therapies. Genomic profiling studies highlighted the high level of heterogeneity of this cancer, which comprises different subtypes with unique phenotypes and response to treatment. Platelet-derived growth factor receptor β (PDGFRβ) is an established mesenchymal/stem cell-specific marker in human glioblastoma and, as recently suggested, it may uniquely mark breast cancer cells with stem-like characteristics and/or that have undergone epithelial-mesenchymal transition. : Immunohistochemical analysis for PDGFRβ expression was performed on a human TNBC tissue microarray. Functional assays were conducted on mesenchymal-like TNBC cells to investigate the effect of a previously validated PDGFRβ aptamer on invasive cell growth in three-dimensional culture conditions, migration, invasion and tube formation. The aptamer was labeled with a near-infrared (NIR) dye and its binding specificity to PDGFRβ was assessed both (confocal microscopy and flow cytometry analyses) and (fluorescence molecular tomography in mice bearing TNBC xenografts). A mouse model of TNBC lung metastases formation was established and NIR-labeled PDGFRβ aptamer was used to detect lung metastases in mice untreated or intravenously injected with unlabeled aptamer. : Here, we present novel data showing that tumor cell expression of PDGFRβ identifies a subgroup of mesenchymal tumors with invasive and stem-like phenotype, and propose a previously unappreciated role for PDGFRβ in driving TNBC cell invasiveness and metastases formation. We show that the PDGFRβ aptamer blocked invasive growth and migration/invasion of mesenchymal TNBC cell lines and prevented TNBC lung metastases formation. Further, upon NIR-labeling, the aptamer specifically bound to TNBC xenografts and detected lung metastases. : We propose PDGFRβ as a reliable biomarker of a subgroup of mesenchymal TNBCs with invasive and stem-like phenotype as well as the use of the PDGFRβ aptamer as a high efficacious tool for imaging and suppression of TNBC lung metastases. This study will allow for the significant expansion of the current repertoire of strategies for managing patients with more aggressive TNBC.
尽管乳腺癌的总体死亡率最近有所下降，但由于其侵袭性行为和缺乏靶向治疗，三阴性乳腺癌（TNBC）的治疗仍然具有挑战性。基因组分析研究强调了这种癌症的高度异质性，它包括不同的亚型，具有独特的表型和对治疗的反应。血小板衍生生长因子受体β（PDGFRβ）是人类胶质母细胞瘤中一种已确立的间质/干细胞特异性标志物，最近有研究表明，它可能是唯一标记具有干细胞样特征和/或经历上皮间质转化的乳腺癌细胞的标志物。 ：我们对人类 TNBC 组织微阵列进行了 PDGFRβ 表达的免疫组织化学分析。在间充质样 TNBC 细胞中进行了功能测定，以研究先前验证的 PDGFRβ 适体对三维培养条件下侵袭性细胞生长、迁移、侵袭和管形成的影响。该适体用近红外（NIR）染料标记，并通过共聚焦显微镜和流式细胞术分析以及在携带 TNBC 异种移植物的小鼠中进行荧光分子断层扫描评估其与 PDGFRβ 的结合特异性。建立了 TNBC 肺转移形成的小鼠模型，并使用 NIR 标记的 PDGFRβ 适体检测未经处理或静脉注射未标记适体的小鼠中的肺转移。 ：在这里，我们提供了新的数据，表明肿瘤细胞 PDGFRβ 的表达可识别具有侵袭性和干细胞样表型的间充质肿瘤亚群，并提出了 PDGFRβ 在驱动 TNBC 细胞侵袭性和转移形成中的以前未被认识的作用。我们表明，PDGFRβ 适体阻断了间充质 TNBC 细胞系的侵袭性生长和迁移/侵袭，并阻止了 TNBC 肺转移的形成。此外，通过近红外标记，该适体特异性结合 TNBC 异种移植物并检测肺转移。 ：我们提出 PDGFRβ 作为具有侵袭性和干细胞样表型的间充质 TNBC 亚群的可靠生物标志物，并提出使用 PDGFRβ 适体作为成像和抑制 TNBC 肺转移的高效工具。这项研究将为管理更具侵袭性的 TNBC 患者的当前策略组合带来重大扩展。
