Xanthopoulos Alexia, Samt Ann-Kathrin, Guder Christiane, Taylor Nicholas, Roberts Erika, Herf Hannah, Messner Verena, Trill Anskar, Holzmann Katharina Larissa Kreszentia, Kiechle Marion, Seifert-Klauss Vanadin, Zschaeck Sebastian, Schatka Imke, Tauber Robert, Schmidt Robert, Enste Katrin, Pockley Alan Graham, Lobinger Dominik, Multhoff Gabriele
Center for Translational Cancer Research TU München (TranslaTUM), Klinikum rechts der Isar, Technical University of Munich (TUM), 81675 Munich, Germany.
Department of Gynecology and Obstetrics, Klinikum rechts der Isar, Technical University of Munich (TUM), 81675 Munich, Germany.
Biomedicines. 2023 Aug 16;11(8):2276. doi: 10.3390/biomedicines11082276.
Heat shock protein 70 (Hsp70) is frequently overexpressed in many different tumor types. However, Hsp70 has also been shown to be selectively presented on the plasma membrane of tumor cells, but not normal cells, and this membrane form of Hsp70 (mHsp70) could be considered a universal tumor biomarker. Since viable, mHsp70-positive tumor cells actively release Hsp70 in lipid micro-vesicles, we investigated the utility of Hsp70 in circulation as a universal tumor biomarker and its potential as an early predictive marker of therapeutic failure. We have also evaluated mHsp70 as a target for the isolation and enumeration of circulating tumor cells (CTCs) in patients with different tumor entities. Circulating vesicular Hsp70 levels were measured in the peripheral blood of tumor patients with the compHsp70 ELISA. CTCs were isolated using cmHsp70.1 and EpCAM monoclonal antibody (mAb)-based bead approaches and characterized by immunohistochemistry using cytokeratin and CD45-specific antibodies. In two out of 35 patients exhibiting therapeutic failure two years after initial diagnosis of non-metastatic breast cancer, progressively increasing levels of circulating Hsp70 had already been observed during therapy, whereas levels in patients without subsequent recurrence remained unaltered. With regards to CTC isolation from patients with different tumors, an Hsp70 mAb-based selection system appears superior to an EpCAM mAb-based approach. Extracellular and mHsp70 can therefore serve as a predictive biomarker for therapeutic failure in early-stage tumors and as a target for the isolation of CTCs in various tumor diseases.
热休克蛋白70（Hsp70）在许多不同类型的肿瘤中经常过度表达。然而，Hsp70也已被证明选择性地呈现在肿瘤细胞而非正常细胞的质膜上，这种膜形式的Hsp70（mHsp70）可被视为一种通用的肿瘤生物标志物。由于存活的mHsp70阳性肿瘤细胞会在脂质微泡中主动释放Hsp70，我们研究了循环中的Hsp70作为通用肿瘤生物标志物的效用及其作为治疗失败早期预测标志物的潜力。我们还评估了mHsp70作为分离和计数不同肿瘤实体患者循环肿瘤细胞（CTC）的靶点。使用compHsp70 ELISA检测肿瘤患者外周血中循环囊泡Hsp70的水平。使用基于cmHsp70.1和EpCAM单克隆抗体（mAb）的磁珠方法分离CTC，并使用细胞角蛋白和CD45特异性抗体通过免疫组织化学进行表征。在35例非转移性乳腺癌初始诊断两年后出现治疗失败的患者中，有两例在治疗期间已观察到循环Hsp70水平逐渐升高，而无后续复发患者的水平保持不变。关于从不同肿瘤患者中分离CTC，基于Hsp70 mAb的选择系统似乎优于基于EpCAM mAb的方法。因此，细胞外和mHsp70可作为早期肿瘤治疗失败的预测生物标志物以及各种肿瘤疾病中分离CTC的靶点。
