Department of Gynaecology and Obstetrics, University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany.
Institute of Immunology, University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany.
J Extracell Vesicles. 2023 Jul;12(7):e12338. doi: 10.1002/jev2.12338.
Ovarian cancer (OvCa) is the gynaecological disorder with the poorest prognosis due to the fast development of chemoresistance. We sought to connect chemoresistance and cancer cell-derived extracellular vesicles (EV). The mechanisms of how chemoresistance is sustained by EV remained elusive. One potentially contributing factor is A Disintegrin and Metalloprotease 17 (ADAM17)-itself being able to promote chemoresistance and inducing tumour cell proliferation and survival via the Epidermal Growth Factor Receptor (EGFR) pathway by shedding several of its ligands including Amphiregulin (AREG). We now demonstrate that upon chemotherapeutic treatment, proteolytically active ADAM17 is released in association with EV from OvCa cells. In terms of function, we show that patient-derived EV induce AREG shedding and restore chemoresistance in ADAM17-deficient cells. Confirming that ADAM17-containing EV transmit chemoresistance in OvCa, we propose that ADAM17 levels (also on EV) might serve as an indicator for tumour progression and the chemosensitivity status of a given patient.
卵巢癌（OvCa）是妇科疾病中预后最差的一种，因为其对化疗药物的耐药性发展迅速。我们试图将化疗耐药性与癌细胞衍生的细胞外囊泡（EV）联系起来。但 EV 维持化疗耐药性的机制仍不清楚。一个潜在的促成因素是解整合素金属蛋白酶 17（ADAM17）——它本身能够通过表皮生长因子受体（EGFR）途径促进化疗耐药性，并通过脱落其包括 Amphiregulin（AREG）在内的几种配体来诱导肿瘤细胞增殖和存活。现在我们证明，在化疗治疗后，具有蛋白水解活性的 ADAM17 与 OvCa 细胞来源的 EV 一起被释放。就功能而言，我们表明患者来源的 EV 诱导 AREG 脱落，并恢复 ADAM17 缺陷细胞的化疗耐药性。为了证实 ADAM17 含量（也在 EV 上）可能作为肿瘤进展和特定患者化疗敏感性状态的指标，我们提出 ADAM17 包含的 EV 传递卵巢癌的化疗耐药性。
