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首页> 外文期刊>Journal of Cellular Physiology >Potential role of HER2-overexpressing exosomes in countering trastuzumab-based therapy.
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Potential role of HER2-overexpressing exosomes in countering trastuzumab-based therapy.

机译:的潜在作用HER2-overexpressing液对付trastuzumab-based疗法。

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摘要

Exosomes are endosome-derived nanovesicles actively released into the extracellular environment and biological fluids, both under physiological and pathological conditions, by different cell types. We characterized exosomes constitutively secreted by HER2-overexpressing breast carcinoma cell lines and analyzed in vitro and in vivo their potential role in interfering with the therapeutic activity of the humanized antibody Trastuzumab and the dual tyrosine kinase inhibitor (TKI) Lapatinib anti-HER2 biodrugs. We show that exosomes released by the HER2-overexpressing tumor cell lines SKBR3 and BT474 express a full-length HER2 molecule that is also activated, although to a lesser extent than in the originating cells. Release of these exosomes was significantly modulated by the growth factors EGF and heregulin, two of the known HER2 receptor-activating ligands and naturally present in the surrounding tumor microenvironment. Exosomes secreted either in HER2-positive tumor cell-conditioned supernatants or in breast cancer patients' serum bound to Trastuzumab. Functional assays revealed that both xenogeneic and autologous HER2-positive nanovesicles, but not HER2-negative ones, inhibited Trastuzumab activity on SKBR3 cell proliferation. By contrast, Lapatinib activity on SKBR3 cell proliferation was unaffected by the presence of autologous exosomes. Together, these findings point to the role of HER2-positive exosomes in modulating sensitivity to Trastuzumab, and, consequently, to HER2-driven tumor aggressiveness.
机译:液是endosome-derived nanovesicles积极地释放到细胞外在环境和生物液体生理和病理条件下,不同的细胞类型。持续分泌HER2-overexpressing乳腺癌细胞系和分析体外在干扰和体内潜在的作用人性化的治疗活动抗体曲妥珠单抗和双重酪氨酸激酶抑制剂(TKI)拉帕替尼anti-HER2 biodrugs。显示发布的液HER2-overexpressing肿瘤细胞系SKBR3和BT474表达一个完整的HER2分子也被激活,尽管程度低于在原始细胞。液明显的调制生长因子EGF和heregulin,两个的已知的HER2 receptor-activating配体自然存在于周围的肿瘤微环境。her2阳性肿瘤cell-conditioned上层清液或在乳腺癌患者的血清曲妥珠单抗。异种的和自体her2阳性nanovesicles,但不是her2阴性的抑制曲妥珠单抗活动SKBR3细胞扩散。SKBR3细胞增殖的影响自体液的存在。结果指向her2阳性的角色液在调节灵敏度曲妥珠单抗,因此,HER2-driven肿瘤侵犯。

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