NK3.3-Derived Extracellular Vesicles Penetrate and Selectively Kill Treatment-Resistant Tumor Cells.
NK3.3-Derived Extracellular Vesicles Penetrate and Selectively Kill Treatment-Resistant Tumor Cells.
复制标题
DOI：
10.3390/cancers16010090
复制
发表时间：
2023-12-23
期刊：
影响因子：
5.2
通讯作者：
Wong, David
中科院分区：
文献类型：
--
作者：
Mccune, Allyson;Kornbluth, Jacki;Wong, David
许多癌症治疗变得无效，因为肿瘤细胞产生耐药性并逃逸，导致患者复发和肿瘤扩散。因此，迫切需要开发靶向癌症并改善患者结局的替代方法。我们报道了来源于人自然杀伤（NK）细胞系NK3.3的细胞外囊泡（EV）具有有效的肿瘤杀伤活性，而不伤害正常细胞。本研究旨在评估NK3.3EV克服治疗有效性的一些障碍的能力。我们使用三维乳腺癌模型来证明NK3.3EV有效地穿透并杀死实体瘤细胞。我们开发了一种耐药白血病细胞系，发现NK3.3EV对这些细胞具有高度细胞毒性。这些EV还消除了逃避治疗并导致肿瘤复发的癌细胞亚群。这些研究表明，NK3.3EV是一种潜在的新的免疫抑制剂，用于难治性癌症。癌症治疗通常由于肿瘤抗性的发展而变得无效，导致转移和复发。治疗也可能失败，因为它们无法进入肿瘤组织深处的细胞。当这种情况发生时，需要新的治疗剂。我们以前报道过，NK3.3EV，细胞外囊泡（EV）来源于正常的人类自然杀伤（NK）细胞系，NK3.3，对白血病和乳腺癌细胞系有很强的细胞毒活性，而不伤害正常细胞。在这里，我们使用了一个三维（3D）MCF 7乳腺癌乳腺球模型来重现NK3.3EV在体内会遇到的更生理的环境。NK3.3EV穿透MCF 7乳腺球，通过细胞凋亡诱导死亡。我们产生了伊马替尼耐药的K562慢性髓性白血病（CML）细胞系，以研究NK3.3EV是否能够杀死对一线化疗耐药的肿瘤细胞。NK3.3EV对伊马替尼耐药细胞的细胞毒性甚至比亲本细胞更强，通过caspase-3/-7激活诱导细胞凋亡。肿瘤内的少量癌症干细胞（CSC）也有助于治疗抗性。NK3.3EV减少了伊马替尼耐药和亲本K562培养物中的CSC样CD 34 +/CD 38 −亚群，并降低了肿瘤促进基因的CSC相关表达。我们的研究结果提供了强有力的证据，表明NK3.3EV可能是一种潜在的新的免疫抑制剂，用于难治性癌症。
Many cancer treatments become ineffective as tumor cells develop resistance and escape, resulting in patient relapse and tumor spread. Therefore, there is an urgent need to develop alternative approaches to target cancer and improve patient outcomes. We reported that extracellular vesicles (EVs) derived from the human natural killer (NK) cell line NK3.3 have potent tumor-killing activity, without harming normal cells. This study was designed to evaluate the ability of NK3.3EVs to overcome some of the obstacles to treatment efficacy. We used a three-dimensional breast cancer model to demonstrate that NK3.3EVs effectively penetrate and kill solid tumor cells. We developed a drug-resistant leukemia cell line and found that NK3.3EVs are highly cytotoxic to these cells. These EVs also eliminate the subpopulation of cancer cells that evade treatment and are responsible for tumor recurrence. These studies indicate that NK3.3EVs are a potential new immunotherapeutic agent for difficult-to-treat cancers. Cancer treatments often become ineffective due to the development of tumor resistance, leading to metastasis and relapse. Treatments may also fail because of their inability to access cells deep within the tumor tissue. When this occurs, new therapeutic agents are needed. We previously reported that NK3.3EVs, extracellular vesicles (EVs) derived from the normal human natural killer (NK) cell line, NK3.3, have strong cytotoxic activity against leukemia and breast cancer cell lines, without harming normal cells. Here, we used a three-dimensional (3D) MCF7 breast cancer mammosphere model to reproduce a more physiological environment that NK3.3EVs would encounter in vivo. NK3.3EVs penetrated MCF7 mammospheres, inducing death by apoptosis. We generated an imatinib-resistant K562 chronic myeloid leukemia (CML) cell line to investigate whether NK3.3EVs were able to kill tumor cells resistant to front-line chemotherapy. NK3.3EVs were even more cytotoxic to imatinib-resistant cells than parental cells, inducing apoptosis via caspase-3/-7 activation. The small population of cancer stem cells (CSCs) within tumors also contributes to therapeutic resistance. NK3.3EVs reduced the CSC-like CD34+/CD38− subpopulation in imatinib-resistant and parental K562 cultures and decreased CSC-associated expression of tumor-promoting genes. Our results provide strong evidence that NK3.3EVs may be a potential new immunotherapeutic agent for difficult-to-treat cancers.
登录
查看更多内容
用于肝癌治疗的人类自然杀伤细胞衍生的外泌体的递送：皮下和原位动物模型的体内研究。
影响因子：
6
作者：
通讯作者：
--
影响因子：
5.2
作者：
Di Pace, Anna Laura;Tumino, Nicola;Moretta, Lorenzo
通讯作者：
Moretta, Lorenzo
影响因子：
5.3
作者：
Kim, JW;Zeller, KI;Dang, CV
通讯作者：
Dang, CV
影响因子：
4.4
作者：
Lugini, Luana;Cecchetti, Serena;Fais, Stefano
通讯作者：
Fais, Stefano
影响因子：
20.3
作者：
LOZZIO, CB;LOZZIO, BB
通讯作者：
LOZZIO, BB