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.
癌症治疗常因肿瘤产生耐药性而失效，导致转移与复发。治疗失败也可能源于药物无法深入肿瘤组织内部。当出现这些情况时，需要开发新的治疗制剂。我们先前研究发现，源自正常人自然杀伤（NK）细胞系NK3.3的细胞外囊泡（NK3.3EVs）对白血病和乳腺癌细胞系具有强烈细胞毒性，且不损伤正常细胞。本研究采用三维MCF7乳腺癌乳腺球模型，模拟NK3.3EVs在体内可能遇到的更接近生理的环境。结果显示，NK3.3EVs能穿透MCF7乳腺球结构，通过诱导细胞凋亡导致肿瘤死亡。为探究NK3.3EVs能否杀死对一线化疗耐药的肿瘤细胞，我们构建了伊马替尼耐药的K562慢性髓系白血病细胞系。实验发现NK3.3EVs对耐药细胞的细胞毒性甚至强于亲代细胞，其通过激活caspase-3/-7通路诱导细胞凋亡。肿瘤内少量存在的癌症干细胞也是导致治疗抵抗的重要因素。NK3.3EVs能减少伊马替尼耐药及亲代K562细胞培养物中具有干细胞特性的CD34+/CD38−亚群，并降低促癌基因中与癌症干细胞相关的表达水平。本研究为NK3.3EVs作为难治性癌症潜在新型免疫治疗制剂提供了有力证据。
NK3.3-Derived Extracellular Vesicles Penetrate and Selectively Kill Treatment-Resistant Tumor Cells
肿瘤(癌症)患者之家