The Key Laboratory of Molecular Epigenetics of Ministry of Education (MOE), Northeast Normal University, Changchun 130024, China.
The Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, China.
Int J Mol Sci. 2021 Jan 15;22(2):849. doi: 10.3390/ijms22020849.
Chemotherapy is one of the most common strategies for tumor treatment but often associated with post-therapy tumor recurrence. While chemotherapeutic drugs are known to induce tumor cell senescence, the roles and mechanisms of senescence in tumor recurrence remain unclear. In this study, we used doxorubicin to induce senescence in breast cancer cells, followed by culture of breast cancer cells with conditional media of senescent breast cancer cells (indirect co-culture) or directly with senescent breast cancer cells (direct co-culture). We showed that breast cancer cells underwent the epithelial-mesenchymal transition (EMT) to a greater extent and had stronger migration and invasion ability in the direct co-culture compared with that in the indirect co-culture model. Moreover, in the direct co-culture model, non-senescent breast cancer cells facilitated senescent breast cancer cells to escape and re-enter into the cell cycle. Meanwhile, senescent breast cancer cells regained tumor cell characteristics and underwent EMT after direct co-culture. We found that the Notch signaling was activated in both senescent and non-senescent breast cancer cells in the direct co-culture group. Notably, the EMT process of senescent and adjacent breast cancer cells was blocked upon inhibition of Notch signaling with -[(3,5-difluorophenyl)acetyl]-l-alanyl-2-phenyl]glycine-1,1-dimethylethyl ester (DAPT) in the direct co-cultures. In addition, DAPT inhibited the lung metastasis of the co-cultured breast cancer cells in vivo. Collectively, data arising from this study suggest that both senescent and adjacent non-senescent breast cancer cells developed EMT through activating Notch signaling under conditions of intratumoral heterogeneity caused by chemotherapy, which infer the possibility that Notch inhibitors used in combination with chemotherapeutic agents may become an effective treatment strategy.
化疗是肿瘤治疗中最常用的策略之一，但常伴有治疗后肿瘤复发。虽然已知化疗药物可诱导肿瘤细胞衰老，但衰老在肿瘤复发中的作用和机制尚不清楚。在这项研究中，我们使用阿霉素诱导乳腺癌细胞衰老，然后用衰老乳腺癌细胞的条件培养基（间接共培养）或直接用衰老乳腺癌细胞培养乳腺癌细胞（直接共培养）。我们发现，与间接共培养模型相比，乳腺癌细胞在直接共培养中更易发生上皮-间充质转化（EMT），且具有更强的迁移和侵袭能力。此外，在直接共培养模型中，非衰老乳腺癌细胞促进衰老乳腺癌细胞逃逸并重新进入细胞周期。同时，衰老乳腺癌细胞在直接共培养后恢复了肿瘤细胞特征并发生 EMT。我们发现，在直接共培养组中，衰老和非衰老乳腺癌细胞中的 Notch 信号均被激活。值得注意的是，在用 -[(3,5-二氟苯甲酰基)-l-丙氨酰基-2-苯基]甘氨酸-1,1-二甲基乙基酯（DAPT）抑制 Notch 信号后，直接共培养中衰老和相邻乳腺癌细胞的 EMT 过程被阻断。此外，DAPT 抑制了共培养乳腺癌细胞在体内的肺转移。总之，这项研究的数据表明，在化疗引起的肿瘤内异质性条件下，通过激活 Notch 信号，衰老和相邻非衰老乳腺癌细胞均发生 EMT，这暗示了 Notch 抑制剂与化疗药物联合使用可能成为一种有效的治疗策略。
