The Interaction of the Senescent and Adjacent Breast Cancer Cells Promotes the Metastasis of Heterogeneous Breast Cancer Cells through Notch Signaling.
The Interaction of the Senescent and Adjacent Breast Cancer Cells Promotes the Metastasis of Heterogeneous Breast Cancer Cells through Notch Signaling.
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衰老和邻近乳腺癌细胞的相互作用通过Notch信号促进异质乳腺癌细胞的转移
DOI：
10.3390/ijms22020849
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发表时间：
2021-01-15
影响因子：
5.6
通讯作者：
Zhang Y
中科院分区：
文献类型：
--
作者：
Zhang N;Ji J;Zhou D;Liu X;Zhang X;Liu Y;Xiang W;Wang M;Zhang L;Wang G;Huang B;Lu J;Zhang Y
化疗是肿瘤治疗的最常见策略之一，但通常与治疗后肿瘤复发相关。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仍不清楚。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）或直接与衰老乳腺癌细胞（直接共培养）培养乳腺癌细胞。结果表明，与间接共培养模型相比，直接共培养模型中乳腺癌细胞发生了更大程度的上皮-间质转化（EMT），并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，衰老的乳腺癌细胞恢复肿瘤细胞的特性，并进行EMT后直接共培养。我们发现，Notch信号在直接共培养组的衰老和非衰老乳腺癌细胞中均被激活。值得注意的是，在直接共培养物中，衰老和相邻乳腺癌细胞的EMT过程在用N-[（3，5-二氟苯基）乙酰基]-1-丙氨酰基-2-苯基]甘氨酸-1，1-二甲基乙酯（DAPT）抑制Notch信号传导后被阻断。此外，DAPT在体内抑制共培养的乳腺癌细胞的肺转移。总的来说，从这项研究中产生的数据表明，衰老和相邻的非衰老乳腺癌细胞通过激活Notch信号传导在由化疗引起的肿瘤内异质性的条件下发展EMT，这推断Notch抑制剂与化疗药物组合使用可能成为有效的治疗策略的可能性。
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 N-[(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.
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DOI：
10.1158/1541-7786.mcr-10-0457
发表时间：
2011-07
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
McGowan PM;Simedrea C;Ribot EJ;Foster PJ;Palmieri D;Steeg PS;Allan AL;Chambers AF
通讯作者：
Chambers AF
影响因子：
11.1
作者：
Carlson, Morgan E.;Suetta, Charlotte;Conboy, Michael J.;Aagaard, Per;Mackey, Abigail;Kjaer, Michael;Conboy, Irina
通讯作者：
Conboy, Irina
DOI：
10.1146/annurev-pathol-121808-102144
发表时间：
2010
期刊：
Annual review of pathology
影响因子：
--
作者：
Coppé JP;Desprez PY;Krtolica A;Campisi J
通讯作者：
Campisi J
影响因子：
64.5
作者：
Kuilman, Thomas;Michaloglou, Chrysiis;Peeper, Daniel S.
通讯作者：
Peeper, Daniel S.
DOI：
10.1073/pnas.211053698
发表时间：
2001-10-09
影响因子：
11.1
作者：
Krtolica, A;Parrinello, S;Campisi, J
通讯作者：
Campisi, J