The Interaction of the Senescent and Adjacent Breast Cancer Cells Promotes the Metastasis of Heterogeneous Breast Cancer Cells through Notch Signaling.

Na Zhang,Xuan Liu,Jun Lu,Yu Zhang,Yingqi Liu,Jiafei Ji,Lian Zhang,Meida Wang,Dandan Zhou,Guannan Wang,Baiqu Huang,Xinglin Zhang,Weifang Xiang

doi:10.3390/ijms22020849

Na Zhang, Xuan Liu + Show 11 more

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https://doi.org/10.3390/ijms22020849

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Abstract

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.

Highlights

IntroductionChemotherapy can trigger increased intratumoral heterogeneity [3] due to limitations in tissue permeability and variable concentrations of drug exposure of tumor cells, and this facilitates the formation of a gradient decrease with increasing distance between tumor cells and blood vessels after drugs enter solid tumors through blood [4,5]
Our results indicated that senescent breast cancer cells can promote the epithelial–mesenchymal transition (EMT) of adjacent breast cancer cells
Our results revealed a significant upregulation of cleaved, active Notch1 intracellular domain (N1ICD) and canonical Notch1target

Summary

Introduction

Chemotherapy can trigger increased intratumoral heterogeneity [3] due to limitations in tissue permeability and variable concentrations of drug exposure of tumor cells, and this facilitates the formation of a gradient decrease with increasing distance between tumor cells and blood vessels after drugs enter solid tumors through blood [4,5]. Chemotherapeutic drugs induce different fates of tumor cells at distinct solid tumor locations. Tumor cells close to blood vessels undergo apoptosis due to exposure to lethal concentrations of the drugs, while those at a moderate distance from blood vessels experience senescence. Tumor cells located far away enough from the vessels are not sensitive to chemotherapy drugs and potentially become seeds of tumor recurrence [6,7,8]. The roles of senescent tumor cells induced by chemotherapy drugs in tumor progression remain unclear at present

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