Chemotherapy exacerbates ovarian cancer cell migration and cancer stem cell-like characteristics through GLI1

Yawei Zhao,Fengli Yue,Jing Li,Yong Jia,Xuehan Yang,Yue Pan,Xiao Zheng,Tongfei Shi,Min Zhang,Mohan Gao,Meihui He,Lianzhi Cui,Dan Shao,Kan He,Li Chen

doi:10.1038/s41416-020-0825-7

Abstract

BackgroundDespite the great clinical response to the first-line chemotherapeutics, metastasis still happens among most of the ovarian cancer patients within 2 years.MethodsUsing multiple human ovarian cancer cell lines, a transwell co-culture system of the carboplatin or VP-16-challenged feeder and receptor cells was established to demonstrate the chemotherapy-exacerbated migration. The migration and cancer stem cell (CSC)-like characteristics were determined by wound healing, transwell migration, flow cytometry and sphere formation. mRNA and protein expression were identified by qPCR and western blot. Bioinformatics analysis was used to investigate the differentially expressed genes. GLI1 expression in tissue samples was analysed by immunohistochemistry.ResultsChemotherapy was found to not only kill tumour cells, but also trigger the induction of CSC-like traits and the migration of ovarian cancer cells. EMT markers Vimentin and Snail in receptor cells were upregulated in the microenvironment of chemotherapy-challenged feeder cells. The transcription factor GLI1 was upregulated by chemotherapy in both clinical samples and cell lines. Follow-up functional experiments illustrated that inhibiting GLI1 reversed the chemotherapy-exacerbated CSC-like traits, including CD44 and CD133, as well as prevented the migration of ovarian cancer cells.ConclusionsTargeting GLI1 may improve clinical benefits in the chemotherapy-exacerbated metastasis in ovarian cancer treatment.

Highlights

Despite the great clinical response to the first-line chemotherapeutics, metastasis still happens among most of the ovarian cancer patients within 2 years
The secretion of cytokine and inflammatory mediators, such as the C–X–C chemokine receptor type-4 (CXCR4) and prostaglandinE2 (PGE2) that are essential for inducing the epithelial–mesenchymal transition (EMT) of cancer, was found to be elevated in the tumour microenvironment after chemotherapy treatments, indicating that the altered tumour microenvironment by chemotherapy may contribute to the chemotherapy-induced metastasis.[8,9]
For SKOV-3 or A2780 cells treated with carboplatin, the cells were cultured for another 3 days (Day1–Day 3); for SKOV-3 treated with VP-16, the cells were cultured for another 6 days (Day1–Day 6); for A2780 treated with VP-16, the cells were cultured for another 5 days (Day 1–Day 5)

Summary

Introduction

Despite the great clinical response to the first-line chemotherapeutics, metastasis still happens among most of the ovarian cancer patients within 2 years. Ovarian cancer is the leading cause of death among gynaecological cancers.[1] Platinum, paclitaxel or the combination of platinum and paclitaxel-based chemotherapy are used as the first-line chemotherapeutics for the clinical management of ovarian cancer.[2] Despite the achievement of a complete clinical response, recurrence and metastasis are still observed among ~70% of the patients within 2 years after initial diagnosis, which is responsible for the high mortality of ovarian cancer.[3] chemotherapy is one of the major efficient medical interventions, our and other recent studies have found that it may induce intratumoural or systemic changes, which may paradoxically exacerbate the proliferation and dissemination of cancer cells.[4] Different chemotherapy drugs, including paclitaxel and carboplatin, were observed to induce the migration of cancer cells in different kinds of cancers.[5,6,7] The secretion of cytokine and inflammatory mediators, such as the C–X–C chemokine receptor type-4 (CXCR4) and prostaglandinE2 (PGE2) that are essential for inducing the epithelial–mesenchymal transition (EMT) of cancer, was found to be elevated in the tumour microenvironment after chemotherapy treatments, indicating that the altered tumour microenvironment by chemotherapy may contribute to the chemotherapy-induced metastasis.[8,9]

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Results

Conclusion