Adipose MSCs Suppress MCF7 and MDA-MB-231 Breast Cancer Metastasis and EMT Pathways Leading to Dormancy via Exosomal-miRNAs Following Co-Culture Interaction.

Norlaily Mohd Ali,Men Yee Chiew,Dilan Amila Satharasinghe,Kuan Chun Lan,Swee Keong Yeap,Wan Yong Ho,Soon Keng Cheong,Sheau Wei Tan,Lily Boo,Hsien Da Huang,Han Kiat Ong,Huynh Ky

doi:10.3390/ph14010008

Abstract

Globally, breast cancer is the most frequently diagnosed cancer in women, and it remains a substantial clinical challenge due to cancer relapse. The presence of a subpopulation of dormant breast cancer cells that survived chemotherapy and metastasized to distant organs may contribute to relapse. Tumor microenvironment (TME) plays a significant role as a niche in inducing cancer cells into dormancy as well as involves in the reversible epithelial-to-mesenchymal transition (EMT) into aggressive phenotype responsible for cancer-related mortality in patients. Mesenchymal stem cells (MSCs) are known to migrate to TME and interact with cancer cells via secretion of exosome- containing biomolecules, microRNA. Understanding of interaction between MSCs and cancer cells via exosomal miRNAs is important in determining the therapeutic role of MSC in treating breast cancer cells and relapse. In this study, exosomes were harvested from a medium of indirect co-culture of MCF7-luminal and MDA-MB-231-basal breast cancer cells (BCCs) subtypes with adipose MSCs. The interaction resulted in different exosomal miRNAs profiles that modulate essential signaling pathways and cell cycle arrest into dormancy via inhibition of metastasis and epithelial-to-mesenchymal transition (EMT). Overall, breast cancer cells displayed a change towards a more dormant-epithelial phenotype associated with lower rates of metastasis and higher chemoresistance. The study highlights the crucial roles of adipose MSCs in inducing dormancy and identifying miRNAs-dormancy related markers that could be used to identify the metastatic pattern, predict relapses in cancer patients and to be potential candidate targets for new targeted therapy.

Highlights

Breast cancer is the fifth leading cause of cancer mortality worldwide, with the highest prevalence diagnosed (24.2%) and cancer mortality (15%) among women [1]
A non-contact co-culture model using the Transwell system was set up to recapitulate the interaction of stromal adipose Mesenchymal stem cells (MSCs) with breast cancer cell lines (BCCs) in the microenvironment (Figure 1A)
We found that culturing BCCs with MSCs reduced proliferation and metastasis of cancer cells, suggesting that a factor secreted by MSCs was responsible for the acquisition of the dormant state of MCF7 and MDA cells

Summary

Introduction

Breast cancer is the fifth leading cause of cancer mortality worldwide, with the highest prevalence diagnosed (24.2%) and cancer mortality (15%) among women [1]. Metastatic or the spread of tumor cells throughout the body remains the underlying cause of death in the majority of breast cancer patients [2]. 30% of women with breast cancer report recurrence with regional lymph node metastases despite early detection and advanced technology in cancer treatment due to the mechanism of resistance and tumor heterogeneity [3]. The difference in the degree of tolerance to therapies among heterogeneous BCCs may render therapies in eliminating some subset of cancer cells such as dormant cells, contributing to late recurrence, in highly metastatic cells [5]

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Conclusion