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Adipose MSC suppress breast cancer progression, metastasis and inhibit EMT pathways via exosomal-miRNAs following co-culture interaction

ABSTRACT: Introduction: Mesenchymal stem cells (MSCs) are commonly known to influence the progression of cancer due to their ability to migrate to the tumor microenvironment and interact with cancer cells. Exosomes have been found secreted by most cell types and have been shown to act as cargo carrying biomolecules including microRNA (miRNAs). Thus, understanding interaction between MSCs and cancer cells via exosomal miRNAs is crucial in determining the therapeutic role of MSC in treating breast cancer cells and relapse. Methods: Exosomes were harvested from the medium of indirect co-culture of MCF7-luminal and MDA-MB-231-basal breast cancer cells (BCCs) subtypes with adipose MSCs and profiled for miRNAs using next-generation sequencing. Results: The interaction resulted in the changes of exosomal miRNAs profiles that modulate essential signalling pathways and cell cycle arrest into dormancy via inhibition of epithelial-to-mesenchymal transition (EMT). The maintenance and induction of epithelial features in MCF7 and MDA cells have led to a positive correlation with the reduction of proliferation and metastasis as well as increased drug resistance. Overall, adipose MSCs mediated delivery of consensus miRNAs particularly miR-200 family in MCF7, miR-146a in MDA and miR-941 in both BCCs subtypes via exosomes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE156380 | GEO | 2020/08/18

REPOSITORIES: GEO

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Project description:Background: Docosahexaenoic acid (DHA) is a natural compound with anticancer and anti-angiogenesis activity that is currently under investigation as both a preventative agent and an adjuvant to breast cancer therapy. However, the precise mechanisms of DHA’s anticancer activities are unclear. It is understood that the intercommunication between cancer cells and their microenvironment is essential to tumor angiogenesis. Exosomes are extracellular vesicles that are important mediators of intercellular communication and play a role in promoting angiogenesis. However, very little is known about the contribution of breast cancer exosomes to tumor angiogenesis or whether exosomes can mediate DHA’s anticancer action. Results: Exosomes were collected from MCF7 and MDA-MB-231 breast cancer cells after treatment with DHA. We observed an increase in exosome secretion and exosome microRNA contents from the DHA-treated cells. The expression of 83 microRNAs in the MCF7 exosomes was altered by DHA (>2-fold). The most abundant exosome microRNAs (let-7a, miR-23b, miR-27a/b, miR-21, let-7, and miR-320b) are known to have anti-cancer and/or anti-angiogenic activity. These microRNAs were also increased by DHA treatment in the exosomes from other breast cancer lines (MDA-MB-231, ZR751 and BT20), but not in exosomes from normal breast cells (MCF10A). When DHA-treated MCF7 cells were co-cultured with or their exosomes were directly applied to endothelial cell cultures, we observed an increase in the expression of these microRNAs in the endothelial cells. Furthermore, overexpression of miR-23b and miR-320b in endothelial cells decreased the expression of their pro-angiogenic target genes (PLAU, AMOTL1, NRP1 and ETS2) and significantly inhibited tube formation by endothelial cells, suggesting that the microRNAs transferred by exosomes mediate DHA’s anti-angiogenic action. These effects could be reversed by knockdown of the Rab GTPase, Rab27A, which controls exosome release. Conclusions: We conclude that DHA alters breast cancer exosome secretion and microRNA contents, which leads to the inhibition of angiogenesis. Our data demonstrate that breast cancer exosome signaling can be targeted to inhibit tumor angiogenesis and provide new insight into DHA’s anticancer action, further supporting its use in cancer therapy. Examination of small RNA populations in MCF7 cells and exosomes after DHA treatment.

Project description:Purpose: Relationship between mesenchymal stem cells (MSCs) and cancer cells became mysterious because of having sufficient evidences regarding both stimulatory and inhibitory role of MSCs to cancer cells. Certainly, there is debate on customary role of MSCs (inhibitory/stimulatory), however, the notable involvement of MSCs in cancer biology is undoubtedly clear. MSCs might support tumor development through immune suppression, epithelial to mesenchymal transition (EMT), angiogenesis, and serving as cancer stromal cells. In contrast, MSCs are also reported to play role in suppression of cancer by downregulating the cancer survival signaling pathways such as Wnt/β-catenin and/or Akt3. Now, it is a rational demand to investigate the mechanism behind these completely contradictory roles of MSCs in cancer biology. Incidentally, cytokines and soluble factors secreted by MSCs have been scrutinized thoroughly and most of the reports with few exceptions concluded that MSCs-secreted cytokines and soluble factors have stimulatory effect in the progression of cancer. While, role of exosomes which is a type of micro-vesicles having 30-200 nm diameters, secreted by all cells, could be up-taken by neighboring cells, containing many important components including RNAs, proteins, DNA and lipids, serving as efficient vehicles for cancer-stromal communication, have been investigated very marginally and deserve to go for intensive investigation. Specially, cell-secreted miRNAs (18-22 nucleotides) are predominantly carried by exosomes and have been focused in recent years for its capacity in post-transcriptional regulation of gene expression through mRNA silencing. Hence, understating the functions of MSCs-derived secretome (particularly exosomes) in cancer is very much important to comprehend the cross-talk between MSCs and cancer cell biology. In this research, next generation sequencing (NGS) was performed for enrichment analysis of miRNAs in hAMSCs-CM derived exosomes. Methods: Exosomal-RNA was isolated from hAMSCs-CM derived exosomes, small RNA libraries were prepared through a series of processes such as adapter ligation, reverse transcription, PCR amplification, and pooled gel purification.Sequence quality was checked by FastQC experiment, unique sequences found for known miRNAs after clustering were verified with miRBase database (www.mirbase.org/) by blast, trimmed read might have considered as miRNA on condition of having 100% identical and whole length sequence of miRNA compare to the ones on miRBase database. Unmatched trimmed read excluded from miRBase were blast to ncRNA database Rfam (http://rfam.sanger.ac.uk/). Unmatched trimmed reads to any of non-miRNA on Rfam database were considered as a potential novel miRNA. Result: The exosomal-RNA sequencing explored that exosomes contains a rich population of miRNAs and many of the obtained miRNAs are reported to have anti-cancer properties through targeting different cancer survival pathways. Conclusion: Outwardly, we outlined that exosomal-miRNA is one of the conceivable reasons behind anti-proliferative effect of MSCs towards cancer cells.

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Adipose MSC suppress breast cancer progression, metastasis and inhibit EMT pathways via exosomal-miRNAs following co-culture interaction

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