Cancer cell-soluble factors reprogram mesenchymal stromal cells to slow cycling, chemoresistant cells with a more stem-like state

Abstract

BackgroundMesenchymal stem cells (MSCs) play different roles in modulating tumor progression, growth, and metastasis. MSCs are recruited to the tumor site in large numbers and subsequently have an important microenvironmental role in modulating tumor progression and drug sensitivity. However, the effect of the tumor microenvironment on MSC plasticity remains poorly understood. Herein, we report a paracrine effect of cancer cells, in which they secrete soluble factors that promote a more stem-like state in bone marrow mesenchymal stem cells (BM-MSCs).MethodsThe effect of soluble factors secreted from MCF7, Hela, and HepG2 cancer cell lines on BM-MSCs was assessed using a Transwell indirect coculture system. After 5 days of coculture, BM-MSCs were characterized by flow cytometry for surface marker expression, by qPCR for gene expression profile, and by confocal immunofluorescence for marker expression. We then measured the sensitivity of cocultured BM-MSCs to chemotherapeutic agents, their cell cycle profile, and their response to DNA damage. The sphere formation, invasive properties, and in-vivo performance of BM-MSCs after coculture with cancer cells were also measured.ResultsIndirect coculture of cancer cells and BM-MSCs, without direct cell contact, generated slow cycling, chemoresistant spheroid stem cells that highly expressed markers of pluripotency, cancer cells, and cancer stem cells (CSCs). They also displayed properties of a side population and enhanced sphere formation in culture. Accordingly, these cells were termed cancer-induced stem cells (CiSCs). CiSCs showed a more mesenchymal phenotype that was further augmented upon TGF-β stimulation and demonstrated a high expression of the β-catenin pathway and ALDH1A1.ConclusionsThese findings demonstrate that MSCs, recruited to the tumor microenvironment in large numbers, may display cellular plasticity, acquire a more stem-like state, and acquire some properties of CSCs upon exposure to cancer cell-secreted factors. These acquired characteristics may contribute to tumor progression, survival, and metastasis. Our findings provide new insights into the interactions between MSCs and cancer cells, with the potential to identify novel molecular targets for cancer therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-017-0709-9) contains supplementary material, which is available to authorized users.

Alterations of The Stem-Like Properties in The Breast Cancer Cell Line MDA-MB-231 Induced by Single Pulsed Doxorubicin Treatment

“…The characteristic ability of CSCs to regenerate the population was observed in post-treatment (DOX+1) culture -the recovery was provided by a relatively small number of cells (Weihua et al, 2011). During post-treatment (DOX+1) cultures we observed non-adherent cell clusters resembling CSCs that have been described in several mammosphere studies (Jia et al, 2016;El-Badawy et al, 2017). Long-term colony formation assay showed a significantly increased capability of post-treatment (DOX+1) cultures to form colonies in comparison to control cells, and this observation is in line with other studies of giant cells with CSC features (Weihua et al, 2011).…”

“…Changes in transcriptional expression of ALDH1A1 were observed in treated cultures. ALDH1A is another marker widely associated with the CSC phenotype; it has been associated with chemoresistance and has been shown to correlate with the outcome of treatment (El-Badawy et al, 2017).…”

Doxorubicin resistance induces IL6 activation in the colon cancer cell line LS180

“…Cancer cells undergo reprogramming and change morphologically when treated with chemoresistant drugs over a period of time ( 28 ). The results of the present study demonstrated that RT-qPCR analysis of the epithelial to mesenchymal responsive genes including neural (N)-cadherin, vimentin, TWIST and TGFR2 was markedly increased in doxorubicin-resistant cells which was further enhanced by shPTEN doxorubicin-resistant cells as compared with LS180 ( Fig.…”

Telomerase reverse transcriptase coordinates with the epithelial-to-mesenchymal transition through a feedback loop to define properties of breast cancer stem cells

“…Cancer stem cells (CSCs) are currently considered the driving force of cancer progression and metastasis because of their tumor initiation properties and resistance to chemotherapeutic agents ( El-Badawy et al, 2017 ; Salem et al, 2015 ). Therefore, understanding the cellular and molecular mechanisms that regulate CSCs will be essential for the development of CSC-targeted therapies.…”