The pro- and anti-tumor roles of mesenchymal stem cells toward BRCA1-IRIS-overexpressing TNBC cells
Abstract Background To evaluate the cross-talk between BRCA1-IRIS (IRIS)-overexpressing (IRISOE) TNBC cells and tumor-resident mesenchymal stem cells (MSCs) that triggers the aggressiveness or elimination of IRISOE TNBC tumors. Methods We analyzed the effect of silencing or inactivating IRIS on the...
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doaj-2c3cfae6252a4c7ea204553cb6698c6d2021-04-02T13:25:07ZengBMCBreast Cancer Research1465-542X2019-04-0121112310.1186/s13058-019-1131-2The pro- and anti-tumor roles of mesenchymal stem cells toward BRCA1-IRIS-overexpressing TNBC cellsDaniel Ryan0Bibbin T. Paul1Jim Koziol2Wael M. ElShamy3Breast Cancer Program, San Diego Biomedical Research InstituteDepartment of Molecular Biology and Biophysics, University of Connecticut Health CenterDepartment of Molecular and Experimental Medicine, The Scripps Research InstituteBreast Cancer Program, San Diego Biomedical Research InstituteAbstract Background To evaluate the cross-talk between BRCA1-IRIS (IRIS)-overexpressing (IRISOE) TNBC cells and tumor-resident mesenchymal stem cells (MSCs) that triggers the aggressiveness or elimination of IRISOE TNBC tumors. Methods We analyzed the effect of silencing or inactivating IRIS on the bi-directional interaction between IRISOE TNBC cells and MSCs on tumor formation and progression. We analyzed the downstream signaling in MSCs induced by IL-6 secreted from IRISOE TNBC cells. We compared the effect of MSCs on the formation and progression of IRIS-proficient and deficient-TNBC cells/tumors using in vitro and in vivo models. Finally, we analyzed the association between IL-6, PTGER2, and PTGER4 overexpression and breast cancer subtype; hormone receptor status; and distant metastasis-free or overall survival. Results We show high-level IL-6 secreted from IRISOE TNBC cells that enhances expression of its receptor (IL-6R) in MSCs, their proliferation, and migration toward IRISOE, in vitro, and recruitment into IRISOE TNBC tumors, in vivo. In serum-free medium, recombinant IL-6 and the IL-6-rich IRISOE TNBC cell condition media (CM) decreased STAT3Y705 phosphorylation (p-STAT3Y705) in MSCs. Inhibiting IRIS expression or activity prolonged STAT3Y705 phosphorylation in MSCs. The interaction with IRISOE TNBC cells skewed MSC differentiation toward prostaglandin E2 (PGE2)-secreting pro-aggressiveness cancer-associated fibroblasts (CAFs). Accordingly, co-injecting human or mouse MSCs with IRISOE TNBC tumor cells promoted the formation of aggressive mammary tumors, high circulating IL-6 and PGE2 levels, and reduced overall survival. In contrast, IRIS-silenced or inactivated cells showed reduced tumor formation ability, limited MSC recruitment into tumors, reduced circulating IL-6 and PGE2 levels, and prolonged overall survival. A positive correlation between IL-6, PTGER2, and PTGER4 expression and basal phenotype; ER-negativity; distant metastasis-free and overall survival in basal; or BRCAmutant carriers was observed. Finally, the bi-directional interaction with MSCs triggered death rather than growth of IRIS-silenced TNBC cells, in vitro and in vivo. Conclusions The IL-6/PGE2-positive feedback loop between IRISOE TNBC tumor cells and MSCs enhances tumor aggressiveness. Inhibiting IRIS expression limits TNBC tumor growth and progression through an MSC-induced death of IRIS-silenced/inactivated TNBC cells.http://link.springer.com/article/10.1186/s13058-019-1131-2BRCA1-IRISTriple-negative breast cancerMetastasisMesenchymal stem cellsIL-6Prostaglandin E2 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Daniel Ryan Bibbin T. Paul Jim Koziol Wael M. ElShamy |
spellingShingle |
Daniel Ryan Bibbin T. Paul Jim Koziol Wael M. ElShamy The pro- and anti-tumor roles of mesenchymal stem cells toward BRCA1-IRIS-overexpressing TNBC cells Breast Cancer Research BRCA1-IRIS Triple-negative breast cancer Metastasis Mesenchymal stem cells IL-6 Prostaglandin E2 |
author_facet |
Daniel Ryan Bibbin T. Paul Jim Koziol Wael M. ElShamy |
author_sort |
Daniel Ryan |
title |
The pro- and anti-tumor roles of mesenchymal stem cells toward BRCA1-IRIS-overexpressing TNBC cells |
title_short |
The pro- and anti-tumor roles of mesenchymal stem cells toward BRCA1-IRIS-overexpressing TNBC cells |
title_full |
The pro- and anti-tumor roles of mesenchymal stem cells toward BRCA1-IRIS-overexpressing TNBC cells |
title_fullStr |
The pro- and anti-tumor roles of mesenchymal stem cells toward BRCA1-IRIS-overexpressing TNBC cells |
title_full_unstemmed |
The pro- and anti-tumor roles of mesenchymal stem cells toward BRCA1-IRIS-overexpressing TNBC cells |
title_sort |
pro- and anti-tumor roles of mesenchymal stem cells toward brca1-iris-overexpressing tnbc cells |
publisher |
BMC |
series |
Breast Cancer Research |
issn |
1465-542X |
publishDate |
2019-04-01 |
description |
Abstract Background To evaluate the cross-talk between BRCA1-IRIS (IRIS)-overexpressing (IRISOE) TNBC cells and tumor-resident mesenchymal stem cells (MSCs) that triggers the aggressiveness or elimination of IRISOE TNBC tumors. Methods We analyzed the effect of silencing or inactivating IRIS on the bi-directional interaction between IRISOE TNBC cells and MSCs on tumor formation and progression. We analyzed the downstream signaling in MSCs induced by IL-6 secreted from IRISOE TNBC cells. We compared the effect of MSCs on the formation and progression of IRIS-proficient and deficient-TNBC cells/tumors using in vitro and in vivo models. Finally, we analyzed the association between IL-6, PTGER2, and PTGER4 overexpression and breast cancer subtype; hormone receptor status; and distant metastasis-free or overall survival. Results We show high-level IL-6 secreted from IRISOE TNBC cells that enhances expression of its receptor (IL-6R) in MSCs, their proliferation, and migration toward IRISOE, in vitro, and recruitment into IRISOE TNBC tumors, in vivo. In serum-free medium, recombinant IL-6 and the IL-6-rich IRISOE TNBC cell condition media (CM) decreased STAT3Y705 phosphorylation (p-STAT3Y705) in MSCs. Inhibiting IRIS expression or activity prolonged STAT3Y705 phosphorylation in MSCs. The interaction with IRISOE TNBC cells skewed MSC differentiation toward prostaglandin E2 (PGE2)-secreting pro-aggressiveness cancer-associated fibroblasts (CAFs). Accordingly, co-injecting human or mouse MSCs with IRISOE TNBC tumor cells promoted the formation of aggressive mammary tumors, high circulating IL-6 and PGE2 levels, and reduced overall survival. In contrast, IRIS-silenced or inactivated cells showed reduced tumor formation ability, limited MSC recruitment into tumors, reduced circulating IL-6 and PGE2 levels, and prolonged overall survival. A positive correlation between IL-6, PTGER2, and PTGER4 expression and basal phenotype; ER-negativity; distant metastasis-free and overall survival in basal; or BRCAmutant carriers was observed. Finally, the bi-directional interaction with MSCs triggered death rather than growth of IRIS-silenced TNBC cells, in vitro and in vivo. Conclusions The IL-6/PGE2-positive feedback loop between IRISOE TNBC tumor cells and MSCs enhances tumor aggressiveness. Inhibiting IRIS expression limits TNBC tumor growth and progression through an MSC-induced death of IRIS-silenced/inactivated TNBC cells. |
topic |
BRCA1-IRIS Triple-negative breast cancer Metastasis Mesenchymal stem cells IL-6 Prostaglandin E2 |
url |
http://link.springer.com/article/10.1186/s13058-019-1131-2 |
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