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Hypoxia-induced secretion stimulates breast cancer stem cell regulatory signalling pathways

Journal article
Authors Hanna Jacobsson
H. Harrison
Éamon Hughes
Emma Persson
Sara Rhost
Paul A. Fitzpatrick
Anna Gustafsson
Daniel Andersson
Pernilla Gregersson
Ylva Magnusson
Anders Ståhlberg
Göran Landberg
Published in Molecular Oncology
Volume 13
Issue 8
Pages 1693-1705
ISSN 1574-7891
Publication year 2019
Published at Sahlgrenska Cancer Center
Department of Laboratory Medicine
Wallenberg Centre for Molecular and Translational Medicine
Pages 1693-1705
Language en
Keywords breast cancer, cancer stem cells, hypoxia, IL-12, IL6, JAK-STAT, secretion
Subject categories Cancer and Oncology


It is well known that tumour cells are dependent on communication with the tumour microenvironment. Previously, it has been shown that hypoxia (HX) induces pronounced, diverse and direct effects on cancer stem cell (CSC) qualities in different breast cancer subtypes. Here, we describe the mechanism by which HX-induced secretion influences the spreading of CSCs. Conditioned media (CM) from estrogen receptor (ER)-α-positive hypoxic breast cancer cell cultures increased the fraction of CSCs compared to normal growth conditions, as determined using sets of CSC assays and model systems. In contrast, media from ERα-negative hypoxic cell cultures instead decreased this key subpopulation of cancer cells. Further, there was a striking overrepresentation of JAK-STAT-associated cytokines in both the ERα-positive and ERα-negative linked hypoxic responses as determined by a protein screen of the CM. JAK-STAT inhibitors and knockdown experiments further supported the hypothesis that this pathway is critical for the CSC-activating and CSC-inactivating effects induced by hypoxic secretion. We also observed that the interleukin-6-JAK2-STAT3 axis was specifically central for the ERα-negative hypoxic behaviour. Our results underline the importance of considering breast cancer subtypes in treatments targeting JAK-STAT or HX-associated processes and indicate that HX is not only a confined tumour biological event, but also influences key tumour properties in widespread normoxic microenvironments. © 2019 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

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