Hypoxia-induced secretion stimulates breast cancer stem cell regulatory signalling pathways
AffiliationDepartment of Pathology and Genetics, Institute of Biomedicine, Sahlgrenska Cancer Center, University of Gothenburg, Medicinaregatan 1F, 413 90, Gothenburg, Sweden
MetadataShow full item record
AbstractIt is well known that tumor cells are dependent on communication with the tumor microenvironment. Previously, it has been shown that hypoxia induces pronounced, diverse and direct effects on cancer stem cell (CSC) qualities in different breast cancer subtypes. Here, we describe the mechanism by which hypoxia-induced secretion influence CSC spreading. Conditioned media from estrogen receptor (ER)-? 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 ER?-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 ER?-positive and ER?-negative linked hypoxic responses as determined by a protein screen of the conditioned media. JAK-STAT inhibitors and knockdown experiments further supported the hypothesis that this pathway is critical for the CSC activating and inactivating effects induced by hypoxic secretion. We also observed that the interleukin (IL)-6 -JAK2-STAT3 axis was specifically central for the ER?-negative hypoxic behaviour. Our results underline the importance of considering breast cancer subtypes in treatments targeting JAK-STAT or hypoxia-associated processes, and indicate that hypoxia is not only a confined tumor biological event, but also influences key tumor properties in widespread normoxic microenvironments. This article is protected by copyright. All rights reserved.
CitationJacobsson H, Harrison H, Hughes E, Persson E, Rhost S, Fitzpatrick P, et al. Hypoxia-induced secretion stimulates breast cancer stem cell regulatory signalling pathways. Mol Oncol. 2019 May 7.
- Sortilin inhibition limits secretion-induced progranulin-dependent breast cancer progression and cancer stem cell expansion.
- Authors: Rhost S, Hughes É, Harrison H, Rafnsdottir S, Jacobsson H, Gregersson P, Magnusson Y, Fitzpatrick P, Andersson D, Berger K, Ståhlberg A, Landberg G
- Issue date: 2018 Nov 20
- Contrasting hypoxic effects on breast cancer stem cell hierarchy is dependent on ER-α status.
- Authors: Harrison H, Rogerson L, Gregson HJ, Brennan KR, Clarke RB, Landberg G
- Issue date: 2013 Feb 15
- Targeting carbonic anhydrase IX depletes breast cancer stem cells within the hypoxic niche.
- Authors: Lock FE, McDonald PC, Lou Y, Serrano I, Chafe SC, Ostlund C, Aparicio S, Winum JY, Supuran CT, Dedhar S
- Issue date: 2013 Oct 31
- Autophagy mediates survival of pancreatic tumour-initiating cells in a hypoxic microenvironment.
- Authors: Rausch V, Liu L, Apel A, Rettig T, Gladkich J, Labsch S, Kallifatidis G, Kaczorowski A, Groth A, Gross W, Gebhard MM, Schemmer P, Werner J, Salnikov AV, Zentgraf H, Büchler MW, Herr I
- Issue date: 2012 Jul
- Hypoxic Conditioned Medium From Human Adipose-Derived Stem Cells Promotes Mouse Liver Regeneration Through JAK/STAT3 Signaling.
- Authors: Lee SC, Jeong HJ, Lee SK, Kim SJ
- Issue date: 2016 Jun