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

Abstract

It 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.