Research ArticleInterleukin 6 mediated recruitment of mesenchymal stem cells to the hypoxic tumor milieu
Introduction
Human mesenchymal stem cells (hMSCs) are a heterogeneous population of progenitor cells, which predominantly reside in the bone marrow [1], [2] and under appropriate conditions have the capacity to differentiate into bone, fat and cartilage cells [3], [4], [5]. While tumor inhibition by hMSCs has been reported, more frequently hMSCs have been shown to have tumor-promoting effects [5], [6], [7], [8]. hMSCs have been shown to stimulate tumor growth by several mechanisms including differentiation into Carcinoma Associated Fibroblasts (CAFs) and contributing to the tumor stroma [9]. The stromally recruited hMSCs promote angiogenesis leading to tumor progression [6], [10], [11].
The TMEN is a dynamic system made up of a heterogeneous cellular population in a background of fluctuating gradients of O2 content, pH, and interstitial fluid pressure (IFP) [12], [13]. Hypoxia occurs within regions of the TMEN as a consequence of inadequate vascular supply [14], [15]. Hypoxia enhances the ability of tumor cells to develop resistance to radiotherapy, endocrine therapy and chemotherapy [12] and is associated with increased metastasis and poor outcome for various cancer types [16]. The hypoxic microenvironment may promote metastasis through the induction of chemokines and cytokines such as interleukin-8 (IL-8), interleukin-6 (IL-6) and through increased levels of genomic instability leading to mutations [17], [18], [19], [20]. In addition to hypoxia, the cellular makeup of the tumor microenvironment also plays a critical role in metastasis. In a current breast carcinoma model, tumor cells have been shown to release paracrine signals that mediate the recruitment of MSCs towards the microenvironment to enhance tumor metastasis [6].
In the present study we set out to better understand the interplay between tumor cells and hMSCs in the context of a hypoxic microenvironment. We show that IL-6, which is produced and secreted at high levels by breast cancer cells in response to hypoxia, regulates hMSC migration towards cancer cells. IL-6 binds to its cognate receptor on hMSCs, leading to Stat3 activation. Signaling events in hMSCs post-Stat3 activation, promote hMSC migration and survival. Inhibition of IL-6 production by breast cancer cells attenuated hMSC migration, demonstrating the significance of IL-6 signaling in mediating tumor-stroma interactions.
Section snippets
Cell lines and transfections
MDA-MB-231 (ER-/PR-, representing basal subtype B), MCF-7 (ER+/PR+; representing luminal subtype) and MDA MB 468 (ER−/PR−; representing basal subtype A) human breast cancer cell lines obtained from ATCC were cultured with DMEM media containing 10% FBS under normoxic (21% O2) or hypoxic (1.5% O2) conditions for 6 and 24 h, unless otherwise noted. Hypoxia was achieved by placing cells in a modular chamber obtained from Billups-Rothenburg according to manufacturer's instructions. Human bone-marrow
Hypoxia enhances hMSC migration towards breast cancer cells
Mesenchymal stem cells have been shown to localize to breast carcinomas in vivo [6]. Previous studies in our laboratory have shown that both human and rat derived MSCs migrate towards MDA-MB-231 cells or conditioned medium collected from these cells under normoxic conditions [21]. To investigate hMSC migration under hypoxia, we established an in vitro transwell migration assay in which hMSCs were allowed to migrate towards MDA-MB-231, MCF-7 and MDA-MB-468 breast cancer cells under normoxic and
Discussion
Hypoxia is a constant and universal feature of solid tumors [28], [29], [30]. It has recently become clear that hypoxia plays a role in tumor progression, metastasis and poor clinical outcome [31], [32]. Regions of hypoxia within the tumor microenvironment are known to activate several genes involved in enhancing tumor cell survival and angiogenesis [33], [34]. The tumor stroma also plays a key role in tumor progression via the increased presence of fibroblasts, macrophages, lymphocytes and
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2022, International ImmunopharmacologyCitation Excerpt :Above all, MSCs could facilitate angiogenesis by different mechanisms. In 2010, Rattigan et al. found that under hypoxia conditions, breast cancer cells could secrete high levels of IL-6, which significantly enhanced recruitment of BM-MSCs to the TME through activating Stat3 and MAPK pathways, leading to the promotion of tumor progression [91]. Moreover, hypoxic BM-MSCs were reported to exhibit more secretion of TGF-β1, which was regulated by HIF-1α in BM-MSCs, resulting in the promotion of proliferation via TGF-β pathway in breast cancer cells [92].
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Present Address: Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.