Abstract
Increased plasticity, migratory and immunosuppressive abilities characterize mesenchymal stromal cells (MSC) which enable them to be active participants in the development of hypoxic solid tumours. Our understanding of the oncogenic adaptation of MSC to hypoxia however lacks the identification and characterization of specific biomarkers. In this study, we assessed the hypoxic regulation of 3BP2/SH3BP2 (Abl SH3-binding protein 2), an immune response adaptor/scaffold protein which regulates leukocyte differentiation and motility. Gene silencing of 3BP2 abrogated MSC migration in response to hypoxic cues and generation of MSC stably expressing the transcription factor hypoxia inducible factor 1alpha (HIF-1α) resulted in increased endogenous 3BP2 expression as well as cell migration. Analysis of the 3BP2 promoter sequence revealed only one potential HIF-1α binding site within the human but none in the murine sequence. An alternate early signalling cascade that regulated 3BP2 expression was found to involve membrane type-1 matrix metalloproteinase (MT1-MMP) transcriptional regulation which gene silencing abrogated 3BP2 expression in response to hypoxia. Collectively, we provide evidence for a concerted HIF-1α/MT1-MMP signalling axis that explains the induction of adaptor protein 3BP2 and which may link protein binding partners together and stimulate oncogenic MSC migration. These mechanistic observations support the potential for malignant transformation of MSC within hypoxic tumour stroma and may contribute to evasion of the immune system by a tumour.
Highlights
Mesenchymal stromal cells (MSC), most commonly isolated from the bone marrow, are a population of pluripotent adult stem cells that can differentiate into many mesenchymal phenotypes [1,2]
We found that hypoxia significantly induced hypoxia inducible factor 1alpha (HIF-1a) transcript levels (Fig. 1, black bars) in agreement with previous reports [26,27]
While 3BP2 gene expression was induced by hypoxia in Mock-transfected cells, we found that its gene expression was efficiently reduced in siHIF-1atransfected mesenchymal stromal cells (MSC) (Fig. 2B). 3BP2 protein expression was assessed in Mock- and in siHIF-1a-transfected cells that were subsequently cultured under hypoxic conditions (Fig. 2C)
Summary
Mesenchymal stromal cells (MSC), most commonly isolated from the bone marrow, are a population of pluripotent adult stem cells that can differentiate into many mesenchymal phenotypes [1,2]. Cotransplantation of MSC with melanoma cells in mice enhanced tumour engraftment and growth [9] These data are in agreement with observations that vascular progenitors derived from bone marrow stromal cells are recruited by tumours both in vivo and in vitro [5]. The sum of this evidence, in line with their increased ability to migrate under an atmosphere of low oxygen [10], suggests that MSC are active participants in the development of hypoxic solid tumours
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