Abstract
BackgroundMicroenvironment is being increasingly recognized as a critical determinant in tumor progression and metastasis. However, the appropriate regulatory mechanism to maintain the normal balance between differentiation and self-renewal of the cancer cell in microenvironment is not well known.Methods4T1 breast cancer cells were treated with embryonic stem (ES) cell conditioned medium which was collected from mouse ES cells. Inhibition of tumor cell growth was based on the reduction of cell proliferation and viability, and inhibition of aggressive properties of tumor cells were examined using the wound-healing and mammosphere assays. The expression of stem cell-associated genes was detected by quantitative RT-PCR.ResultsWe used a real-time imaging system to investigate the effect of the mouse ES cell microenvironment on aggressive breast cancer cells in vitro and in vivo. Exposure of breast cancer cells in mouse ES cell conditioned medium resulted in inhibition of growth, migration, metastasis, and angiogenesis of cancer cells. For many tumors, aggressive properties were tightly related to Stat3 signaling activation. We specifically discovered that the ES cell microenvironment sufficiently suppressed Stat3 signaling pathway activation in aggressive tumor cells, leading to a reduction in tumorigenesis and invasiveness.ConclusionsWe identified important functions of Stat3 and their implications for antitumor effects of ES cell conditioned medium. Some factors secreted by ES cells could efficiently suppress Stat3 pathway activation in breast cancer cells, and were then involved in cancer cell growth, survival, invasion, and migration. This study may act as a platform to understand tumor cell plasticity and may offer new therapeutic strategies to inhibit breast cancer progression.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-016-0360-x) contains supplementary material, which is available to authorized users.
Highlights
Microenvironment is being increasingly recognized as a critical determinant in tumor progression and metastasis
We found that exposure of breast cancer cells to the embryonic stem (ES) cell microenvironment resulted in reduced invasive potential, which might be mediated by signal transducer activator of transcription 3 (Stat3) signaling inactivation
To perform the experiments using imaging, 4T1 cells were transduced with a lentiviral vector carrying a ubiquitin promoter driving firefly luciferase (Fluc) and enhanced green fluorescence protein followed by a Stat3 specificbinding promoter driving renilla luciferase (Rluc) reporter gene responding to activated Stat3
Summary
Microenvironment is being increasingly recognized as a critical determinant in tumor progression and metastasis. The appropriate regulatory mechanism to maintain the normal balance between differentiation and self-renewal of the cancer cell in microenvironment is not well known. The extracellular matrix plays a critical role in normal development and in regulating stem cell differentiation into various lineages, as well as in cell migration and proliferation [1]. Cancer cells interact with their surrounding microenvironment. He et al Stem Cell Research & Therapy (2016) 7:95 constitutively activated Stat has been found in many types of cancer, including breast cancer. Recent studies have suggested that Stat activation is important for the tumorigenic ability of cancer stem cells in breast cancer [7, 8]
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