Stem Cell and Cancer Biology Laboratory, School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Western Australia, Australia.
Ear Sciences Centre, University of Western Australia, Western Australia, Australia.
Int J Biochem Cell Biol. 2018 Feb;95:63-72. doi: 10.1016/j.biocel.2017.12.013. Epub 2017 Dec 19.
Tumours exhibit a heterogeneous mix of cell types that reciprocally regulate their growth in the tumour stroma, considerably affecting the progression of the disease. Both adipose-derived mesenchymal stem cells and Wnt signalling pathway are vital in driving breast tumour growth. Hence, we examined the effect of secreted factors released by adipose-derived mesenchymal stem cells, and further explored the anti-tumour property of the Wnt antagonist secreted frizzled-related protein 4 (sFRP4) on MCF-7 and MDA-MB-231 breast tumour cells. We observed that conditioned medium and extracellular matrix derived from adipose-derived mesenchymal stem cells inhibited tumour viability. The inhibitory effect of the conditioned medium was retained within its low molecular weight and non-protein component. The conditioned medium also induced apoptosis accompanied by a decrease in the mitochondrial membrane potential in tumour cells, Furthermore, it downregulated the protein expression of active β-catenin and Cyclin D1, which are major target proteins of the Wnt signalling pathway, and reduced the expression of anti-apoptotic protein Bcl-xL. The combination of conditioned medium and sFRP4 further potentiated the effects, depending on the tumour cell line and experimental assay. We conclude that factors derived from conditioned medium of adipose-derived mesenchymal stem cells and sFRP4 significantly decreased the tumour cell viability and migration rates (MCF-7), accompanied with an enhanced apoptotic activity through inhibition of canonical Wnt signalling. Besides giving an insight to possible paracrine interactions and influence of signalling pathways, reflective of a breast tumour microenvironment, this study emphasises the utilization of cell free-secreted factors and Wnt antagonists to improve conventional anti-cancer strategies.
肿瘤表现出细胞类型的异质性混合，这些细胞类型在肿瘤基质中相互调节其生长，这极大地影响了疾病的进展。脂肪来源的间充质干细胞和 Wnt 信号通路在驱动乳腺癌生长方面都至关重要。因此，我们研究了脂肪来源的间充质干细胞释放的分泌因子的作用，并进一步探索了 Wnt 拮抗剂分泌卷曲相关蛋白 4（sFRP4）对 MCF-7 和 MDA-MB-231 乳腺癌细胞的抗肿瘤特性。我们观察到脂肪来源的间充质干细胞的条件培养基和细胞外基质抑制了肿瘤的活力。条件培养基的抑制作用保留在其低分子量和非蛋白质成分中。条件培养基还诱导了肿瘤细胞的凋亡，并伴有线粒体膜电位的降低。此外，它下调了 Wnt 信号通路的主要靶蛋白活性 β-连环蛋白和细胞周期蛋白 D1 的蛋白表达，并降低了抗凋亡蛋白 Bcl-xL 的表达。条件培养基和 sFRP4 的组合进一步增强了效果，这取决于肿瘤细胞系和实验测定。我们得出结论，脂肪来源的间充质干细胞的条件培养基和 sFRP4 衍生的因子显著降低了肿瘤细胞的活力和迁移率（MCF-7），并通过抑制经典 Wnt 信号通路增强了凋亡活性。除了深入了解可能的旁分泌相互作用和信号通路的影响，反映了乳腺癌的肿瘤微环境外，本研究还强调了利用无细胞分泌因子和 Wnt 拮抗剂来改善传统的抗癌策略。
