文章基本信息

标题：Multiple pathways coordinating reprogramming of endothelial cells into osteoblasts by BMP4
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作者：Guoyu Yu ; Pengfei Shen ; Yu-Chen Lee 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2021
卷号：24
期号：4
页码：1-32
DOI：10.1016/j.isci.2021.102388
语种：English
出版社：Elsevier
摘要：SummaryCell type transition occurs during normal development and under pathological conditions. In prostate cancer bone metastasis, prostate cancer-secreted BMP4 induces endothelial cell-to-osteoblast (EC-to-OSB) transition. Such tumor-induced stromal reprogramming supports prostate cancer progression. We delineate signaling pathways mediating EC-to-OSB transition using EC lines 2H11 and SVR. We found that BMP4-activated pSmad1-Notch-Hey1 pathway inhibits EC migration and tube formation. BMP4-activated GSK3β-βcatenin-Slug pathway stimulates Osx expression. In addition, pSmad1-regulated Dlx2 converges with the Smad1 and β-catenin pathways to stimulate osteocalcin expression. By co-expressing Osx, Dlx2, Slug and Hey1, we were able to achieve EC-to-OSB transition, leading to bone matrix mineralization in the absence of BMP4. In human prostate cancer bone metastasis specimens and MDA-PCa-118b and C4-2b-BMP4 osteogenic xenografts, immunohistochemical analysis showed that β-catenin and pSmad1 are detected in activated osteoblasts rimming the tumor-induced bone. Our results elucidated the pathways and key molecules coordinating prostate cancer-induced stromal programming and provide potential targets for therapeutic intervention.Graphical abstractDisplay OmittedHighlights•BMP4 upregulates several pathways essential for EC-to-OSB transition•BMP4 activates pSmad1-Notch-Hey1 and GSK3β-βcatenin-Slug-OSX pathways•pSmad1-regulated Dlx2 expression connects the pSmad1 and β-catenin pathways•Coexpression of OSX, Dlx2, Slug, and Hey1 is sufficient to induce EC-to-OSB transitionMolecular Biology ; Cell Biology ; Cancer