Multiple pathways coordinating reprogramming of endothelial cells into osteoblasts by BMP4
Guoyu Yu,
Pengfei Shen,
Yu-Chen Lee,
Jing Pan,
Jian H. Song,
Tianhong Pan,
Song-Chang Lin,
Xin Liang,
Guocan Wang,
Theocharis Panaretakis,
Christopher J. Logothetis,
Gary E. Gallick,
Li-Yuan Yu-Lee,
Sue-Hwa Lin
Affiliations
Guoyu Yu
Department of Translational Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA
Pengfei Shen
Department of Translational Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA
Yu-Chen Lee
Department of Translational Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA
Jing Pan
Department of Genitourinary Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA
Jian H. Song
Department of Genitourinary Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA
Tianhong Pan
Department of Orthopedic Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA
Song-Chang Lin
Department of Translational Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA
Xin Liang
Department of Genitourinary Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA
Guocan Wang
Department of Genitourinary Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA
Theocharis Panaretakis
Department of Genitourinary Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA
Christopher J. Logothetis
Department of Genitourinary Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA
Gary E. Gallick
Department of Genitourinary Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA
Li-Yuan Yu-Lee
Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA; Corresponding author
Sue-Hwa Lin
Department of Translational Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA; Department of Genitourinary Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA; Corresponding author
Summary: Cell 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.
