title: BMP4/Thrombospondin-1 loop paracrinically inhibits tumor angiogenesis and suppresses the growth of solid tumors.
abstract: Bone morphogenetic protein 4 (BMP4) has potential as an anticancer agent. Recent studies have suggested that BMP4 inhibits the survival of cancer stem cells (CSCs) of neural and colon cancers. Here, we showed that BMP4 paracrinically inhibited tumor angiogenesis via the induction of Thrombospondin-1 (TSP1), and consequently suppressed tumor growth in vivo. Although HeLa (human cervical cancer), HCI-H460-LNM35 (highly metastatic human lung cancer) and B16 (murine melanoma) cells did not respond to the BMP4 treatment in vitro, the growth of xeno- and allografts of these cells was suppressed via reductions in tumor angiogenesis after intraperitoneal treatment with BMP4. When we assessed the mRNA expression of major angiogenesis-related factors in grafted tumors, we found that the expression of TSP1 was significantly upregulated by BMP4 administration. We then confirmed that BMP4 was less effective in suppressing the tumor growth of TSP1-knockdown cancer cells. Furthermore, we found that BMP4 reduced vascular endothelial growth factor (VEGF) expression in vivo in a TSP1-dependent manner, which indicates that BMP4 interfered with the stabilization of tumor angiogenesis. In conclusion, the BMP4/TSP1 loop paracrinically suppressed tumor angiogenesis in the tumor microenvironment, which subsequently reduced the growth of tumors. BMP4 may become an antitumor agent and open a new field of antiangiogenic therapy.
authors.affiliation: 1] Department of Molecular Oncology, Tokyo Medical and Dental University, Tokyo, Japan [2] Department of Pediatrics, Tokyo Medical and Dental University, 1-5-45 Yushima, Tokyo, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Tsuchida
authors.affiliation: 1] Department of Molecular Oncology, Tokyo Medical and Dental University, Tokyo, Japan [2] Laboratory for System Biology and Medicine, RCAST, University of Tokyo, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Osawa
authors.affiliation: 1] Department of Molecular Oncology, Tokyo Medical and Dental University, Tokyo, Japan [2] Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: F
authors.initials: F
authors.lastname: Wang
authors.affiliation: 1] Department of Molecular Oncology, Tokyo Medical and Dental University, Tokyo, Japan [2] Department of Pediatrics, Tokyo Medical and Dental University, 1-5-45 Yushima, Tokyo, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Nishii
authors.affiliation: Division of Oncology, Departments of Medicine and Pathology, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Das
authors.affiliation: 1] Department of Molecular Oncology, Tokyo Medical and Dental University, Tokyo, Japan [2] Department of Pediatrics, University of Tokyo Hospital, Tokyo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Tsuchida
authors.affiliation: 1] Department of Molecular Oncology, Tokyo Medical and Dental University, Tokyo, Japan [2] Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: M
authors.initials: M
authors.lastname: Muramatsu
authors.affiliation: Division of Molecular Carcinogenesis, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: Laboratory for System Biology and Medicine, RCAST, University of Tokyo, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Laboratory for System Biology and Medicine, RCAST, University of Tokyo, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Wada
authors.affiliation: Laboratory for System Biology and Medicine, RCAST, University of Tokyo, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Minami
authors.affiliation: Department of Molecular Oncology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Yuasa
authors.affiliation: 1] Department of Molecular Oncology, Tokyo Medical and Dental University, Tokyo, Japan [2] Institute of Physiology and Medicine, Jobu University, 270-1 Shin-machi, Takasaki, Gunma, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Shibuya
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008546:Melanoma, Experimental; D051379:Mice; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D019899:Paracrine Communication; D015398:Signal Transduction; D051898:Smad1 Protein / Q000378:metabolism; D051902:Smad5 Protein / Q000378:metabolism; D019700:Thrombospondin 1 / Q000378:metabolism*; D047368:Tumor Burden
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D055415:Bone Morphogenetic Protein 4; C481348:SPZ1 protein, human; D051898:Smad1 Protein; D051902:Smad5 Protein; D019700:Thrombospondin 1