PTHrP regulates angiogenesis and bone resorption via VEGF expression

Sachiko Isowa, Tsuyoshi Shimo, Soichiro Ibaragi, Naito Kurio, Tatsuo Okui, Kiminori Matsubara, Nur Mohammad Monsur Hassan, Koji Kishimoto, Akira Sasaki

Research output: Contribution to journalArticlepeer-review

52 Citations (Scopus)


Background: Parathyroid hormone-related protein (PTHrP) is a key regulator of osteolytic metastasis of breast cancer (BC) cells, but its targets and mechanisms of action are not fully understood. This study investigated whether/how PTHrP (1-34) signaling regulates expression of vascular endothelial growth factor (VEGF) produced by BC cells. Materials and Methods: A mouse model of bone metastasis was prepared by inoculating mice with tumour cell suspensions of the human BC cell line MDA-MB-231 via the left cardiac ventricle. VEGF expression was examined by Western blot and real-time RT-PCR analysis, as well as by confocal microscopy in the bone microenvironment. Results: PTHrP was expressed in cancer cells producing PTHIPTHrP receptor and VEGF that had invaded the bone marrow, and PTHrP was up-regulated VEGF in MDA-MB-231 in vitro. The culture medium conditioned by PTHrP-treated MDA-MB-231 cells stimulated angiogenesis and osteoclastogenesis compared with control medium, giving a response that was inhibited by VEGF-neutralizing antibody treatment. Inhibition of protein kinase C (PKC) prevented PTHrP-induced extracellular signal-regulated kinase (ERK1/2) and p38 activation, and PTHrP-induced VEGF expression. Conclusion: PTHrP plays an important role in modulating the angiogenic and bone osteolytic actions of VEGF through PKC-dependent activation of an ERK1/2 and p38 signaling pathway during bone metastasis by breast cancer cells.

Original languageEnglish
Pages (from-to)2755-2767
Number of pages13
JournalAnticancer research
Issue number7
Publication statusPublished - Jul 2010


  • Angiogenesis
  • Bone resorption
  • MAPK
  • Mitogen-activated protein kinase
  • PTHrP
  • Parathyroid hormone-related protein
  • VEGF
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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