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 journalArticle

41 Citations (Scopus)

Abstract

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
Volume30
Issue number7
Publication statusPublished - Jul 2010

Fingerprint

Parathyroid Hormone-Related Protein
Bone Resorption
Vascular Endothelial Growth Factor A
Breast Neoplasms
Bone and Bones
Neoplasm Metastasis
Protein Kinase C
Heart Ventricles
Vascular Endothelial Growth Factor Receptor
Mitogen-Activated Protein Kinase 1
Conditioned Culture Medium
Neutralizing Antibodies
Osteogenesis
Confocal Microscopy
Real-Time Polymerase Chain Reaction
Neoplasms
Suspensions
Bone Marrow
Western Blotting
Cell Line

Keywords

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

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

PTHrP regulates angiogenesis and bone resorption via VEGF expression. / Isowa, Sachiko; Shimo, Tsuyoshi; Ibaragi, Soichiro; Kurio, Naito; Okui, Tatsuo; Matsubara, Kiminori; Hassan, Nur Mohammad Monsur; Kishimoto, Koji; Sasaki, Akira.

In: Anticancer Research, Vol. 30, No. 7, 07.2010, p. 2755-2767.

Research output: Contribution to journalArticle

Isowa, S, Shimo, T, Ibaragi, S, Kurio, N, Okui, T, Matsubara, K, Hassan, NMM, Kishimoto, K & Sasaki, A 2010, 'PTHrP regulates angiogenesis and bone resorption via VEGF expression', Anticancer Research, vol. 30, no. 7, pp. 2755-2767.
Isowa S, Shimo T, Ibaragi S, Kurio N, Okui T, Matsubara K et al. PTHrP regulates angiogenesis and bone resorption via VEGF expression. Anticancer Research. 2010 Jul;30(7):2755-2767.
Isowa, Sachiko ; Shimo, Tsuyoshi ; Ibaragi, Soichiro ; Kurio, Naito ; Okui, Tatsuo ; Matsubara, Kiminori ; Hassan, Nur Mohammad Monsur ; Kishimoto, Koji ; Sasaki, Akira. / PTHrP regulates angiogenesis and bone resorption via VEGF expression. In: Anticancer Research. 2010 ; Vol. 30, No. 7. pp. 2755-2767.
@article{6d13906a978244048b9e2202062c7805,
title = "PTHrP regulates angiogenesis and bone resorption via VEGF expression",
abstract = "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.",
keywords = "Angiogenesis, Bone resorption, MAPK, Mitogen-activated protein kinase, Parathyroid hormone-related protein, PTHrP, Vascular endothelial growth factor, VEGF",
author = "Sachiko Isowa and Tsuyoshi Shimo and Soichiro Ibaragi and Naito Kurio and Tatsuo Okui and Kiminori Matsubara and Hassan, {Nur Mohammad Monsur} and Koji Kishimoto and Akira Sasaki",
year = "2010",
month = "7",
language = "English",
volume = "30",
pages = "2755--2767",
journal = "Anticancer Research",
issn = "0250-7005",
publisher = "International Institute of Anticancer Research",
number = "7",

}

TY - JOUR

T1 - PTHrP regulates angiogenesis and bone resorption via VEGF expression

AU - Isowa, Sachiko

AU - Shimo, Tsuyoshi

AU - Ibaragi, Soichiro

AU - Kurio, Naito

AU - Okui, Tatsuo

AU - Matsubara, Kiminori

AU - Hassan, Nur Mohammad Monsur

AU - Kishimoto, Koji

AU - Sasaki, Akira

PY - 2010/7

Y1 - 2010/7

N2 - 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.

AB - 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.

KW - Angiogenesis

KW - Bone resorption

KW - MAPK

KW - Mitogen-activated protein kinase

KW - Parathyroid hormone-related protein

KW - PTHrP

KW - Vascular endothelial growth factor

KW - VEGF

UR - http://www.scopus.com/inward/record.url?scp=77955806602&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77955806602&partnerID=8YFLogxK

M3 - Article

C2 - 20683010

AN - SCOPUS:77955806602

VL - 30

SP - 2755

EP - 2767

JO - Anticancer Research

JF - Anticancer Research

SN - 0250-7005

IS - 7

ER -