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 PTH/PTHrP 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.

journal_name

Anticancer Res

journal_title

Anticancer research

authors

Isowa S,Shimo T,Ibaragi S,Kurio N,Okui T,Matsubara K,Hassan NM,Kishimoto K,Sasaki A

subject

Has Abstract

pub_date

2010-07-01 00:00:00

pages

2755-67

issue

7

eissn

0250-7005

issn

1791-7530

pii

30/7/2755

journal_volume

30

pub_type

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