甲状旁腺激素相关蛋白通过血管内皮生长因子的表达来调节血管生成和骨吸收。

PTHrP regulates angiogenesis and bone resorption via VEGF expression.

机构信息

Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikatacho, Okayama, 700-8525, Japan.

出版信息

Anticancer Res. 2010 Jul;30(7):2755-67.

PMID:20683010

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.

摘要

背景

甲状旁腺激素相关蛋白（PTHrP）是乳腺癌（BC）细胞溶骨性转移的关键调节因子，但它的靶标和作用机制尚不完全清楚。本研究探讨了 PTHrP（1-34）信号如何调节 BC 细胞产生的血管内皮生长因子（VEGF）的表达。

材料与方法

通过左心室内接种人 BC 细胞系 MDA-MB-231 的肿瘤细胞悬液，制备骨转移小鼠模型。通过 Western blot 和实时 RT-PCR 分析以及骨微环境中的共聚焦显微镜检查，检测 VEGF 的表达。

结果

PTHrP 在产生 PTH/PTHrP 受体和已侵入骨髓的 VEGF 的癌细胞中表达，并且 PTHrP 在体外上调 MDA-MB-231 中的 VEGF。与对照培养基相比，用 PTHrP 处理的 MDA-MB-231 细胞的培养基条件刺激了血管生成和破骨细胞生成，而 VEGF 中和抗体处理抑制了这种反应。蛋白激酶 C（PKC）的抑制作用阻止了 PTHrP 诱导的细胞外信号调节激酶（ERK1/2）和 p38 的激活，以及 PTHrP 诱导的 VEGF 表达。