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Roles of Parathyroid hormone-related protein (PTHrP) in bone metastases and cachexia of malignancy

甲状旁腺激素相关蛋白（PTHrP）在骨转移和恶性肿瘤恶病质中的作用

基本信息

批准号：
16590917
负责人：
TAKAHASHI Shunji
金额：
$ 2.3万
依托单位：
Japanese Foundation For Cancer Research
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590917/
关键词：
PTHrP hypercalcemia cachexia bone metastases breast cancer hypercalcemia hypercalcinoma

项目摘要

Parathyroid hormone-related protein (PTHrP) was isolated as a causal protein for humoral hypercalcemia of malignancy (HHM), but PTHrP and its receptor are expressed ubiquitously in almost all organ tissues. PTHrP may effect not only hypercalcemia, but bone metastases, proliferation, and secretion of various cytokines in cancer patients. We undertook investigation of PTHrP in bone metastases and cachexia of malignancy.1) Roles of PTHrP in bone metastases of breast cancer : We used a bone metastasis model of human breast cancer cell line MDA-MB-231 intraventricular injection into nude mice, and isolated highly bone-metastatic subline of MDA-MB-231. Those cells expressed the same level of PTHrP mRNA as parent cells, but expressed higher level of PTHrP mRNA when stimulated with TGF-beta. On the other hand, TGF-beta effects on proliferation of the subline was the same as the parent cells, but BMP-4 stimulated growth of the subline, although it did not stimulated growth of the parent cells. PTHrP-neutralizing antibody did not inhibit the cell proliferation, so PTHrP seemed to have no effect on the proliferation of those cells. PTHrP antibody inhibits formation of bone metastases in nude mice model when it was administrated in the early phase, not in the late phase, so PTHrP seems to have effects on bone metastases in the early phase. We are now investigating effects of new molecular target drugs (EGF receptor inhibitor, SRC inhibitor, etc.) on bone metastases and PTHrP expression.2) Roles of PTHrP in cachexia : We investigated blood cytokine levels of patients with high blood PTHrP levels, and showed they had high levels of blood IL-6, IL-8, and TNF-alpha. These high levels of PTHrP and cytokines correlated with some symptoms of cachexia, such as body weight loss. We are also investigating effect of bisphosphonates on cytokine levels and blood levels of hepcidin, which is considered to be one of causal proteins for anemia of chronic disease.

甲状旁腺素相关蛋白（PTHrP）是一种引起恶性肿瘤体液性高钙血症（HHM）的蛋白质，但PTHrP及其受体在几乎所有器官组织中都广泛表达。PTHrP不仅可以影响高钙血症，还可以影响癌症患者的骨转移、增殖和各种细胞因子的分泌。1）PTHrP在乳腺癌骨转移中的作用：采用人乳腺癌细胞株MDA-MB-231裸鼠脑室内注射建立骨转移模型，分离出高骨转移的MDA-MB-231亚株。这些细胞表达与亲本细胞相同水平的PTHrP mRNA，但在TGF-β刺激时表达更高水平的PTHrP mRNA。另一方面，TGF-β对亚系增殖的影响与亲本细胞相同，但BMP-4刺激亚系的生长，尽管它不刺激亲本细胞的生长。PTHrP中和抗体不抑制细胞增殖，因此PTHrP似乎对这些细胞的增殖没有影响。PTHrP抗体在裸鼠骨转移模型中早期给药抑制骨转移的形成，而在晚期不抑制骨转移，因此PTHrP似乎在早期对骨转移有作用。我们正在研究新的分子靶向药物（EGF受体抑制剂，SRC抑制剂等）的作用。2）PTHrP在恶病质中的作用：我们研究了具有高血液PTHrP水平的患者的血液细胞因子水平，并且显示他们具有高水平的血液IL-6、IL-8和TNF-α。这些高水平的PTHrP和细胞因子与恶病质的一些症状相关，如体重减轻。我们也在研究双膦酸盐对细胞因子水平和hepcidin血液水平的影响，hepcidin被认为是慢性疾病贫血的致病蛋白之一。