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.

甲状旁腺激素相关蛋白（PTHRP）被分离为恶性体液高钙血症（HHM）的因果蛋白，但PTHRP及其受体在几乎所有器官组织中都无处不在。 PTHRP不仅可能影响高钙血症，而且会影响癌症患者各种细胞因子的骨转移，增殖和分泌。我们对PTHRP进行了调查。1）PTHRP在乳腺癌的骨转移酶中的作用：我们使用了人类乳腺癌细胞系MDA-MB-231室内注入裸小鼠的骨转移模型，并隔离了高度骨骼骨骼骨化的骨骼骨骨化subline Mda-Mda-Mda-Mda-Mda-Mda-Mda-Mda-Mda-231。这些细胞表达与母细胞相同的PTHRP mRNA水平，但是当用TGF-β刺激时，PTHRP mRNA水平较高。另一方面，TGF-beta对subline的增殖作用与母细胞相同，但是BMP-4刺激了subline的生长，尽管它没有刺激亲本细胞的生长。 PTHRP中和抗体没有抑制细胞增殖，因此PTHRP似乎对这些细胞的增殖没有影响。 PTHRP抗体在裸鼠模型中抑制骨转移的形成，而不是在早期阶段进行给药时，因此PTHRP似乎在早期对骨转移产生了影响。现在，我们正在研究新分子靶标（EGF受体抑制剂，SRC抑制剂等）对骨转移和PTHRP表达的影响。2）PTHRP在恶病质中的作用：我们研究了血液PTHRP水平的血细胞因子水平的血细胞因子水平，并显示它们的血液水平高IL-6，IL-6，IL-8，IL-8和TNN，和TNN，和Tnn和TTN，和TTN和TTN和TTN，和TTN和TTN。这些高水平的PTHRP和细胞因子与缓存的某些症状相关，例如体重减轻。我们还正在研究双膦酸盐对肝素的细胞因子水平和血液水平的作用，这被认为是慢性疾病贫血的因果蛋白之一。

项目成果

期刊论文数量（30）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Efficacy and safety of trastuzumab as a single agent in heavily pretreated patients with HER-2/NEU-overexpressing metastatic breast cancer

DOI：
10.1177/030089160409000110
发表时间：
2004-01-01
期刊：
TUMORI JOURNAL
影响因子：
1.9
作者：
Sawaki, M;Ito, Y;Hatake, K
通讯作者：
Hatake, K

Tolerability and safety of classic cyclophosphamide, methotrexate, and fluorouracil treatment in Japanese patients with early breast cancer.

日本早期乳腺癌患者经典环磷酰胺、甲氨蝶呤和氟尿嘧啶治疗的耐受性和安全性。

DOI：
发表时间：
2006
期刊：
Breast Cancer. 13・3
影响因子：
0
作者：
Tada K;et al.
通讯作者：
et al.

Gene therapy for breast cancer. --Review of clinical gene therapy trials for breast cancer and MDR1 gene therapy trial in Cancer Institute Hospital. (Review)

乳腺癌的基因治疗。

DOI：
发表时间：
2006
期刊：
Breast Cancer. 13・1
影响因子：
0
作者：
Takahashi S;et al.
通讯作者：
et al.

Blockade of bulky lymphoma-associated CD55 expression by RNA interference overcomes resistance to CDC with rituximab.

通过 RNA 干扰阻断大体积淋巴瘤相关的 CD55 表达，克服了利妥昔单抗对 CDC 的耐药性。

DOI：
发表时间：
2006
期刊：
Cancer Science 97(1)
影响因子：
0
作者：
Terui Y;Sakurai T;Mishima Y;Mishima Y;Sugimura N;Sasaoka C;Kojima K;Yokoyama M;Mizunuma N;Takahashi S;Ito Y;Hatake K
通讯作者：
Hatake K

High prevalence of HER-2/neu and p53 overexpression in inflammatory breast cancer.