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)是一种与恶性体液高钙血症(HHM)相关的致病蛋白，但PTHrP及其受体在几乎所有器官组织中都有表达。PTHrP可能不仅影响高钙血症，还可能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：采用人乳腺癌细胞系MDA-MB-231裸鼠脑室内注射建立骨转移模型，分离出高转移性的人乳腺癌MDA-MB-231亚系。这些细胞表达与亲本细胞相同的PTHrP mRNA，但在转化生长因子-β刺激下表达更高水平的PTHrP。另一方面，转化生长因子-β对子代细胞的增殖作用与亲本细胞相同，但BMP-4虽然不刺激亲本细胞的生长，但却促进了子代细胞的生长。PTHrP中和抗体不能抑制细胞的增殖，因此PTHrP似乎对这些细胞的增殖没有影响。PTHrP抗体早期给药抑制裸鼠模型骨转移的形成，而不是在晚期给药，因此PTHrP似乎对早期骨转移有作用。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)甲状旁腺素rP在恶病质中的作用：我们调查了血液中甲状旁腺素水平较高的患者的血液细胞因子水平，发现他们的血液中IL-6、IL-8和肿瘤坏死因子-α水平较高。这些高水平的甲状旁腺素和细胞因子与恶病质的一些症状有关，比如体重减轻。我们还在研究双膦酸盐对细胞因子水平和血液中海普西丁水平的影响，海普西丁被认为是慢性疾病贫血的原因之一。

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.