| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2006: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 2005: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2004: ¥1,500,000 (Direct Cost: ¥1,500,000)
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| Research Abstract |
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.
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