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Ultrastructural and cytochemical studies on cancer and apoptosis in bone.

骨癌症和细胞凋亡的超微结构和细胞化学研究。

基本信息

批准号：
09557164
负责人：
SHINGAKI Susumu
金额：
$ 7.04万
依托单位：
NIIGATA UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 2000
项目状态：
已结题

项目摘要

We examined the mechanisms of bone metastasis and bone invasion. The tumor mass was surrounded by a membrane consisting of fibroblastic cells. These cells were positive for ALP ase. TRAPase-positive cells were localized close to the ALP ase-positive cells and numerous osteoclasts were observed on the neighboring bone surfaces. It seems that PTHrP secreted by the tumor cells appears to stimulate differentiation of osteoclasts and bone resorption in a paracrine manner through PTH/PTHrP receptor-immunopositive osteoblastic cells. In bone metastatic, breast cancer cells produced VEGF and induced many CD31-positive blood vessels in bone. TRAPase-positive osteoclasts directly contacted to RANKL-positive cells. It seems that VEGF of the tumor cells induce growth of cancer and osteoclasts progenitor, and stimulate differentiation and activation of osteoclasts via RANKL of osteoblastic cells. Furthermore, we found that bisphosphonate inhibited the number of osteoclasts and blood vessels in bone metastatic area. We investigated the mechanism which a mutant ALPase induced bone disease in vitro. The mutant ALPase gene resulted in protein synthesis but not ER-to-Golgi apparatus trafficking. Then, osteoclasts apoptosis were studied in the tibia of rats treated with a bisphosphonate. They became devoid of ruffled borders and detached from bone surface, and showed formation of many vesicles and degradation of Golgi apparatus and DNA fragmentation. The majority of them are eliminated by macrophages, but there are some that escape into blood vessels. Furthermore, we found that bisphosphonates directly affect osteoclasts without mediating its deposition to the bone matrix.

我们研究了骨转移和骨侵袭的机制。肿瘤被成纤维细胞组成的膜包围。这些细胞碱性磷酸酶阳性。TRAPases阳性细胞位于ALP阳性细胞附近，在相邻的骨表面观察到大量破骨细胞。肿瘤细胞分泌的PTHrP似乎通过PTH/PTHrP受体免疫阳性的成骨细胞以旁分泌方式刺激破骨细胞的分化和骨吸收。在骨转移中，乳腺癌细胞产生VEGF并在骨中诱导许多CD 31阳性血管。TRAPases阳性破骨细胞直接接触RANKL阳性细胞。肿瘤细胞中的VEGF可能通过诱导成骨细胞的RANKL而诱导肿瘤细胞和破骨细胞祖细胞的生长，并刺激破骨细胞的分化和活化。此外，我们发现双膦酸盐抑制骨转移区破骨细胞和血管的数量。我们在体外研究了突变型ALP 13诱导骨疾病的机制。突变的ALP 13基因导致蛋白质合成，但不是ER到高尔基体运输。然后，破骨细胞凋亡进行了研究，在大鼠胫骨与双磷酸盐治疗。细胞边缘无皱褶，从骨表面脱落，可见囊泡形成，高尔基体降解，DNA断裂。它们中的大多数被巨噬细胞消除，但也有一些逃逸到血管中。此外，我们发现双膦酸盐直接影响破骨细胞，而不介导其沉积到骨基质。