权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Cloning of the molecules associated with bone metastases of cancers and its characterization

癌症骨转移相关分子的克隆及其表征

基本信息

批准号：
11557136
负责人：
YONEDA Toshiyuki
金额：
$ 8.64万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11557136/
关键词：
Cancer Bone metastases TGF-beta Soft tissues metastases Bone resorption Smad DDR1 Bisphosohonate TGF-β IGF-1 TGF 遠隔転移乳癌前立腺癌レポーターアッセイ

项目摘要

(1) Role of TGF-beta and IGF-1 in bone metastases of breast cancersIn bone tissues/there are large amount of Transforming growth factor-beta (TGF-beta) and Insulin-like growth factor-1 (IGF-1), it is, therefore, likely that these two major growth factors play some roles in bone remodeling in physiological or pathological conditions. It is well know that breast cancers resorb the bone after metastasizing into bone. To examine the role of IGF-1 in bone metastases, we established the breast cancer cell line MDA231 overexpressing dominant-negative IGF-1 receptor, and assessed its bone-metastatic effects using animal model. We found that the cell line showed much less bone metastatic activity compared with parental MDA231 cells. We next evaluated the effects of TGF-beta on MDA231 cells. TGF-beta had little effects on the growth of MDA231 cells but markedly enhanced the production of PTHrP which is one of the important factor in bone metastases by cancers. In addtion, TGF-beta activates the Smad signaling through Smad2, Smad3 and Smad4. Finally, we found the breast cancer cell line that is deficient in Smad4 showed no ability to metastasize into bone. These finding suggest that important roles of TGF-beta and IGF-1 in bone metastases by breast cancers.(2) The effects of bisphosphonate on soft-tissue metastases of breast cancersIt is well know that bisphosphonate is a powerful inhibitor for osteoclasts and useful to treat the bone metastasized cancers. However, little is know the effects on soft tissue metastases of breast cancers. To address this, we established the system in which we can evaluate the bone metastases as well as soft tissues metastases. Using this system, we found that bisphosphonate blocked the bone metastases but stimulated the metastases into soft tissues such as lung and liver. It is likely that bisphosphonate has distinct effects on bone and soft tissues.

(1)TGF-β和IGF-1在乳腺癌骨转移中的作用在骨组织中/存在大量的转化生长因子-β（TGF-β）和胰岛素样生长因子-1（IGF-1），因此，这两种主要的生长因子可能在生理或病理条件下的骨重建中发挥一定作用。众所周知，乳腺癌在转移到骨中之后再吸收骨。为了研究IGF-1在骨转移中的作用，我们建立了过表达显性阴性IGF-1受体的乳腺癌细胞系MDA 231，并使用动物模型评估其骨转移效应。我们发现，该细胞系显示出更少的骨转移活性与亲本MDA 231细胞相比。我们接下来评估了TGF-β对MDA 231细胞的作用。TGF-β对MDA 231细胞生长无明显影响，但能显著促进PTHrP的产生，PTHrP是肿瘤骨转移的重要因素之一。此外，TGF-β通过Smad 2、Smad 3和Smad 4激活Smad信号传导。最后，我们发现Smad 4缺陷的乳腺癌细胞系没有能力转移到骨中。这些发现表明TGF-β和IGF-1在乳腺癌骨转移中的重要作用。(2)二膦酸盐对乳腺癌软组织转移的影响众所周知，二膦酸盐是一种强有力的破骨细胞抑制剂，对治疗骨转移癌有重要作用。然而，对乳腺癌软组织转移的影响知之甚少。为了解决这个问题，我们建立了一个系统，我们可以评估骨转移以及软组织转移。使用这个系统，我们发现双膦酸盐阻断骨转移，但刺激转移到软组织，如肺和肝。双膦酸盐可能对骨和软组织有不同的影响。