Soluble receptor activator of nuclear factor-kB ligand : involvement and significance as therapeutics in the osteolysis associated with breast cancer growth in the bone microenvironment

核因子-kB配体的可溶性受体激活剂：骨微环境中与乳腺癌生长相关的骨溶解的参与及其治疗意义

• 批准号: 21590442
• 负责人: FUTAKUCHI Mitsuru
• 金额: $ 3.08万
• 依托单位: Nagoya City University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2009
• 资助国家: 日本
• 起止时间: 2009 至 2011
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21590442/
• 关键词: 腫瘍; 骨転移; sRANKL; TGFβ; 乳癌; 腫瘍間質相互作用; 骨微小環境; 腫瘍・間質相互作用

Understanding how cancer cells induce bone metastases is essential for the identification of new therapies to control bone metastasis. Using a mouse model that mimics osteolytic changes associated with breast cancer-induced bone metastases, we identified cathepsin G to be proteases that are up-regulated at the tumor bone(TB)-interface. Moreover, we showed that cathepsin G is capable of shedding the extracellular domain of receptor activator of nuclear factor-KB ligand(RANKL), generating active soluble version(sRANKL) that is capable of inducing differentiation and activation of osteoclast precursors. The major source of cathepsin G seems to be osteoclasts. Furthermore, we showed that in vivo inhibition of cathepsin G reduces mammary tumor. induced osteolysis.Next we examined the preventive effects of a competitive inhibitor of sRANKL, osteoprotegrin fusion protein(OCIF) was administered to mice before osteolysis induction by implantation of mammary tumor cells(pre), after osteolysis induction(post) or during the entire experimental period(whole). Tumor growth at the TB-interface was significantly suppressed in the pre as well as the post and whole treatment groups of OCIF. The extent of bone destruction was significantly reduced in the pre, post and whole treatment groups. In addition, significantly fewer osteoclasts wereobserved in the OCIF treatment groups regardless of treatment period.Together, our data indicate that inhibition of cathepsin G activity at the TB interface could be therapeutic targets, and sRANKL which is generated by cathepsin G is a potentially target for prevention as well as treatment of breast cancer bone metastasis.

了解癌细胞如何诱导骨转移对于确定控制骨转移的新疗法至关重要。使用模拟与乳腺癌诱导的骨转移相关的溶骨性变化的小鼠模型，我们确定组织蛋白酶G是在肿瘤骨（TB）界面上调的蛋白酶。此外，我们发现，组织蛋白酶G能够脱落的细胞外结构域的受体活化因子-KB配体（RANKL），产生活性可溶性版本（sRANKL），能够诱导破骨细胞前体的分化和活化。组织蛋白酶G的主要来源似乎是破骨细胞。此外，我们表明，在体内抑制组织蛋白酶G减少乳腺肿瘤。接下来，我们检查了sRANKL的竞争性抑制剂护骨素融合蛋白（OCIF）的预防作用，在通过植入乳腺肿瘤细胞诱导骨质溶解之前（前）、骨质溶解诱导之后（后）或在整个实验期间（整个）向小鼠施用。OCIF治疗前、治疗后和整个治疗组的TB界面肿瘤生长均受到显著抑制。治疗前、治疗后和整个治疗组的骨破坏程度均显著降低。此外，OCIF治疗组中破骨细胞显著减少，无论治疗期如何，我们的数据表明，抑制TB界面的组织蛋白酶G活性可能是治疗靶点，组织蛋白酶G产生的sRANKL是预防和治疗乳腺癌骨转移的潜在靶点。

项目成果

Lack of promoting effect of titanium dioxide particles on ultraviolet B-initiated skin carcinogenesis in rats

二氧化钛颗粒对紫外线 B 引发的大鼠皮肤癌形成缺乏促进作用

• 发表时间: 2011
• 期刊: Food and Chemical Toxicology
• 影响因子: 4.3
• 作者: J Xu;Y Sagawa;M Futakuchi;K Fukamachim;DB Alexander;F Furukawa;Y Ikarashi;T Uchino;T Nishimura;A Morita;M Suzui;H Tsuda
• 通讯作者: H Tsuda

Anticarcinogenesis pathways activated by bovine lactoferrin in the murine small intestine

• DOI: 10.1016/j.biochi.2008.06.012
• 发表时间: 2009-01-01
• 期刊: BIOCHIMIE
• 影响因子: 3.9
• 作者: Iigo, Masaaki;Alexander, David B.;Tsuda, Hiroyuki
• 通讯作者: Tsuda, Hiroyuki

Crosstalk between TGFbeta and AKT/PTEN signaling pathway in the bone microenvironment : mechanism for tumor cell proliferation in the bone metastasis of breast cancer

骨微环境中TGFbeta与AKT/PTEN信号通路的串扰：乳腺癌骨转移中肿瘤细胞增殖的机制

• 发表时间: 2011
• 作者: Hiraoka N;et al.;Mitsuru Futakuchi Katsumi Fukamachi Masumi Suzui
• 通讯作者: Mitsuru Futakuchi Katsumi Fukamachi Masumi Suzui

A cross-species analysis of a mouse model of breast cancer-specific osteolysis and human bone metastases using gene expression profiling.

• DOI: 10.1186/1471-2407-11-304
• 发表时间: 2011-07-20
• 期刊: BMC cancer
• 影响因子: 3.8
• 作者: Sadanandam A;Futakuchi M;Lyssiotis CA;Gibb WJ;Singh RK
• 通讯作者: Singh RK

Crosstalk between TGFbeta and AKT/PTEN signaling pathway in the bone microenvironment ; mechanism for tumor cell proliferation in the bone metastasis of breast cancer

骨微环境中TGFbeta与AKT/PTEN信号通路的串扰；

• 发表时间: 2011
• 作者: Futakuchi;M.;Fukamachi;K.;and Suzui;M
• 通讯作者: M