Conversion of Osteoclasts into Bone-Protective, Tumor-Suppressing Cells.
Conversion of Osteoclasts into Bone-Protective, Tumor-Suppressing Cells.
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DOI：
10.3390/cancers13225593
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发表时间：
2021-11-09
期刊：
影响因子：
5.2
通讯作者：
Yokota H
中科院分区：
文献类型：
--
作者：
Li KX;Sun X;Li BY;Yokota H
破骨细胞是骨吸收细胞，与骨形成成骨细胞一起，它们负责维持健康的骨骼。然而，当癌细胞侵入骨骼时，破骨细胞会协助癌症进展并刺激骨质流失。在这项研究中，我们通过激活破骨细胞的Wnt信号转导来转化破骨细胞的骨破坏作用，并产生了一种破骨细胞衍生的、骨保护性的、肿瘤抑制性的条件培养基。条件培养基能够抑制乳腺肿瘤和骨转移的小鼠模型中的肿瘤生长和骨丢失。所描述的方法预计将增加一种新的策略来治疗原发性乳腺癌以及骨转移。破骨细胞是乳腺癌细胞恶性骨破坏循环的驱动因素。在这里，我们研究了这种恶性循环是否可以通过用其激活剂BML 284激活Wnt信号传导而改变为有益的循环。来自Wnt激活的RAW264.7前破骨细胞（BM CM）的条件培养基减少了EO 771乳腺肿瘤细胞的增殖、迁移和侵袭。用BML 284处理的原代人巨噬细胞获得相同的抑制作用。在小鼠模型中，BM CM减少了乳腺肿瘤和肿瘤诱导的骨质溶解的进展，并抑制了肿瘤对肺的侵袭。它还抑制RANKL刺激的破骨细胞的分化并增强成骨细胞的分化。BM CM富含非典型肿瘤抑制蛋白，如Hsp 90 ab 1和烯醇化酶1（Eno 1）。免疫沉淀显示，细胞外的Hsp 90 ab 1与潜伏的TGFβ（LAP-TGFβ）相互作用，作为TGFβ活化的抑制剂，而Hsp 90 ab 1和Eno 1通过CD 44（细胞粘附受体和癌症干细胞标志物）相互作用并抑制肿瘤进展。这项研究表明，破骨细胞衍生的CM可以通过激活Wnt信号转导转化为骨保护剂，肿瘤抑制剂。这些结果揭示了破骨细胞作为一种潜在的骨保护剂的未开发功能，可能会开发一种非传统的策略来对抗骨转移。
Osteoclasts are bone-resorbing cells and, together with bone-forming osteoblasts, they are responsible for maintaining healthy bones. When cancer cells invade into the bone, however, osteoclasts assist in cancer progression and stimulate bone loss. In this study, we converted the bone-destructive action of osteoclasts by activating their Wnt signaling and generated an osteoclast-derived, bone-protective, tumor-suppressive conditioned medium. The conditioned medium was able to suppress tumor growth and bone loss in a mouse model of mammary tumors and bone metastasis. The described approach is expected to add a novel strategy to treat primary breast cancer as well as bone metastasis. Osteoclasts are a driver of a vicious bone-destructive cycle with breast cancer cells. Here, we examined whether this vicious cycle can be altered into a beneficial one by activating Wnt signaling with its activating agent, BML284. The conditioned medium, derived from Wnt-activated RAW264.7 pre-osteoclast cells (BM CM), reduced the proliferation, migration, and invasion of EO771 mammary tumor cells. The same inhibitory effect was obtained with BML284-treated primary human macrophages. In a mouse model, BM CM reduced the progression of mammary tumors and tumor-induced osteolysis and suppressed the tumor invasion to the lung. It also inhibited the differentiation of RANKL-stimulated osteoclasts and enhanced osteoblast differentiation. BM CM was enriched with atypical tumor-suppressing proteins such as Hsp90ab1 and enolase 1 (Eno1). Immunoprecipitation revealed that extracellular Hsp90ab1 interacted with latent TGFβ (LAP-TGFβ) as an inhibitor of TGFβ activation, while Hsp90ab1 and Eno1 interacted and suppressed tumor progression via CD44, a cell-adhesion receptor and a cancer stem cell marker. This study demonstrated that osteoclast-derived CM can be converted into a bone-protective, tumor-suppressing agent by activating Wnt signaling. The results shed a novel insight on the unexplored function of osteoclasts as a potential bone protector that may develop an unconventional strategy to combat bone metastasis.
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影响因子：
4.1
作者：
Bellido, Teresita;Plotkin, Lilian I.
通讯作者：
Plotkin, Lilian I.
影响因子：
27.4
作者：
Shkhyan R;Van Handel B;Bogdanov J;Lee S;Yu Y;Scheinberg M;Banks NW;Limfat S;Chernostrik A;Franciozi CE;Alam MP;John V;Wu L;Ferguson GB;Nsair A;Petrigliano FA;Vangsness CT;Vadivel K;Bajaj P;Wang L;Liu NQ;Evseenko D
通讯作者：
Evseenko D
DOI：
10.1073/pnas.1219181110
发表时间：
2012-12-18
影响因子：
11.1
作者：
Li, Wendong;Tian, E.;Shi, Yanhong
通讯作者：
Shi, Yanhong
影响因子：
4.6
作者：
Hwang, Phillip W.;Horton, Jason A.
通讯作者：
Horton, Jason A.
影响因子：
82.9
作者：
Nakashima, Tomoki;Hayashi, Mikihito;Takayanagi, Hiroshi
通讯作者：
Takayanagi, Hiroshi