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Overexpression of Lrp5 enhanced the anti-breast cancer effects of osteocytes in bone
Bone Research ( IF 14.3 ) Pub Date : 2021-07-06 , DOI: 10.1038/s41413-021-00152-2
Shengzhi Liu 1 , Di Wu 1, 2, 3 , Xun Sun 1, 2 , Yao Fan 1, 2 , Rongrong Zha 1, 2 , Aydin Jalali 1 , Yan Feng 1, 2 , Kexin Li 1, 2 , Tomohiko Sano 1, 4 , Nicole Vike 5 , Fangjia Li 6 , Joseph Rispoli 5 , Akihiro Sudo 4 , Jing Liu 6 , Alexander Robling 7, 8 , Harikrishna Nakshatri 9, 10 , Bai-Yan Li 2 , Hiroki Yokota 1, 2, 7, 8, 10
Affiliation  

Osteocytes are the most abundant cells in bone, which is a frequent site of breast cancer metastasis. Here, we focused on Wnt signaling and evaluated tumor-osteocyte interactions. In animal experiments, mammary tumor cells were inoculated into the mammary fat pad and tibia. The role of Lrp5-mediated Wnt signaling was examined by overexpressing and silencing Lrp5 in osteocytes and establishing a conditional knockout mouse model. The results revealed that administration of osteocytes or their conditioned medium (CM) inhibited tumor progression and osteolysis. Osteocytes overexpressing Lrp5 or β-catenin displayed strikingly elevated tumor-suppressive activity, accompanied by downregulation of tumor-promoting chemokines and upregulation of apoptosis-inducing and tumor-suppressing proteins such as p53. The antitumor effect was also observed with osteocyte-derived CM that was pretreated with a Wnt-activating compound. Notably, silencing Lrp5 in tumors inhibited tumor progression, while silencing Lrp5 in osteocytes in conditional knockout mice promoted tumor progression. Osteocytes exhibited elevated Lrp5 expression in response to tumor cells, implying that osteocytes protect bone through canonical Wnt signaling. Thus, our results suggest that the Lrp5/β-catenin axis activates tumor-promoting signaling in tumor cells but tumor-suppressive signaling in osteocytes. We envision that osteocytes with Wnt activation potentially offer a novel cell-based therapy for breast cancer and osteolytic bone metastasis.



中文翻译:

Lrp5的过表达增强骨中骨细胞的抗乳腺癌作用

骨细胞是骨骼中最丰富的细胞,是乳腺癌转移的常见部位。在这里,我们专注于 Wnt 信号传导并评估肿瘤-骨细胞相互作用。在动物实验中,将乳腺肿瘤细胞接种到乳腺脂肪垫和胫骨中。通过在骨细胞中过表达和沉默 Lrp5 并建立条件性敲除小鼠模型来检查 Lrp5 介导的 Wnt 信号传导的作用。结果表明,施用骨细胞或其条件培养基(CM)可抑制肿瘤进展和骨溶解。过度表达 Lrp5 或 β-catenin 的骨细胞显示出显着升高的肿瘤抑制活性,伴随着肿瘤促进趋化因子的下调和凋亡诱导和肿瘤抑制蛋白(如 p53)的上调。用 Wnt 激活化合物预处理的骨细胞来源的 CM 也观察到了抗肿瘤作用。值得注意的是,在肿瘤中沉默 Lrp5 抑制了肿瘤进展,而在条件敲除小鼠的骨细胞中沉默 Lrp5 促进了肿瘤进展。骨细胞在响应肿瘤细胞时表现出升高的 Lrp5 表达,这意味着骨细胞通过典型的 Wnt 信号传导保护骨骼。因此,我们的结果表明 Lrp5/β-catenin 轴激活肿瘤细胞中的肿瘤促进信号,但激活骨细胞中的肿瘤抑制信号。我们设想具有 Wnt 激活的骨细胞可能为乳腺癌和溶骨性骨转移提供一种新的基于细胞的疗法。而在条件敲除小鼠的骨细胞中沉默 Lrp5 可促进肿瘤进展。骨细胞在响应肿瘤细胞时表现出升高的 Lrp5 表达,这意味着骨细胞通过典型的 Wnt 信号传导保护骨骼。因此,我们的结果表明 Lrp5/β-catenin 轴激活肿瘤细胞中的肿瘤促进信号,但激活骨细胞中的肿瘤抑制信号。我们设想具有 Wnt 激活的骨细胞可能为乳腺癌和溶骨性骨转移提供一种新的基于细胞的疗法。而在条件敲除小鼠的骨细胞中沉默 Lrp5 可促进肿瘤进展。骨细胞在响应肿瘤细胞时表现出升高的 Lrp5 表达,这意味着骨细胞通过典型的 Wnt 信号传导保护骨骼。因此,我们的结果表明 Lrp5/β-catenin 轴激活肿瘤细胞中的肿瘤促进信号,但激活骨细胞中的肿瘤抑制信号。我们设想具有 Wnt 激活的骨细胞可能为乳腺癌和溶骨性骨转移提供一种新的基于细胞的疗法。我们的结果表明,Lrp5/β-catenin 轴激活肿瘤细胞中的促肿瘤信号,但激活骨细胞中的肿瘤抑制信号。我们设想具有 Wnt 激活的骨细胞可能为乳腺癌和溶骨性骨转移提供一种新的基于细胞的疗法。我们的结果表明,Lrp5/β-catenin 轴激活肿瘤细胞中的促肿瘤信号,但激活骨细胞中的肿瘤抑制信号。我们设想具有 Wnt 激活的骨细胞可能为乳腺癌和溶骨性骨转移提供一种新的基于细胞的疗法。

更新日期:2021-07-07
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