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Notch3 promotes prostate cancer-induced bone lesion development via MMP-3.

Notch3 通过MMP-3 促进前列腺癌诱导的骨病变发展。

  • 影响因子:6.29
  • DOI:10.1038/s41388-019-0977-1
  • 作者列表:"Ganguly SS","Hostetter G","Tang L","Frank SB","Saboda K","Mehra R","Wang L","Li X","Keller ET","Miranti CK
  • 发表时间:2020-01-01
Abstract

:Prostate cancer metastases primarily localize in the bone where they induce a unique osteoblastic response. Elevated Notch activity is associated with high-grade disease and metastasis. To address how Notch affects prostate cancer bone lesions, we manipulated Notch expression in mouse tibia xenografts and monitored tumor growth, lesion phenotype, and the bone microenvironment. Prostate cancer cell lines that induce mixed osteoblastic lesions in bone expressed 5-6 times more Notch3, than tumor cells that produce osteolytic lesions. Expression of active Notch3 (NICD3) in osteolytic tumors reduced osteolytic lesion area and enhanced osteoblastogenesis, while loss of Notch3 in osteoblastic tumors enhanced osteolytic lesion area and decreased osteoblastogensis. This was accompanied by a respective decrease and increase in the number of active osteoclasts and osteoblasts at the tumor-bone interface, without any effect on tumor proliferation. Conditioned medium from NICD3-expressing cells enhanced osteoblast differentiation and proliferation in vitro, while simultaneously inhibiting osteoclastogenesis. MMP-3 was specifically elevated and secreted by NICD3-expressing tumors, and inhibition of MMP-3 rescued the NICD3-induced osteoblastic phenotypes. Clinical osteoblastic bone metastasis samples had higher levels of Notch3 and MMP-3 compared with patient matched visceral metastases or osteolytic metastasis samples. We identified a Notch3-MMP-3 axis in human prostate cancer bone metastases that contributes to osteoblastic lesion formation by blocking osteoclast differentiation, while also contributing to osteoblastogenesis. These studies define a new role for Notch3 in manipulating the tumor microenvironment in bone metastases.

摘要

: 前列腺癌转移主要定位于骨,在骨中诱导独特的成骨细胞反应。Notch活性升高与高级别疾病和转移相关。为了解决Notch如何影响前列腺癌骨病变,我们操纵了小鼠胫骨异种移植物中的Notch表达,并监测肿瘤生长、病变表型和骨微环境。诱导骨混合性成骨细胞病变的前列腺癌细胞系表达Notch3 是产生溶骨性病变的肿瘤细胞的 5-6 倍。溶骨性肿瘤中活性Notch3 (NICD3) 的表达减少了溶骨性病变区域,增强了成骨细胞生成,而成骨细胞肿瘤中Notch3 的缺失增强了溶骨性病变区域,降低了成骨细胞生成。这伴随着肿瘤-骨界面活性破骨细胞和成骨细胞数量的相应减少和增加,对肿瘤增殖没有任何影响。来自NICD3-expressing细胞的条件培养基在体外增强成骨细胞分化和增殖,同时抑制破骨细胞生成。MMP-3 特异性升高并由NICD3-expressing肿瘤分泌,抑制MMP-3 挽救了成骨细胞表型NICD3-induced。与患者匹配的内脏转移或溶骨性转移样本相比,临床成骨骨转移样本的Notch3 和MMP-3 水平较高。我们在人类前列腺癌骨转移中发现了一个Notch3-MMP-3 轴,它通过阻断破骨细胞分化促进成骨细胞病变的形成,同时也促进成骨细胞的形成。这些研究定义了Notch3 在操纵骨转移肿瘤微环境中的新作用。

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发表时间:2020-03-01
DOI:10.1177/1078155219842277
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影响因子:2.83
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骨肿瘤方向

骨肿瘤是发生于骨骼或其附属组织的肿瘤。有良性,恶性之分,良性骨肿瘤易根治,预后良好,恶性骨肿瘤发展迅速,预后不佳,死亡率高。

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