High fat diet increases melanoma cell growth in the bone marrow by inducing osteopontin and interleukin 6.
High fat diet increases melanoma cell growth in the bone marrow by inducing osteopontin and interleukin 6.
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DOI：
10.18632/oncotarget.8474
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发表时间：
2016-05-03
期刊：
影响因子：
--
通讯作者：
Bozec A
中科院分区：
文献类型：
--
作者：
Chen GL;Luo Y;Eriksson D;Meng X;Qian C;Bäuerle T;Chen XX;Schett G;Bozec A
肥胖引起的代谢应激对骨髓黑色素瘤生态位的影响在很大程度上是未知的。我们采用饮食诱导的肥胖小鼠模型，在用B16F10黑色素瘤细胞攻击之前，给予高脂饮食(HFD)或正常饮食(ND)6周。对胫骨中的肿瘤大小、骨丢失和破骨细胞数量进行组织学评估。为了明确分子途径，在相同的模型上进行了骨桥蛋白基因敲除小鼠、白细胞介素6中和抗体或Janus激酶2抑制。还进行了脂肪细胞-黑色素瘤共培养等机制研究，以确定脂肪细胞诱导的肿瘤细胞增殖和表达谱的变化。因此，HFD通过增加肿瘤面积和破骨细胞数量来增加骨中黑色素瘤的负担。这一过程与直接靠近肿瘤细胞表达IL-6的骨髓脂肪细胞的数量增加有关。抑制IL-6或下游JAK2可阻断HFD诱导的肿瘤进展。此外，黑色素瘤细胞的表型变化引发了巨噬细胞和破骨细胞的聚集，并伴随着骨桥蛋白表达的增加。骨桥蛋白触发了破骨细胞的形成，也对肿瘤细胞施加了正反馈环，但在没有骨桥蛋白的情况下，这一环被取消了。HFD的代谢应激通过增加骨髓脂肪细胞和IL-6-JAK2-骨桥蛋白介导的肿瘤细胞激活和破骨细胞分化，促进骨髓中黑色素瘤的生长。
The impact of metabolic stress induced by obesity on the bone marrow melanoma niche is largely unknown. Here we employed diet induced obese mice model, where mice received high-fat (HFD) or normal diet (ND) for 6 weeks before challenge with B16F10 melanoma cells. Tumor size, bone loss and osteoclasts numbers were assessed histologically in the tibial bones. For defining the molecular pathway, osteopontin knock-out mice, interleukin 6 neutralizing antibody or Janus kinase 2 inhibition were carried out in the same model. Mechanistic studies such as adipocyte-melanoma co-cultures for defining adipocyte induced changes of tumor cell proliferation and expression profiles were also performed. As results, HFD enhanced melanoma burden in bone by increasing tumor area and osteoclast numbers. This process was associated with higher numbers of bone marrow adipocytes expressing IL-6 in direct vicinity to tumor cells. Inhibition of IL-6 or of downstream JAK2 blocked HFD-induced tumor progression. Furthermore, the phenotypic changes of melanoma cells triggered macrophage and osteoclast accumulation accompanied by increased osteopontin expression. Osteopontin triggered osteoclastogenesis and also exerted a positive feedback loop to tumor cells, which was abrogated in its absence. Metabolic stress by HFD promotes melanoma growth in the bone marrow by an increase in bone marrow adipocytes and IL-6-JAK2-osteopontin mediated activation of tumor cells and osteoclast differentiation.
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影响因子：
4.1
作者：
Chi, M.;Chen, J.;Zhang, X. D.
通讯作者：
Zhang, X. D.
影响因子：
11.2
作者：
Andarawewa, KL;Motrescu, ER;Rio, MC
通讯作者：
Rio, MC
影响因子：
4.8
作者：
Kwan, Hiu Yee;Fu, Xiuqiong;Yu, Zhi-Ling
通讯作者：
Yu, Zhi-Ling
影响因子：
4
作者：
Chen, Jiezhong;Chi, Mengna;Zhang, Xu Dong
通讯作者：
Zhang, Xu Dong
DOI：
10.1186/1756-9966-30-21
发表时间：
2011-02-21
影响因子：
11.3
作者：
Amjadi, Fatemehsadat;Javanmard, Shaghaygh Haghjooy;Narimani, Manijeh
通讯作者：
Narimani, Manijeh