Prostate cancer promotes a vicious cycle of bone metastasis progression through inducing osteocytes to secrete GDF15 that stimulates prostate cancer growth and invasion.
Prostate cancer promotes a vicious cycle of bone metastasis progression through inducing osteocytes to secrete GDF15 that stimulates prostate cancer growth and invasion.
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前列腺癌通过诱导骨细胞分泌GDF15刺激前列腺癌生长和侵袭，从而促进骨转移进展的恶性循环
DOI：
10.1038/s41388-019-0736-3
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发表时间：
2019-06
期刊：
影响因子：
8
通讯作者：
Keller, Evan T.
中科院分区：
文献类型：
--
作者：
Wang, Wenchu;Yang, Xin;Dai, Jinlu;Lu, Yi;Zhang, Jian;Keller, Evan T.
骨是前列腺癌(PCa)最常见的转移部位，然而，骨中最常见的细胞--骨细胞(Ocy)在癌症生物学中的作用却知之甚少。在这项研究中，我们探索了PCa细胞和OCys之间的串扰，以确定它是否有助于PCa的进展。PCa细胞诱导OCys促进PCa的增殖、迁移和侵袭。趋化因子筛选显示，PCa细胞诱导OCys产生生长衍生因子15(GDF15)。OCys中GDF15基因的敲除表明Pca细胞通过GDF15赋予OCys促进Pca增殖、迁移和侵袭的能力。与这一发现相一致的是，观察到GDF15受体GFra在多个PCa细胞系中表达。转录因子阵列筛选结果显示，OCys中的GDF15可促进PCa细胞早期生长反应1(Egr1)的表达。下调Egr1在PCa细胞中的表达表明它是Ocy来源的GDF15介导的体外诱导PCa细胞增殖、迁移和侵袭所必需的。皮下联合注射PCa细胞和OCys表明OCys促进了体内肿瘤的生长，这种促进作用被OCys中GDF15基因敲除而减弱。在胫骨中GDF15基因的敲除抑制了注射到胫骨中的前列腺癌癌细胞的生长，并伴随着肿瘤细胞增殖和Egr1表达的下降。这些结果揭示了一种新的机制，即PCa细胞通过培养OCys来促进PCa骨转移的进展。他们还建议，靶向的基于GDF15和Egr1的信号通路应该进一步探索它们在减少前列腺癌骨转移进展方面的潜力。
Bone is the most frequent site of prostate cancer (PCa) metastasis; however, little is known about the role of the most common cell in bone, the osteocyte (OCy), in cancer biology. In this study we explored the crosstalk between PCa cells and OCys to determine if it contributes to PCa progression. PCa cells induced OCys to promote PCa proliferation, migration and invasion. A chemokine screen revealed that PCa cell induced OCys to produce growth-derived factor 15 (GDF15). Knockdown of GDF15 in OCys demonstrated that PCa cells conferred the ability on OCys to promote PCa proliferation, migration and invasion through GDF15. Consistent with this finding was the observation that the GDF15 receptor, GFRAL, was expressed on multiple PCa cell lines. Transcription factor array screening of PCa cells exposed to OCys with or without knockdown of GDF15 revealed that GDF15 in OCys promoted early growth response 1 (EGR1) expression in the PCa cells. Knockdown of EGR1 expression in PCa cells revealed it was required for the OCy-derived GDF15-mediated induction of in vitro PCa cell proliferation, migration and invasion. Subcutaneous co-injection of PCa cells and OCys into mice revealed that OCys promoted tumor growth in vivo, which was diminished by knockdown of GDF15 in the OCys. Knockdown of GDF15 in the tibiae diminished growth of PCa cancer cells injected into the tibiae, which was accompanied by decreased tumor cell proliferation and EGR1 expression. These results shed light on a novel mechanism through which PCa cells educate OCys to promote progression of PCa bone metastasis. They also suggest that targeting of GDF15-based and EGR1-based signaling pathways should be further explored for their potential to diminish progression of PCa bone metastasis.
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影响因子：
82.9
作者：
Emmerson, Paul J.;Wang, Feng;Wu, Xinle
通讯作者：
Wu, Xinle
影响因子：
11.8
作者：
Deng, Xiyun;He, Guangchun;Liu, Junwen;Luo, Feijun;Peng, Xiaoning;Tang, Shigang;Gao, Zhiyong;Lin, Qinlu;Keller, Jill M.;Yang, Tao;Keller, Evan T.
通讯作者：
Keller, Evan T.
影响因子：
4.1
作者：
Kalajzic, Ivo;Matthews, Brya G.;Torreggiani, Elena;Harris, Marie A.;Pajevic, Paola Divieti;Harris, Stephen E.
通讯作者：
Harris, Stephen E.
DOI：
10.2217/fon.09.67
发表时间：
2009-09
期刊：
Future oncology (London, England)
影响因子：
--
作者：
Gitenay D;Baron VT
通讯作者：
Baron VT
影响因子：
64.8
作者：
Hsu, Jer-Yuan;Crawley, Suzanne;Allan, Bernard B. .
通讯作者：
Allan, Bernard B. .