Prostate cancer promotes a vicious cycle of bone metastasis progression through inducing osteocytes to secrete GDF15 that stimulates prostate cancer growth and invasion

Wang, Wenchu1,2,3,4; Yang, Xin1,2,3,4; Dai, Jinlu2; Lu, Yi5; Zhang, Jian1,3,4,5; Keller, Evan T.2,6

2019-06-06

10.1038/s41388-019-0736-3

ONCOGENE   影响因子和分区

0950-9232

1476-5594

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.

SCI

英语

其他

NSFC[81130046] ; NSFC[81773146] ; NSFC[JCYJ20170412154619484]

Biochemistry & Molecular Biology ; Oncology ; Cell Biology ; Genetics & Heredity

Biochemistry & Molecular Biology ; Oncology ; Cell Biology ; Genetics & Heredity

WOS:000470240300008

NATURE PUBLISHING GROUP

MOLECULAR BIOLOGY & GENETICS

Web of Science

1.Guangxi Med Univ, Ctr Translat Med, Guangxi 530021, Peoples R China
2.Univ Michigan, Dept Urol, Ann Arbor, MI 48109 USA
3.Guangxi Med Univ, Sch Preclin Med, Guangxi, Peoples R China
4.Minist Educ, Key Lab Longev & Ageing Related Dis, Nanning, Peoples R China
5.Southern Univ Sci & Technol, Sch Med, Shenzhen, Guangdong, Peoples R China
6.Univ Michigan, Biointerfaces Inst, Ann Arbor, MI 48109 USA

Wang, Wenchu,Yang, Xin,Dai, Jinlu,et al. Prostate cancer promotes a vicious cycle of bone metastasis progression through inducing osteocytes to secrete GDF15 that stimulates prostate cancer growth and invasion[J]. ONCOGENE,2019,38(23):4540-4559.

Wang, Wenchu,Yang, Xin,Dai, Jinlu,Lu, Yi,Zhang, Jian,&Keller, Evan T..(2019).Prostate cancer promotes a vicious cycle of bone metastasis progression through inducing osteocytes to secrete GDF15 that stimulates prostate cancer growth and invasion.ONCOGENE,38(23),4540-4559.

Wang, Wenchu,et al."Prostate cancer promotes a vicious cycle of bone metastasis progression through inducing osteocytes to secrete GDF15 that stimulates prostate cancer growth and invasion".ONCOGENE 38.23(2019):4540-4559.