Tumour-associated macrophages secrete pleiotrophin to promote PTPRZ1 signalling in glioblastoma stem cells for tumour growth

• Published in: Nature communications Vol. 8; no. 1; pp. 15080 - 17
• Main Authors: Shi, Yu, Ping, Yi-Fang, Zhou, Wenchao, He, Zhi-Cheng, Chen, Cong, Bian, Bai-Shi-Jiao, Zhang, Lin, Chen, Lu, Lan, Xun, Zhang, Xian-Chao, Zhou, Kai, Liu, Qing, Long, Hua, Fu, Ti-Wei, Zhang, Xiao-Ning, Cao, Mian-Fu, Huang, Zhi, Fang, Xiaoguang, Wang, Xiuxing, Feng, Hua, Yao, Xiao-Hong, Yu, Shi-Cang, Cui, You-Hong, Zhang, Xia, Rich, Jeremy N, Bao, Shideng, Bian, Xiu-Wu
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/31; 13/51; 13/89; 14/19; 14/5; 42; 631/67/1922; 631/67/327; 631/67/580; 631/67/71; Brain cancer; Humanities and Social Sciences; Infiltration; Medical prognosis; multidisciplinary; Science; Science (multidisciplinary); Signal transduction; Stem cells; Tumors; United States > US; China
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms15080

Intense infiltration of tumour-associated macrophages (TAMs) facilitates malignant growth of glioblastoma (GBM), but the underlying mechanisms remain undefined. Herein, we report that TAMs secrete abundant pleiotrophin (PTN) to stimulate glioma stem cells (GSCs) through its receptor PTPRZ1 thus promoting GBM malignant growth through PTN–PTPRZ1 paracrine signalling. PTN expression correlates with infiltration of CD11b + /CD163 + TAMs and poor prognosis of GBM patients. Co-implantation of M2-like macrophages (MLCs) promoted GSC-driven tumour growth, but silencing PTN expression in MLCs mitigated their pro-tumorigenic activity. The PTN receptor PTPRZ1 is preferentially expressed in GSCs and also predicts GBM poor prognosis. Disrupting PTPRZ1 abrogated GSC maintenance and tumorigenic potential. Moreover, blocking the PTN–PTPRZ1 signalling by shRNA or anti-PTPRZ1 antibody potently suppressed GBM tumour growth and prolonged animal survival. Our study uncovered a critical molecular crosstalk between TAMs and GSCs through the PTN–PTPRZ1 paracrine signalling to support GBM malignant growth, indicating that targeting this signalling axis may have therapeutic potential. Tumour-associated macrophages (TAMs) facilitate malignant growth of glioblastoma (GBM). Here, the authors show that TAMs support glioma stem cell renewal via paracrine signalling to the pleiotrophin receptor PTPRZ1 and that blocking this axis results in increased survival of tumour-bearing animals.