Tumor-associated macrophages promote neuroblastoma via STAT3 phosphorylation and up-regulation of c-MYC
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Michael D. Hadjidaniel1,*, Sakunthala Muthugounder1,*, Long T. Hung1,*, Michael A. Sheard1, Soheila Shirinbak1, Randall Y. Chan1,3, Rie Nakata1, Lucia Borriello1, Jemily Malvar1, Rebekah J. Kennedy1, Hiroshi Iwakura2, Takashi Akamizu2, Richard Sposto1,3, Hiroyuki Shimada1,3, Yves A. DeClerck1,3 and Shahab Asgharzadeh1,3
1Children's Hospital Los Angeles, Children's Center for Cancer and Blood Diseases, Division of Hematology, Oncology and Blood & Marrow Transplantation, and The Saban Research Institute, Los Angeles, CA, USA
2The First Department of Medicine, Wakayama Medical University, Wakayama, Japan
3Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
*These authors have contributed equally to this work
Shahab Asgharzadeh, email: firstname.lastname@example.org
Keywords: neuroblastoma, tumor-associated macrophages, tumor microenvironment, STAT3, MYC
Received: March 17, 2017 Accepted: July 19, 2017 Published: September 16, 2017
Tumor-associated macrophages (TAMs) are strongly associated with poor survival in neuroblastomas that lack MYCN amplification. To study TAM action in neuroblastomas, we used a novel murine model of spontaneous neuroblastoma lacking MYCN amplification, and observed recruitment and polarization of TAMs, which in turn enhanced neuroblastoma proliferation and growth. In both murine and human neuroblastoma cells, we found that TAMs increased STAT3 activation in neuroblastoma cells and transcriptionally up-regulated the MYC oncogene. Analysis of human neuroblastoma tumor specimens revealed that MYC up-regulation correlates with markers of TAM infiltration. In an IL6ko neuroblastoma model, the absence of IL-6 protein had no effect on tumor development and prevented neither STAT3 activation nor MYC up-regulation. In contrast, inhibition of JAK-STAT activation using AZD1480 or the clinically admissible inhibitor ruxolitinib significantly reduced TAM-mediated growth of neuroblastomas implanted subcutaneously in NOD scid gamma mice. Our results point to a unique mechanism in which TAMs promote tumor cells that lack amplification of an oncogene common to the malignancy by up-regulating transcriptional expression of a distinct oncogene from the same gene family, and underscore the role of IL-6-independent activation of STAT3 in this mechanism. Amplification of MYCN or constitutive up-regulation of MYC protein is observed in approximately half of high-risk tumors; our findings indicate a novel role of TAMs as inducers of MYC expression in neuroblastomas lacking independent oncogene activation.
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