The role of JAK/STAT signaling pathway in the interaction of bone marrow mesenchymal stromal cells on neuroblastoma

Abstract

Neuroblastoma (NB) is the most common extra-cranial solid tumor of children and frequently metastasizes to bone marrow. The interaction between bone marrow microenvironment and metastatic tumor cells has been identified as a key step in tumor growth and metastasis. Particularly, mesenchymal stromal cells (MSCs) as one of the important stromal cells located in bone marrow play an essential role in the process. Our group has previously shown that bone marrow derived MSCs can enhance the growth and metastasis of NB. However, the exact mechanism of such interaction remains elusive. In this study, we postulate that JAK/STAT signaling pathway is vital for NB cells proliferation and migration. We also postulate that JAK/STAT signaling might be an important pathway by which MSCs enhance the tumorigenicity of neuroblastoma. In this study, small-molecule STAT3 inhibitor suppressed NB cells growth and blocked the supportive effect of MSCs. However, genetic downregulation of STAT3 in NB cells paradoxically enhanced the tumor proliferation and it may be due to the compensatory upregulation of STAT1. Subsequently, we found that conditioned medium obtained from MSCs derived factors activated both STAT3 and STAT1 in NB cells. However, single gene knockdown of either STAT1 or STAT3 failed to block the pro-tumorigenic activity of MSCs. On the other hand, blocking JAK/STAT pathway using JAK inhibitor or knockdown of both STAT1 and STAT3 drastically attenuated the NB cells proliferation and the supportive effect of MSCs. Similarly, the migratory effect of NB cells could be suppressed by JAK inhibitor as well. To evaluate the anti-tumor effect of JAK/STAT inhibition on neuroblastoma in vivo, we established an orthotopic mouse models by injecting NB cells alone, or mixture of NB cells and MSCs, to the suprarenal fat pad followed by monitoring of tumor growth and metastases. Our findings showed that mice treated with ruxolitinib had significantly reduced tumor size and metastatic lesions compared with mice treated with vehicle. Therefore, targeting JAK/STAT signaling pathway warrant further exploration as a potential therapeutic strategy in treating metastatic neuroblastoma.