STAT3 in Neurofibroma Tumorigenesis and Therapy.

摘要

Neurofibromatosis type 1 patients develop benign neurofibromas and malignant peripheral nerve sheath tumors (MPNSTs). Growth factor receptors, particularly EGFR, have been implicated in neurofibroma formation and progression, but their precise roles and relevant signaling pathways remain unknown. We found that EGFR modifies neurofibroma-initiating cell number and promotes transformation to aggressive GEM-PNST. Unbiased insertional mutagenesis screening suggested that these effects were mediated by STAT3 signaling. Immunohistochemistry demonstrated phosphorylated STAT3 (Tyr705) in human and mouse tumors. A specific STAT3 inhibitor blocked neurofibroma-sphere formation in vitro, and reduced neurofibroma growth in vivo; STAT3 knockdown by shRNA prevented MPNST formation in vivo. Finally, reducing EGFR activity strongly reduces pSTAT3 in vivo. Thus, an EGFR-STAT3 pathway regulates neurofibroma number and neurofibroma growth, and promotes transformation.