Neuregulin-1β and Neuregulin-1α Differentially Affect the Migration and Invasion of Malignant Peripheral Nerve Sheath Tumor Cells

摘要

Malignant peripheral nerve sheath tumors (MPNSTs) are the most common malignancy associated with neurofibromatosis type 1 (NF1). These Schwann cell lineage-derived sarcomas aggressively invade adjacent nerve and soft tissue, frequently precluding surgical resection. Little is known regarding the mechanisms underlying this invasive behavior. We have shown that MPNSTs express neuregulin-1 (NRG-1) β isoforms, which promote Schwann cell migration during development, and NRG-1α isoforms, whose effects on Schwann cells are poorly understood. Hypothesizing that NRG-1β and/or NRG-1α promote MPNST invasion, we found that NRG-1β promoted MPNST migration in a substrate-specific manner, markedly enhancing migration on laminin but not on collagen type I or fibronectin. The NRG-1 receptors erbB3 and erbB4 were present in MPNST invadopodia (processes mediating invasion), partially colocalized with focal adhesion kinase and the laminin receptor β1-integrin and coimmunoprecipitated with β1-integrin. NRG-1β stimulated human and murine MPNST cell migration and invasion in a concentration-dependent manner in three-dimensional migration assays, acting as a chemotactic factor. Both baseline and NRG-1β induced migration were erbB-dependent and required the action of MEK 1/2, SAPK/JNK, PI-3 kinase, Src family kinases and ROCK-I/II. In contrast, NRG-1α had no effect on the migration and invasion of some MPNST lines and inhibited the migration of others. While NRG-1β potently and persistently activated Erk 1/2, SAPK/JNK, Akt and Src family kinases, NRG-1α did not activate Akt and activated these other kinases with kinetics distinct from those evident in NRG-1β stimulated cells. These findings suggest that NRG-1β enhances MPNST migration and that NRG-1β and NRG-1α differentially modulate this process.