Role of receptor tyrosine kinases and Rho GTPase mediated signaling in the regulation of the invasive phenotype in malignant gliomas

Abstract

[eng] Gliomas, tumours originated from glial cells, are the most frequent primary brain tumours in adults. Among these, glioblastomas constitute one of the most aggressive types of human cancer due to their capacity to invade healthy brain tissue and their enhanced resistance to radio- and chemotherapy. These biological features severely hamper glioblastoma treatment, making them one of the human cancers with worst outcome. Although effective therapy for glioblastoma remains a challenge, many efforts have been made in order to determine the genetic alterations responsible for their malignancy. For instance, several receptor tyrosine kinases such as EGFR, PDGFR, VEGFR and c-Met have been reported to be overexpressed or present mutant variants with increased activity, leading to enhanced downstream signalling. These receptors are known to activate the PI3K/Akt and Raf/MEK/ERK pathways, as well as controlling the activity of Rho GTPases, a family of proteins involved in cytoskeleton dynamics. Here we have used two glioblastoma cell lines, U87MG and LN229, and patientderived primary cells (p#04) in order to evaluate the effects of RTK inhibition on cell morphology and motility, as well as its impact on the activity of RhoA, a Rho GTPase implicated in the formation of stress fibres and focal adhesions. Treatment with the RTK inhibitors erlotinib, sunitinib and SU11274 induced cell morphology changes and a reduction in cell motility, alongside with an increase in RhoA activity. Furthermore, coinhibition of RTKs and ROCK, a downstream effector of RhoA, restored cell motility to similar conditions as those observed in untreated cells. These results confirm that RTK inhibition effects on glioblastoma cell motility are conducted through RhoA activity modulation, leading to a less invasive phenotype.