Paired Overexpression of ErbB3 and Sox10 in Pilocytic Astrocytoma

Abstract

Pilocytic astrocytoma (PA) is the most common glioma of childhood. Despite their relatively high incidence, the molecular mechanisms responsible for tumorigenesis and growth of PA are poorly understood. Previous in vitro studies in our laboratory showed that despite the absence of ErbB1, PA was sensitive to ErbB1 tyrosine kinase inhibitor gefitinib. To identify alternative targets of gefitinib in PA, we studied other members of the ErbB receptor tyrosine kinase family that have been identified in brain tumors. Using gene expression microarray and Western blot analyses, we found that ErbB3 is highly overexpressed in PA compared with other pediatric brain tumors (glioblastoma, ependymoma, medulloblastoma, atypical teratoid/rhabdoid tumor, and choroid plexus papilloma). Developmental biology studies have identified Sox10 as a regulator of ErbB3 expression during development of the neural crest. Investigation of Sox10 in PA revealed that it is highly overexpressed relative to other pediatric brain tumors, lending support to the theory that Sox10-regulated overexpression of ErbB3 may be driving growth in PA. Sox10-regulated ErbB3 overexpression is a novel insight into the biology of PA, suggests possible recapitulation of developmental pathways in tumorigenesis, and presents possible targets for therapeutic intervention that might be used for hypothalamic variants not amenable to surgical cure.

The Role of Sox Transcription Factors in Brain Tumourigenesis

“…Sox10 has in pilocytic astrocytomas been correlated with high expression of ErbB3 suggesting that Sox10 is driving the overexpression of ErbB3 which may result in induced cell proliferation (Addo-Yobo, et al, 2006). This finding is supported by the knowledge that Sox10 is regulating ErbB3 in neural crest cells during development (Britsch, et al, 2001).…”

“…Consistently with several other studies we have reported that Sox10 is expressed in both paediatric and adult gliomas and ependymomas with a higher expression in low grade tumours compared to high grade tumours (Addo-Yobo, et al, 2006;Bannykh, et al, 2006;Colin, et al, 2007;Ferletta, et al, 2007). On the contrary Schlierf et al found that when investigating the mRNA levels of Sox10 in glioma the expression levels were lower compared to adult brain (Schlierf, et al, 2007).…”

The ERBB3 receptor in cancer and cancer gene therapy

“…296 ERBB3 and brain cancer-ERBB3 and the transcription factor SOX10, which regulates ERBB3 directly or indirectly in neural tissue, are notably overexpressed in pilocytic astrocytoma (a common childhood glioma), compared with other pediatric brain tumors. 297,298 Since SOX10 is an embryonic neural regulator of ERBB3, these childhood neoplasms may reflect a dysregulated developmental pathway. SOX10 was expressed in three-fourths of schwannomas, and in relatively differentiated neoplasms, for example in schwann-like cells of neuroblastoma (all ganglioneuromas and some stage IV neuroblastomas), correlated with widespread expression of ERBB3.…”

Kinome Profiling in Pediatric Brain Tumors as a New Approach for Target Discovery

“…The most prominent signal transduction pathways implicated to mediate these growth and suppressive signals include the Janusactivated kinase/Stat, phosphatidylinositol 3-kinase/Akt, and Ras/ extracellular signal-regulated kinase and protein kinase Ca pathways (2). In pediatric brain tumors, research mainly focused on the potential involvement of specific protein kinases such as epidermal growth factor receptor, platelet-derived growth factor receptor, phosphatidylinositol 3-kinase, and Janus-activated kinase in cell proliferation and survival (3)(4)(5)(6)(7)(8). The overall complexity and coregulation of the various signaling networks, however, has not been unraveled yet.…”