Identification of IGF2 signaling through phosphoinositide-3-kinase regulatory subunit 3 as a growth-promoting axis in glioblastoma

Abstract

Amplification or overexpression of growth factor receptors is a frequent occurrence in malignant gliomas. Using both expression profiling and in situ hybridization, we identified insulin-like growth factor 2 (IGF2) as a marker for a subset of glioblastomas (GBMs) that lack amplification or overexpression of EGF receptor. Among 165 primary high-grade astrocytomas, 13% of grade IV tumors and 2% of grade III tumors expressed IGF2 mRNA levels >50-fold the sample population median. IGF2-overexpressing tumors frequently displayed PTEN loss, were highly proliferative, exhibited strong staining for phospho-Akt, and belonged to a subclass of GBMs characterized by poor survival. Using a serum-free culture system, we discovered that IGF2 can substitute for EGF to support the growth of GBMderived neurospheres. The growth-promoting effects of IGF2 were mediated by the insulin-like growth factor receptor 1 and phosphoinositide-3-kinase regulatory subunit 3 (PIK3R3), a regulatory subunit of phosphoinositide 3-kinase that shows genomic gains in some highly proliferative GBM cases. PIK3R3 knockdown inhibited IGF2-induced growth of GBM-derived neurospheres. The current results provide evidence that the IGF2-PIK3R3 signaling axis is involved in promoting the growth of a subclass of highly aggressive human GBMs that lack EGF receptor amplification. Our data underscore the importance of the phosphoinositide 3-kinase/Akt pathway for growth of high-grade gliomas and suggest that multiple molecular alterations that activate this signaling cascade may promote tumorigenesis. Further, these findings highlight the parallels between growth factors or receptors that are overexpressed in GBMs and those that support in vitro growth of tumor-derived stem-like cells.astrocytoma ͉ brain tumor ͉ expression profiling ͉ glioma ͉ gliomagenesis

Antixenograft tumor activity of a humanized anti-insulin-like growth factor-I receptor monoclonal antibody is associated with decreased AKT activation and glucose uptake

“…In contrast, the p55 g-regulatory subunit of phosphoinositide 3-kinase (PIK3R3) and Aurora kinase A (AURKA) are examples of the class II genes that remain significantly down-regulated after 2 weeks. PIK3R3 is frequently up-regulated in ovarian, prostate, breast, and liver cancers (31), and its down-regulation of PIK3R3 has been associated with decreased IGF-II-dependent growth of glioblastomaderived neurospheres (32) and increased apoptosis in ovarian cancer cells (31). Thus, these microarray data implicate intermediate molecular links between IGF-IR pathway inhibition and decreased tumor growth and highlight the dynamic and complex effects induced by a therapeutic antibody.…”

Truncating PREX2 mutations activate its GEF activity and alter gene expression regulation in NRAS-mutant melanoma

“…One compounding factor as shown in our expression analysis is that PREX2 mutant tumors have high levels of IGF2, which is known to activate the PI3K pathway (35,36). Indeed addition of IGF2 to serum deprived immortalized melanocytes potently activated Akt phosphorylation, suggesting this as a possible additional mechanism of Akt activation by PREX2 mutation that deserves further study (SI Appendix, Fig.…”

Matrix metalloproteinase‐9 interplays with the IGFBP2–IGFII complex to promote cell growth and motility in astrocytomas

“…Second, IGFII binds IGFBP2 with higher affinity than IGFI (Rajaram et al, 1997). Finally, IGFII is thought to play crucial roles in the pathogenesis of various human cancers (Toretsky and Helman, 1996), and its gene was recently showed to be overexpressed in a subclass of glioblastoma characterized by poor survival (Soroceanu et al, 2007).…”