Activation of Sonic hedgehog signaling in neural progenitor cells promotes glioma development in the zebrafish optic pathway

Abstract

Dysregulation of Sonic hedgehog (Shh) signaling has been implicated in glioma pathogenesis. Yet, the role of this pathway in gliomagenesis remains controversial because of the lack of relevant animal models. Using the cytokeratin 5 promoter, we ectopically expressed a constitutively active zebrafish Smoothened (Smoa1) in neural progenitor cells and analyzed tumorigenic capacity of activated Shh signaling in both transient and stable transgenic fish. Transient transgenic fish overexpressing Smoa1 developed retinal and brain tumors, suggesting smoa1 is oncogenic in the zebrafish central nervous system (CNS). We further established stable transgenic lines that simultaneously developed optic pathway glioma (OPG) and various retinal tumors. In one of these lines, up to 80% of F1 and F2 fish developed tumors within 1 year of age. Microarray analysis of tumor samples showed upregulated expression of genes involved in the cell cycle, cancer signaling and Shh downstream targets ptc1, gli1 and gli2a. Tumors also exhibited specific gene signatures characteristic of radial glia and progenitor cells as transcriptions of radial glia genes cyp19a1b, s100β, blbp, gfap and the stem/progenitor genes nestin and sox2 were significantly upregulated. Overexpression of GFAP, S100β, BLBP and Sox2 was confirmed by immunofluorescence. We also detected overexpression of Mdm2 throughout the optic pathway in fish with OPG, therefore implicating the Mdm2–Tp53 pathway in glioma pathogenesis. In conclusion, we demonstrate that activated Shh signaling initiates tumorigenesis in the zebrafish CNS and provide the first OPG model not associated with neurofibromatosis 1.

Penfluridol suppresses glioblastoma tumor growth by Akt-mediated inhibition of GLI1

“…Several recent studies demonstrated the role of sonic hedgehog signaling, specifically GLI1 in glioblastoma progression and the role of GLI1 in imparting stem cells characteristics [2]. Interestingly, GLI1 was found to be up-regulated in glioblastoma and responsible for chemo-resistance [9, 10]. We observed that penfluridol treatment reduced the expression of GLI1 in all the glioblastoma cells in a concentration-dependent manner.…”

Activation of sonic hedgehog signaling enhances cell migration and invasion by induction of matrix metalloproteinase-2 and -9 via the phosphoinositide-3 kinase/AKT signaling pathway in glioblastoma

“…Once SHH binds to its receptor Patched 1, the transmembrane protein Smoothened is released, causing the transport of the transcription factor glioma-associated oncogene (Gli) into the nucleus, where it regulates the transcription of target genes that control cell differentiation, survival and growth (5,6). Three Gli genes (Gli1, Gli2 and Gli3) have been identified in mammalian tissues, among which Gli1 is considered to be the only loyal marker of hedgehog pathway activity (8)(9)(10) studies have shown that the hedgehog pathway is associated with the migration and invasion of ovarian, pancreatic, esophageal and gastric carcinomas (6,(11)(12)(13). However, to date, the implication of the hedgehog pathway in the aggressiveness of GBM has not been elucidated.…”

A vascular perspective on neuronal migration

“…Ju and colleagues demonstrated that constitutively active smoothened is oncogenic in zebrafish and that co-expression with the human constitutively active Akt leads to glioblastoma-like tumors in the brain, retina and spinal cord (Ju et al, 2009). Recently, they also reported that Shh activation in neural progenitor cells prone the development of optic pathway glioma in the zebrafish (Ju et al, 2014). Beneath the fact that zebrafish can develop almost any kind of tumor it was shown that the zebrafish is suited as xenograft model for multiple human cancer cell lines.…”