Expression of Hedgehog ligand and signal transduction components in mutually distinct isocitrate dehydrogenase mutant glioma cells supports a role for paracrine signaling

Abstract

Hedgehog signaling regulates the growth of malignant gliomas by a ligand dependent mechanism. The cellular source of Hedgehog ligand and mode of signaling have not been clearly defined due to the lack of methods to definitively identify neoplastic cells in glioma specimens. Using an antibody specific for mutant isocitrate dehydrogenase protein expression to identify glioma cells, we demonstrate that Sonic hedgehog ligand and the pathway components Patched1 and GLI1 are expressed in neoplastic cells. Further, Sonic hedgehog ligand production and GLI1 transcription factor expression occur in mutually distinct populations of neoplastic cells. These findings support a role for paracrine Hedgehog signaling in malignant gliomas.

Rare Tumor-Normal Matched Whole Exome Sequencing Identifies Novel Genomic Pathogenic Germline and Somatic Aberrations

“…The IDH1 variant occurred at amino acid 132 in the IDH1 gene in two sarcoma cases; chondrosarcoma R132C and pleiomorphic sarcoma R132G substitution respectively. The pleomorphic sarcoma with a concurrent IDH1 R132G mutation and a SUFU splice site mutation may indicate that the Hedgehog (Hh) pathway is operant in these cells independent of SHH ligand expression [39] since SUFU is a negative regulator of Hh signaling [40]. Further, a frameshift mutation in SUFU was found in our metastatic mucoepidermoid sarcoma patient indicative of active Hh signaling amenable for therapeutic intervention.…”

Abnormal activity of transcription factors gli in high-grade gliomas

“…It has been shown, that glioma cells are regulated by the Shh signaling pathway, however, normal astrocytes and endothelial cells of blood vessels, sprouting into the tumor, but not the tumor cells themselves, are the source of the ligand [2, 47, 53, 54]. At the same time, activation or inhibition of the Shh signaling pathway often did not affect gli activity or tumor cell growth in multiform glioblastomas [2, 46, 55–57].…”

The role of micro-RNA in the regulation of signal pathways in gliomas

“…Известно, что мутации в генах метаболических ферментов IDH1/2 (наиболее распространена замена R132H гена IDH1) -практически уникальная характеристика патогенеза глиом, приводящая к превращению 2-оксоглутарата в онкометаболит 2-гидроксиглутарат и указывающая на более благоприятный прогноз исхода заболевания [18]. Используя специфические антитела к мутантной IDH1 [19] было установлено, что Hh-путь (экспрессия PTCH1, GLI1) активен в трансформированных клетках глиомы.…”