Role of the Shh Signaling Pathway in the Most Common Brain Tumor “Glioma” role in Glioma Growth
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The sonic hedgehog (Shh) signaling pathway is not only critical for brain development but also contributes to glioma growth. It was reported that glioma samples showed high expression of Gli1/Gli2 transcription factors. There was even a positive correlation between Shh and Gli1 expression, which suggests the role of the Shh signaling pathway in brain tumor development (Fig. 5.1) (Dahmane et al. 2001).Keywords:
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The Hedgehog (Hh)-glioma-associated oncogene homolog (GLI) signaling pathway is highly conserved among mammals, with crucial roles in regulating embryonic development as well as in cancer initiation and progression. The GLI transcription factors (GLI1, GLI2, and GLI3) are effectors of the Hh pathway and are regulated via Smoothened (SMO)-dependent and SMO-independent mechanisms. The SMO-dependent route involves the common Hh-PTCH-SMO axis, and mutations or transcriptional and epigenetic dysregulation at these levels lead to the constitutive activation of GLI transcription factors. Conversely, the SMO-independent route involves the SMO bypass regulation of GLI transcription factors by external signaling pathways and their interacting proteins or by epigenetic and transcriptional regulation of GLI transcription factors expression. Both routes of GLI activation, when dysregulated, have been heavily implicated in tumorigenesis of many known cancers, making them important targets for cancer treatment. Hence, this review describes the various SMO-dependent and SMO-independent routes of GLI regulation in the tumorigenesis of multiple cancers in order to provide a holistic view of the paradigms of hedgehog signaling networks involving GLI regulation. An in-depth understanding of the complex interplay between GLI and various signaling elements could help inspire new therapeutic breakthroughs for the treatment of Hh-GLI-dependent cancers in the future. Lastly, we have presented an up-to-date summary of the latest findings concerning the use of Hh inhibitors in clinical developmental studies and discussed the challenges, perspectives, and possible directions regarding the use of SMO/GLI inhibitors in clinical settings.
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The hedgehog signalling pathway plays a crucial role during regulation of hair cycle and homeostasis of mammalian skin. Furthermore, misregulation of this pathway is attributed to a range of skin diseases and cancers. In previous studies Indian hedgehog was identified to be the only Hedgehog ligand expressed in sebaceous glands. Moreover, modulation of hedgehog pathway activity was shown to affect size and number of sebaceous glands in the skin. Thereby, local inactivation of the canonical Wnt pathway seems to be prerequisite for correct sebaceous gland development. However, the underlying molecular mechanism has not been clarified, yet.
Therefore, we hypothesise that Indian hedgehog signalling regulates proliferation and/or differentiation in human sebocytes. Thereby, activation of Hedgehog pathway and inactivation of canonical Wnt signalling might be cross-linked.
To test this, we applied the human sebocyte cell line SZ95 as in vitro model by comparing three distinct sebocyte populations depending on their differentiation state: “undifferentiated”, “differentiating” and “terminally differentiated” after induction by arachidonic acid treatment.
Terminally differentiated sebocytes displayed increased expression of IHH without endogenous pathway activation. In contrast, undifferentiated sebocyte displayed increased proliferation rate upon pathway activation by GLI1 and GLI2 expression. Additionally, our findings point to a role of the lipid metabolism in regulating these processes as shown by modulation of gene expression by addition of arachidonic acid.
Importantly, overexpression of GLI1, GLI2 and GLI3 also revealed that each GLI transcription factors preferentially activates a distinct set of established and potentially new Hedgehog target genes in human sebocytes.
Additionally, we identified a new mechanism of mutual regulation between Hedgehog and Wnt pathways on protein level in human sebocytes. More precisely, overexpression of GLI3 and GLI2 transcription factors resulted in accumulation of non-phosphorylated, active β-CATENIN, although Wnt pathway activity was not increased. Conversely, augmented levels of β-CATENIN in combination with GLI1 activator dramatically increased Gli reporter activity.
In summary, we propose the following model where undifferentiated sebocytes are the target cells of Hedgehog signals originating from mature sebocytes and GLI repressors might block endogenous Wnt pathway by interference with β-CATENIN.
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Abstract GLI1 expression is broadly accepted as a marker of Hedgehog pathway activation in tumors. Efficacy of Hedgehog inhibitors is essentially limited to tumors bearing activating mutations of the pathway. GLI2, a critical Hedgehog effector, is necessary for GLI1 expression and is a direct transcriptional target of TGF-β/SMAD signaling. We examined the expression correlations of GLI1/2 with TGFB and HH genes in 152 distinct transcriptome datasets totaling over 23,500 patients and representing 37 types of neoplasms. Their prognostic value was measured in over 15,000 clinically annotated tumor samples from 26 tumor types. In most tumor types, GLI1 and GLI2 follow a similar pattern of expression and are equally correlated with HH and TGFB genes. However, GLI1 / 2 broadly share prognostic value with TGFB genes and a mesenchymal/EMT signature, not with HH genes. Our results provide a likely explanation for the frequent failure of anti-Hedgehog therapies in tumors, as they suggest a key role for TGF-β, not Hedgehog, ligands, in tumors with elevated GLI1/2 -expression.
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BACKGROUND During development, the Hedgehog pathway plays important roles regulating the proliferation and differentiation of chondrocytes, providing a template for growing bone. In this study, the authors investigated the components of dysregulated Hedgehog signaling as potential therapeutic targets for osteosarcoma. METHODS Small‐molecule agonists and antagonists that modulate the Hedgehog pathway at different levels were used to investigate the mechanisms of dysregulation and the efficacy of Hedgehog blockade in osteosarcoma cell lines. The inhibitory effect of a small‐molecule Smoothened (SMO) antagonist, IPI‐926 (saridegib), also was examined in patient‐derived xenograft models. RESULTS An inverse correlation was identified in osteosarcoma cell lines between endogenous glioma‐associated oncogene 2 ( GLI2 ) levels and Hedgehog pathway induction levels. Cells with high levels of GLI2 were sensitive to GLI inhibition, but not SMO inhibition, suggesting that GLI2 overexpression may be a mechanism of ligand‐independent activation. In contrast, cells that expressed high levels of the Hedgehog ligand gene Indian hedgehog ( IHH ) and the target genes patched 1 ( PTCH1 ) and GLI1 were sensitive to modulation of both SMO and GLI, suggesting ligand‐dependent activation. In 2 xenograft models, active autocrine and paracrine, ligand‐dependent Hedgehog signaling was identified. IPI‐926 inhibited the Hedgehog signaling interactions between the tumor and the stroma and demonstrated antitumor efficacy in 1 of 2 ligand‐dependent models. CONCLUSIONS The current results indicate that both ligand‐dependent and ligand‐independent Hedgehog dysregulation may be involved in osteosarcoma. It is the first report to demonstrate Hedgehog signaling crosstalk between the tumor and the stroma in osteosarcoma. The inhibitory effect of IPI‐926 warrants additional research and raises the possibility of using Hedgehog pathway inhibitors as targeted therapeutics to improve treatment for osteosarcoma. Cancer 2014;120:537–547 . © 2013 American Cancer Society .
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Abstract GLI1 expression is broadly accepted as a marker of Hedgehog pathway activation in tumors. Efficacy of Hedgehog inhibitors is essentially limited to tumors bearing activating mutations of the pathway. GLI2, a critical Hedgehog effector, is necessary for GLI1 expression and is a direct transcriptional target of TGF-β/SMAD signaling. We examined the expression correlations of GLI1/2 with TGFB and HH genes in 152 distinct transcriptome datasets totaling over 23,500 patients and representing 37 types of neoplasms. Their prognostic value was measured in over 15,000 clinically annotated tumor samples from 26 tumor types. In most tumor types, GLI1 and GLI2 follow a similar pattern of expression and are equally correlated with HH and TGFB genes. However, GLI1 / 2 broadly share prognostic value with TGFB genes and a mesenchymal/EMT signature, not with HH genes. Our results provide a likely explanation for the frequent failure of anti-Hedgehog therapies in tumors, as they suggest a key role for TGF-β, not Hedgehog, ligands, in tumors with elevated GLI1/2 -expression.
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