Chapter twenty-three - Hedgehog Inhibition as an Anti-Cancer Strategy
Introduction
The secreted signaling molecule, Hedgehog (Hh), and several components of its signal transduction pathway were initially identified secondary to their roles in early embryonic patterning through classical genetic mutagenesis screens in Drosophila (Nusslein-Volhard and Wieschaus, 1980). Subsequent analysis has revealed that most of the components of the pathway are conserved in higher organisms, including humans. Although the Hh signal transduction pathway has been described in detail in other chapters of this volume and in recent reviews (Ingham et al., 2011; Ng and Curran, 2011), the pathway in vertebrates will be summarized here as an introduction to this chapter that describes the dysregulation of Hh signaling in various cancers as well as within stromal cells of the tumor microenvironment.
In brief, Hh ligands bind to a 12-pass transmembrane receptor, Patched 1 (PTCH1), a negative regulator of the pathway, that results in its internalization and subsequent degradation. This results in release of the negative influence of PTCH1 on the 16-pass transmembrane protein, Smoothened (SMO), which then can enter the primary cilia through a poorly understood mechanism. Activated SMO then promotes dissociation of a Suppressor of fused (SUFU)-glioma associated oncogene homolog (GLI) protein complex that results in alterations in proteolytic processing of GLI proteins. This results in nuclear translocation and activation of the GLI2 transcription factor and degradation of the repressor, GLI3. The activated GLI2 protein stimulates the transcription of Hh pathway target genes, many of which are critical for important processes including cell proliferation, differentiation, and migration. Normally, the precise timing and duration of Hh signaling results in proper embryonic patterning as well as tissue differentiation during organogenesis (McMahon et al., 2003). However, alterations of the Hh pathway, primarily through mutations of pathway components or through mechanisms that result in upregulated GLI transcriptional activity, often result in dysregulated cell proliferation thus resulting in cancer.
Section snippets
Hh Signaling in Normal Development
The multiple roles for Hh signaling in normal developmental processes must be emphasized to better understand the mechanisms by which Hh pathway alterations contribute to oncogenesis as well as the potential consequences of Hh pathway inhibition for cancer therapy. In mammals, three related proteins, Desert Hedgehog (Dhh), Indian Hedgehog (Ihh), and Sonic Hedgehog (Shh), function as ligands for PTCH1. All mammalian Hh proteins are thought to have similar physiological effects on proliferation
Ligand-independent mechanisms
Genetic studies in Drosophila had identified the Hh receptor, PTCH1, as a negative regulator of Hh signal transduction. Binding of Hh ligand to PTCH1 relieves this inhibitory effect on the pathway, thus resulting in pathway activation. The initial evidence for the role of Hh signaling in cancer centered on identified mutations within the PTCH1 gene in patients with hereditary cancer syndromes. Specifically, patients with the hereditary Gorlin's syndrome, or basal-cell nevus syndrome, develop
SMO antagonists
Based on preclinical mouse modeling through tissue-specific Hh activation that recapitulates the biology of the human tumors, several Hh antagonists have been developed through in vitro screening of chemical libraries and proven to be efficacious in preclinical studies both in vitro and in vivo (Tremblay et al., 2010). Over 50 compounds have been identified as having an inhibitory effect on the Hh pathway. To date, most of these Hh antagonists have targeted the Hh receptor, SMO.
SMO small
Conclusions and Future Directions
A combination of intense investigation in both developmental biology and cancer research has led to the identification of Hh signaling as a critical component in both disciplines. The basic science understanding of this pathway and its effects on proliferation and differentiation of both normal cells and transformed cells has resulted in significant breakthroughs that are beginning to be translated into the clinical setting. The contributions of the medicinal chemistry field and biotechnology
Acknowledgments
G. P. R. was a Fellow of the Pediatric Scientist Development Program (NICHD K12-HD00850) and is currently supported by an NIH K08 Clinical Scientist Career Development Award (NINDS 5K08NS066083). The authors declare no competing financial interests.
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Targeting Hedgehog signaling pathway: Paving the road for cancer therapy
2019, Pharmacological ResearchCitation Excerpt :IPI-926 (a Smo antagonist) in conjunction with gemcitabine, demonstrated a decrease in fibrotic reaction [34,94]. In cell viability assays, another compound, robotnikinin, was found to act as a Hh pathway inhibitor by binding the amino terminal region of SHh (SHhN) [95,96]. Taladegib (LY2940680) was reported to restrain Smo-resistant mutant cells [97] and Itraconazole showed the capability to bind the Smo receptor and inhibit its accumulation in the cilium [98].
Inhibition of Hedgehog signaling in the gastrointestinal tract: Targeting the cancer microenvironment
2014, Cancer Treatment ReviewsCitation Excerpt :Subsequent studies confirmed the expression of Hh pathway components in cancer tissue and cell lines, putative cancer stem cells and the stroma [26,58–60]. The pattern of Hh ligand expression and its signaling components have been used to determine the direction of signaling with implications for developing anti-cancer strategies [61]. Typically canonical Hh signaling indicates that the ligand is produced in an epithelial cell and received by a stromal cell (Fig. 1).
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