Autophagy, a conserved biological process for cellular component elimination, plays critical roles in the initiation, progression, and drug resistance of cancer, and therefore, implied potential to be targeted. The Hedgehog (Hh) signaling pathway regulates embryonic development and may be aberrantly activated in a wide variety of human cancers. Therefore, HH signaling has emerged as a therapeutic target of interest for cancer therapy. In cells receiving the Hh signal, pathway transmission is regulated at multiple levels. Nusslein-Volhard C., Wieschaus E. Mutations affecting segment number and polarity in Drosophila. This model is supported by in vitro data showing that proliferation of tumor cell lines is accelerated by addition of Hh ligand (41) and inhibited by a Hh neutralizing antibody (40) or by addition of cyclopamine, a Hh pathway antagonist. The vismodegib at that point is discontinued. Targeting Hedgehog signaling pathway and autophagy overcomes drug resistance of BCR-ABL-positive chronic myeloid leukemia. Mutations in the pathway (*) or overexpression of the Hh ligand are highlighted (**) in (A) and (B) along with possible avenues of treatment using antibodies or small molecules (red arrows). Nature. In mammals, there are three Hh proteins: Sonic Hh, Indian Hh, and Desert Hh. It is a highly conserved evolutionary pathway of signal transmission from the cell membrane to the nucleus. Nature. Interestingly, cell lines established from the Ptch1+/−P53−/− medulloblastoma model also become insensitive to Hh antagonists, whereas tumors directly passaged s.c. in mice (i.e., direct allografts) maintained their molecular signature and were reproducibly responsive to Hh antagonists (59). Most of the brain tumors are resistant to chemotherapeutic drugs, consequently, they have a poor prognosis. The authors declare no conflict of interest. Abidi A. Hedgehog signaling pathway: a novel target for cancer therapy: vismodegib, a promising therapeutic option in treatment of basal cell carcinomas. Diseases associated with the malfunction of this pathway include cancer. FOIA Elegantly illustrating the former, small-molecule Hh antagonists have been used to treat endogenous medulloblastoma in the Ptch1+/−P53−/− mouse model where tumors develop with 100% incidence (63). 10) and growth arrest-specific gene (Gas1; ref. The amount of Hh available to bind Ptch1 is tightly regulated by Hh-binding proteins, such as Hh-interacting protein (Hip; ref. Hedgehog (Hh) signaling pathway plays an essential role during vertebrate embryonic development and tumorigenesis. In postembryonic life, the pathway may be activated to stimulate tissue repair or cell proliferation. eISSN: 1557-3265 Abnormal activation of Hh pathway is responsible for tumorigenesis and maintenance of multiple cancers, and thus addressing this represents promising therapeutic opportunities. Alingar et al. The clear link between Hh pathway and human cancers, such as BCC and medulloblastoma, drove the effort to identify small-molecule Hh antagonists to block the pathway. The mechanism by which Hh acts in ligand-overexpressing cancers is still unclear. Green arrow: upregulate; Red line: inhibit; Box with dash line: both GLI1 and GLI2 were involved in Bnip3 inhibition. These drugs are regarded as promising cancer therapies, especially for patients with refractory or advanced cancers. The Hedgehog pathway plays an essential role in cell growth and differentiation in the developing embryo. In recent years, the Hedgehog (Hh) signalling pathway has emerged as a critical determinant of cancer initiation, progression and metastasis of an important subset of human cancers [ 3 – 5 ]. Deregulation of the Hh pathway is a key driver of basal cell carcinoma, and therapeutic targeting led to approval of Hh inhibitor, vismodegib, in the management of this cancer. Green arrow: upregulate;…, National Library of Medicine The mechanisms of Hedgehog signalling and its roles in development and disease. In the presence of Hh ligand, the precise mechanism by which the Hh signal is transmitted from Smo to Gli is not well understood in vertebrates. Nat. See this image and copyright information in PMC. Abnormal activation may lead to cancer, including basal cell carcinoma. NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. doi: 10.1101/gad.938601. Several key signalling pathways, such as Hedgehog, Notch, Wnt and BMP–TGFβ–Activin (bone morphogenetic... References. At the molecular level, Hh ligands drive cell proliferation in some cell types while causing others to undergo differentiation. Hedgehog (Hh) pathway controls complex developmental processes in vertebrates. The Hh signaling pathway plays an important role in the embryonic development. The pathway also has roles in the adult. 1A; refs. In some of these experiments, high concentrations of Hh antagonist, 100- to 1,000-fold higher than what is needed to block Hh signaling, were necessary to cause growth inhibition. However, because the pathway is reactivated during tissue repair and regeneration through stimulation of endogenous stem cell populations, the effect of systemic administration of Hh antagonists on stem cell populations within the bone marrow, gut, muscle, liver, skin, brain, and others will have to be carefully monitored. Garcia N, Al-Hendy A, Baracat EC, Carvalho KC, Yang Q. Inactivating mutations in PTCH1 have been detected in the majority of sporadic BCC, although a small number (∼10%) are caused by a specific SMO mutation that make tumors less sensitive to PTCH1 repression (35, 36). 1–3 for a comprehensive review of Hh signaling). In the absence of Hh, Patched1 (Ptch1), a 12-transmembrane receptor, acts catalytically to suppress the activity of Smoothened (Smo), a seven-transmembrane protein, by preventing its localization to the cell surface (Fig. However, in prostate, Hh pathway activity seems to correlate with higher-grade tumors, and treatment of an aggressive prostate xenograft model with cyclopamine, a pathway antagonist (see below), prevents metastasis to the lung. Thank you for sharing this Clinical Cancer Research article. 2015 Dec;35:154-67. doi: 10.1016/j.semcancer.2015.08.003. ISSN: 1078-0432, Sign In to Email Alerts with your Email Address. Zeng X, Zhao H, Li Y, Fan J, Sun Y, Wang S, Wang Z, Song P, Ju D. Autophagy. Therapeutic Targeting of the Liver Microenvironment, Targeting the Protein Kinase Wee1 in Cancer, Metabolic Control of Histone Methylation and Gene Expression, Cancer Epidemiology, Biomarkers & Prevention, Role of the Hh Pathway in Ligand-Overexpressing Tumors. The hedgehog (Hh) pathway plays an important role in cancer development and maintenance, as ~25% of all cancers have aberrant Hh pathway activation. Keywords: 30–32). Zhang J, Fan J, Zeng X, Nie M, Luan J, Wang Y, Ju D, Yin K. Acta Pharm Sin B. 1B; refs. -, Ingham P.W., McMahon A.P. Hedgehog, a crucial signaling pathway involved in embryonic development and patterning, is postulated to be active during carcinogenesis. This review will highlight recent advances of Hh pathway and autophagy in cancers, and focus on their crosstalk and the implied therapeutic opportunities. Abstract Background: The hedgehog pathway (HH) is one of the key regulators involved in many biological events. 2014 Jul;40(6):750-9. doi: 10.1016/j.ctrv.2014.02.003. Inhibition of the Hh pathway may provide a therapeutic opportunity for treatment of tumors, such as pancreatic cancer, where few options are available. The hedgehog (Hh) pathway plays a key role in embryonic development and stem cell programs. 7, 8). However, to date, few universal target genes have been identified across different systems and much work still needs to be done to determine how Hh overexpression contributes to tumorigenesis. Hedgehog pathway inhibitors are small molecules that inhibit the activity of a component of the Hedgehog signaling pathway. Hh signaling is most active during embryogenesis, and aberrant reactivation of the pathway in adult tissue can lead to the development … Please describe the FDA-approved treatments in this setting. Suppressor of fused (Sufu) acts as another negative regulator of the pathway by binding to Gli, both in the cytoplasm and in the nucleus, to prevent it from activating Hh target genes (20–23). The Hedgehog signaling pathway is a signaling pathway that transmits information to embryonic cells required for proper cell differentiation. The Hedgehog (Hh) pathway is a signaling cascade that directs patterning in most animals and is crucial for proper development. In xenograft models of Hh-overexpressing tumors, including small cell lung cancer, gastric and upper gastrointestinal track cancer, pancreatic cancer, and prostate cancer, tumor growth inhibition on treatment with cyclopamine has also been shown (40–44). Alternatively, Hh may be acting on a small fraction of cancer stem cells that are capable of self-renewal and differentiation among multiple lineages. Subsequent release of Hh depends on Dispatched (Disp), a multitransmembrane protein, whereas diffusion of Hh requires Tout-velu-dependent synthesis of heparan sulfate proteoglycans (5, 6). 2020 Oct 17;12(10):3018. doi: 10.3390/cancers12103018. Privacy, Help Hedgehog signaling in gastrointestinal carcinogenesis and the gastrointestinal tumor microenvironment. In the absence of Hh signaling, protein kinases, such as protein kinase A, glycogen synthase kinase 3β, and casein kinase 1α, phosphorylate Gli, leading to proteosome-mediated cleavage of Gli into an NH2-terminal truncated form, which acts as a repressor of Hh target gene expression (Fig. In almost all BCC cases, the Hh pathway is hyperactivated as indicated by up-regulation of Hh target genes (37). At the molecular level, Hh ligands drive cell proliferation in some cell types while causing others to undergo differentiation. 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