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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (11 July 2018) | Viewed by 67407

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Dr. Maria Domenica Castellone

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Guest Editor

Consiglio Nazionale delle Ricerche, Rome, Italy
Interests: cancer; tumor–stroma interaction; signaling pathways; GPCR; kinase receptors; target therapy; thyroid
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

The Hedgehog pathway plays a crucial role in regulating cell growth, differentiation and tissue patterning during normal human embryonic development and regulates tissue homeostasis and repair of adult tissues as well as stem cell maintenance. The canonical Hh signaling activation is initiated by binding secreted hedgehog ligands to the 12-span-protein receptor Patched (Ptch). In vertebrates the Hh pathway localizes at the primary cilium, a slim microtubule-based organelle that protrudes from the cellular surface. In particular, Ptch receptor as well as its target, the seven-span-transmembrane receptor Smoothned (Smo), show dynamic trafficking in cilia depending on Shh ligand binding. Upon Hh binding, Ptch looses its inhibitory activity on Smo, which, in turn, moves into the cilium and transduces the Hh signaling downstream, triggering a cascade of events that culminates in the activation of the zinc finger transcription factors glioma-associated oncogene Gli.

Recent evidences indicate that Hh signaling is involved, through different mechanisms, in human malignancies where it promotes growth, enables proliferation of tumor stem cells and regulates tumor-stroma interaction. A ligand independent Shh pathway activation has been described in familial cancers, such as basal cell carcinoma, medulloblastoma and rhabdomyosarcoma, as a consequence of genetic aberrations, targeting mainly the Ptch inhibitory receptor. Ligand-independent non-canonical Shh pathway activation has been reported in several tumor models as a result of a crosstalk with different tumorigenic pathways. Finally, ligand-dependent autocrine or paracrine activation has also been described. Research articles, reviews and communications on every aspect of Hh signaling in cancer and other human diseases as well as on the role of Hh moleculs as diagnostic, prognostic and therapeutic targets are invited.

Dr. Maria Domenica Castellone
Guest Editor

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Keywords

hedgehog
Ptch
Smo
Gli
primary cilium
cancer
tumor-stroma
targeted therapy
oncogene
stem cells
embryonic development
tissue homeostasis

Published Papers (11 papers)

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Research

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12 pages, 2192 KiB

Open AccessArticle

Microparticles Carrying Sonic Hedgehog Are Increased in Humans with Peripheral Artery Disease

by Igor Giarretta, Ilaria Gatto, Margherita Marcantoni, Giulia Lupi, Diego Tonello, Eleonora Gaetani, Dario Pitocco, Roberto Iezzi, Addolorata Truma, Angelo Porfidia, Adriana Visonà, Paolo Tondi and Roberto Pola

Int. J. Mol. Sci. 2018, 19(12), 3954; https://doi.org/10.3390/ijms19123954 - 09 Dec 2018

Cited by 12 | Viewed by 2889

Abstract

Sonic hedgehog (Shh) is a prototypical angiogenic agent with a crucial role in the regulation of angiogenesis. Experimental studies have shown that Shh is upregulated in response to ischemia. Also, Shh may be found on the surface of circulating microparticles (MPs) and MPs bearing Shh (Shh + MPs) have shown the ability to contribute to reparative neovascularization after ischemic injury in mice. The goal of this study was to test the hypothesis that, in humans with peripheral artery disease (PAD), there is increased number of circulating Shh + MPs. This was done by assessing the number of Shh + MPs in plasma of patients with PAD and control subjects without PAD. We found significantly higher number of Shh + MPs in plasma of subjects with PAD, compared to controls, while the global number of MPs—produced either by endothelial cells, platelets, leukocytes, and erythrocytes—was not different between PAD patients and controls. We also found a significant association between the number of Shh + MPs and the number of collateral vessels in the ischemic limbs of PAD patients. Interestingly, the concentration of Shh protein unbound to MPs—which was measured in MP-depleted plasma—was not different between subjects with PAD and the controls, indicating that, in the setting of PAD, the call for Shh recapitulation does not lead to secretion of protein into the blood but to binding of the protein to the membrane of MPs. These findings provide novel information on Shh signaling during ischemia in humans, with potentially important biological and clinical implications. Full article

(This article belongs to the Special Issue Hedgehog Signaling)

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13 pages, 1868 KiB

Open AccessArticle

Widespread Expression of Hedgehog Pathway Components in a Large Panel of Human Tumor Cells and Inhibition of Tumor Growth by GANT61: Implications for Cancer Therapy

by Jiri Réda, Jiri Vachtenheim, Kateřina Vlčková, Pavel Horák, Jiri Vachtenheim, Jr. and Lubica Ondrušová

Int. J. Mol. Sci. 2018, 19(9), 2682; https://doi.org/10.3390/ijms19092682 - 10 Sep 2018

Cited by 9 | Viewed by 3602

Abstract

The sonic Hedgehog/GLI signaling pathway (HH) is critical for maintaining tissue polarity in development and contributes to tumor stemness. Transcription factors GLI1–3 are the downstream effectors of HH and activate oncogenic targets. To explore the completeness of the expression of HH components in tumor cells, we performed a screen for all HH proteins in a wide spectrum of 56 tumor cell lines of various origin using Western blot analysis. Generally, all HH proteins were expressed. Important factors GLI1 and GLI2 were always expressed, only exceptionally one of them was lowered, suggesting the functionality of HH in all tumors tested. We determined the effect of a GLI inhibitor GANT61 on proliferation in 16 chosen cell lines. More than half of tumor cells were sensitive to GANT61 to various extents. GANT61 killed the sensitive cells through apoptosis. The inhibition of reporter activity containing 12xGLI consensus sites by GANT61 and cyclopamine roughly correlated with cell proliferation influenced by GANT61. Our results recognize the sensitivity of tumor cell types to GANT61 in cell culture and support a critical role for GLI factors in tumor progression through restraining apoptosis. The use of GANT61 in combined targeted therapy of sensitive tumors, such as melanomas, seems to be immensely helpful. Full article

(This article belongs to the Special Issue Hedgehog Signaling)

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Review

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19 pages, 1158 KiB

Open AccessReview

The Hedgehog Signaling Pathway in Ischemic Tissues

by Igor Giarretta, Eleonora Gaetani, Margherita Bigossi, Paolo Tondi, Takayuki Asahara and Roberto Pola

Int. J. Mol. Sci. 2019, 20(21), 5270; https://doi.org/10.3390/ijms20215270 - 24 Oct 2019

Cited by 9 | Viewed by 2673

Abstract

Hedgehog (Hh) proteins are prototypical morphogens known to regulate epithelial/mesenchymal interactions during embryonic development. In addition to its pivotal role in embryogenesis, the Hh signaling pathway may be recapitulated in post-natal life in a number of physiological and pathological conditions, including ischemia. This review highlights the involvement of Hh signaling in ischemic tissue regeneration and angiogenesis, with particular attention to the heart, the brain, and the skeletal muscle. Updated information on the potential role of the Hh pathway as a therapeutic target in the ischemic condition is also presented. Full article

(This article belongs to the Special Issue Hedgehog Signaling)

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22 pages, 2538 KiB

Open AccessReview

Hedgehog Signaling Regulates Taste Organs and Oral Sensation: Distinctive Roles in the Epithelium, Stroma, and Innervation

by Charlotte M. Mistretta and Archana Kumari

Int. J. Mol. Sci. 2019, 20(6), 1341; https://doi.org/10.3390/ijms20061341 - 16 Mar 2019

Cited by 30 | Viewed by 5342

Abstract

The Hedgehog (Hh) pathway has regulatory roles in maintaining and restoring lingual taste organs, the papillae and taste buds, and taste sensation. Taste buds and taste nerve responses are eliminated if Hh signaling is genetically suppressed or pharmacologically inhibited, but regeneration can occur if signaling is reactivated within the lingual epithelium. Whereas Hh pathway disruption alters taste sensation, tactile and cold responses remain intact, indicating that Hh signaling is modality-specific in regulation of tongue sensation. However, although Hh regulation is essential in taste, the basic biology of pathway controls is not fully understood. With recent demonstrations that sonic hedgehog (Shh) is within both taste buds and the innervating ganglion neurons/nerve fibers, it is compelling to consider Hh signaling throughout the tongue and taste organ cell and tissue compartments. Distinctive signaling centers and niches are reviewed in taste papilla epithelium, taste buds, basal lamina, fibroblasts and lamellipodia, lingual nerves, and sensory ganglia. Several new roles for the innervation in lingual Hh signaling are proposed. Hh signaling within the lingual epithelium and an intact innervation each is necessary, but only together are sufficient to sustain and restore taste buds. Importantly, patients who use Hh pathway inhibiting drugs confront an altered chemosensory world with loss of taste buds and taste responses, intact lingual touch and cold sensation, and taste recovery after drug discontinuation. Full article

(This article belongs to the Special Issue Hedgehog Signaling)

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16 pages, 599 KiB

Open AccessReview

Targeting Smoothened as a New Frontier in the Functional Recovery of Central Nervous System Demyelinating Pathologies

by Alice Del Giovane and Antonella Ragnini-Wilson

Int. J. Mol. Sci. 2018, 19(11), 3677; https://doi.org/10.3390/ijms19113677 - 20 Nov 2018

Cited by 12 | Viewed by 4890

Abstract

Myelin sheaths on vertebrate axons provide protection, vital support and increase the speed of neuronal signals. Myelin degeneration can be caused by viral, autoimmune or genetic diseases. Remyelination is a natural process that restores the myelin sheath and, consequently, neuronal function after a demyelination event, preventing neurodegeneration and thereby neuron functional loss. Pharmacological approaches to remyelination represent a promising new frontier in the therapy of human demyelination pathologies and might provide novel tools to improve adaptive myelination in aged individuals. Recent phenotypical screens have identified agonists of the atypical G protein-coupled receptor Smoothened and inhibitors of the glioma-associated oncogene 1 as being amongst the most potent stimulators of oligodendrocyte precursor cell (OPC) differentiation in vitro and remyelination in the central nervous system (CNS) of mice. Here, we discuss the current state-of-the-art of studies on the role of Sonic Hedgehog reactivation during remyelination, referring readers to other reviews for the role of Hedgehog signaling in cancer and stem cell maintenance. Full article

(This article belongs to the Special Issue Hedgehog Signaling)

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14 pages, 1254 KiB

Open AccessReview

Sonic Hedgehog Signaling Pathway in Endothelial Progenitor Cell Biology for Vascular Medicine

by Amankeldi A. Salybekov, Ainur K. Salybekova, Roberto Pola and Takayuki Asahara

Int. J. Mol. Sci. 2018, 19(10), 3040; https://doi.org/10.3390/ijms19103040 - 05 Oct 2018

Cited by 17 | Viewed by 5412

Abstract

The Hedgehog (HH) signaling pathway plays an important role in embryonic and postnatal vascular development and in maintaining the homeostasis of organs. Under physiological conditions, Sonic Hedgehog (SHH), a secreted protein belonging to the HH family, regulates endothelial cell growth, promotes cell migration and stimulates the formation of new blood vessels. The present review highlights recent advances made in the field of SHH signaling in endothelial progenitor cells (EPCs). The canonical and non-canonical SHH signaling pathways in EPCs and endothelial cells (ECs) related to homeostasis, SHH signal transmission by extracellular vesicles (EVs) or exosomes containing single-strand non-coding miRNAs and impaired SHH signaling in cardiovascular diseases are discussed. As a promising therapeutic tool, the possibility of using the SHH signaling pathway for the activation of EPCs in patients suffering from cardiovascular diseases is further explored. Full article

(This article belongs to the Special Issue Hedgehog Signaling)

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17 pages, 841 KiB

Open AccessReview

Hedgehog Signaling in Lung Cancer: From Oncogenesis to Cancer Treatment Resistance

by Etienne Giroux-Leprieur, Adrien Costantini, Vivianne W. Ding and Biao He

Int. J. Mol. Sci. 2018, 19(9), 2835; https://doi.org/10.3390/ijms19092835 - 19 Sep 2018

Cited by 70 | Viewed by 6687

Abstract

Hedgehog signaling pathway is physiologically activated during embryogenesis, especially in lung development. It is also reactivated in many solid tumors. In lung cancer, Hedgehog pathway is closely associated with cancer stem cells (CSCs). Recent works have shown that CSCs produced a full-length Sonic Hedgehog (Shh) protein, with paracrine activity and induction of tumor development. Hedgehog pathway is also involved in tumor drug resistance in lung cancer, as cytotoxic chemotherapy, radiotherapy, and targeted therapies. This review proposes to describe the activation mechanisms of Hedgehog pathway in lung cancer, the clinical implications for overcoming drug resistance, and the perspectives for further research. Full article

(This article belongs to the Special Issue Hedgehog Signaling)

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37 pages, 1002 KiB

Open AccessReview

Role of GLI Transcription Factors in Pathogenesis and Their Potential as New Therapeutic Targets

by Maja Sabol, Diana Trnski, Vesna Musani, Petar Ozretić and Sonja Levanat

Int. J. Mol. Sci. 2018, 19(9), 2562; https://doi.org/10.3390/ijms19092562 - 29 Aug 2018

Cited by 48 | Viewed by 5998

Abstract

GLI transcription factors have important roles in intracellular signaling cascade, acting as the main mediators of the HH-GLI signaling pathway. This is one of the major developmental pathways, regulated both canonically and non-canonically. Deregulation of the pathway during development leads to a number of developmental malformations, depending on the deregulated pathway component. The HH-GLI pathway is mostly inactive in the adult organism but retains its function in stem cells. Aberrant activation in adult cells leads to carcinogenesis through overactivation of several tightly regulated cellular processes such as proliferation, angiogenesis, EMT. Targeting GLI transcription factors has recently become a major focus of potential therapeutic protocols. Full article

(This article belongs to the Special Issue Hedgehog Signaling)

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21 pages, 1364 KiB

Open AccessReview

Emerging Roles of Sonic Hedgehog in Adult Neurological Diseases: Neurogenesis and Beyond

by Shang-Der Chen, Jenq-Lin Yang, Wei-Chao Hwang and Ding-I Yang

Int. J. Mol. Sci. 2018, 19(8), 2423; https://doi.org/10.3390/ijms19082423 - 16 Aug 2018

Cited by 30 | Viewed by 7917

Abstract

Sonic hedgehog (Shh), a member of the hedgehog (Hh) family, was originally recognized as a morphogen possessing critical characters for neural development during embryogenesis. Recently, however, Shh has emerged as an important modulator in adult neural tissues through different mechanisms such as neurogenesis, anti-oxidation, anti-inflammation, and autophagy. Therefore, Shh may potentially have clinical application in neurodegenerative diseases and brain injuries. In this article, we present some examples, including ours, to show different aspects of Shh signaling and how Shh agonists or mimetics are used to alter the neuronal fates in various disease models, both in vitro and in vivo. Other potential mechanisms that are discussed include alteration of mitochondrial function and anti-aging effect; both are critical for age-related neurodegenerative diseases. A thorough understanding of the protective mechanisms elicited by Shh may provide a rationale to design innovative therapeutic regimens for various neurodegenerative diseases. Full article

(This article belongs to the Special Issue Hedgehog Signaling)

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22 pages, 719 KiB

Open AccessReview

Hedgehog Signaling Pathway and Autophagy in Cancer

by Xian Zeng and Dianwen Ju

Int. J. Mol. Sci. 2018, 19(8), 2279; https://doi.org/10.3390/ijms19082279 - 03 Aug 2018

Cited by 81 | Viewed by 10168

Abstract

Hedgehog (Hh) pathway controls complex developmental processes in vertebrates. Abnormal activation of Hh pathway is responsible for tumorigenesis and maintenance of multiple cancers, and thus addressing this represents promising therapeutic opportunities. In recent years, two Hh inhibitors have been approved for basal cell carcinoma (BCC) treatment and show extraordinary clinical outcomes. Meanwhile, a series of novel agents are being developed for the treatment of several cancers, including lung cancer, leukemia, and pancreatic cancer. Unfortunately, Hh inhibition fails to show satisfactory benefits in these cancer types compared with the success stories in BCC, highlighting the need for better understanding of Hh signaling in cancer. 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. Recent evidence demonstrated that Hh signaling interplays with autophagy in multiple cancers. Importantly, modulating this crosstalk exhibited noteworthy capability to sensitize primary and drug-resistant cancer cells to Hh inhibitors, representing an emerging opportunity to reboot the efficacy of Hh inhibition in those insensitive tumors, and to tackle drug resistance challenges. This review will highlight recent advances of Hh pathway and autophagy in cancers, and focus on their crosstalk and the implied therapeutic opportunities. Full article

(This article belongs to the Special Issue Hedgehog Signaling)

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15 pages, 1262 KiB

Open AccessReview

FGF Family: From Drug Development to Clinical Application

by Qi Hui, Zi Jin, Xiaokun Li, Changxiao Liu and Xiaojie Wang

Int. J. Mol. Sci. 2018, 19(7), 1875; https://doi.org/10.3390/ijms19071875 - 26 Jun 2018

Cited by 112 | Viewed by 11136

Abstract

Fibroblast growth factor (FGF) belongs to a large family of growth factors. FGFs use paracrine or endocrine signaling to mediate a myriad of biological and pathophysiological process, including angiogenesis, wound healing, embryonic development, and metabolism regulation. FGF drugs for the treatment of burn and ulcer wounds are now available. The recent discovery of the crucial roles of the endocrine-acting FGF19 subfamily in maintaining homeostasis of bile acid, glucose, and phosphate further extended the activity profile of this family. Here, the applications of recombinant FGFs for the treatment of wounds, diabetes, hypophosphatemia, the development of FGF receptor inhibitors as anti-neoplastic drugs, and the achievements of basic research and applications of FGFs in China are reviewed. Full article

(This article belongs to the Special Issue Hedgehog Signaling)

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