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Hedgehog Signaling in Organogenesis and Tumor Microenvironment

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

Deadline for manuscript submissions: closed (31 October 2019) | Viewed by 52361

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Special Issue Editor

Division of Reconstructive Surgery for Oral and Maxillofacial Region, Department of Human Biology and Pathophysiology, School of Dentistry, Health Sciences University of Hokkaido, 1757 Ishikari-Tobetsu, Hokkaido 061-0293, Japan
Interests: cancer biology; cell proliferation; signal transduction; cell differentiation; cell adhesion
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Special Issue Information

Dear Colleaues,

Hedgehog signaling pathways govern complex developmental processes, including stem-cell maintenance, proliferation, differentiation, and patterning. However, hedgehog signaling is frequently activated in various human cancers. Several recent studies have shown that the aberrant activation of hedgehog signaling is associated with neoplastic transformation, cancer cell proliferation, metastasis, drug resistance of multiple cancers, and survival rate.

This Special Issue focuses on several aspects of hedgehog signaling in organogenesis and tumor microenvironment, and we invite contributions of reviews and/or original papers reporting on the recent efforts in the field of hedgehog signaling.

Prof. Dr. Tsuyoshi Shimo
Guest Editor

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Keywords

  • hedgehog
  • stem cell
  • target genes
  • primary cilia
  • organogenesis
  • microenvironment
  • immune surveillance
  • hedgehog signaling pathway
  • metastasis
  • angiogenesis
  • tumor-stroma interaction
  • hedgehog signaling inhibitors
  • targeted cancer therapy
  • cancer treatment resistance

Published Papers (10 papers)

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Editorial

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2 pages, 148 KiB  
Editorial
Hedgehog Signaling in Organogenesis and the Tumor Microenvironment
by Tsuyoshi Shimo
Int. J. Mol. Sci. 2020, 21(8), 2788; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21082788 - 17 Apr 2020
Cited by 1 | Viewed by 1529
Abstract
The Hedgehog signaling pathway was first discovered in 1980 during a large-scale genetic screening seeking to find mutations that affect larval body segment development in the fruit fly, Drosophila melanogaster [...] Full article
(This article belongs to the Special Issue Hedgehog Signaling in Organogenesis and Tumor Microenvironment)

Research

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14 pages, 2967 KiB  
Article
Discrete Hedgehog Factor Expression and Action in the Developing Phallus
by Gerard A. Tarulli, Andrew J. Pask and Marilyn B. Renfree
Int. J. Mol. Sci. 2020, 21(4), 1237; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21041237 - 12 Feb 2020
Cited by 5 | Viewed by 2543
Abstract
Hypospadias is a failure of urethral closure within the penis occurring in 1 in 125 boys at birth and is increasing in frequency. While paracrine hedgehog signalling is implicated in the process of urethral closure, how these factors act on a tissue level [...] Read more.
Hypospadias is a failure of urethral closure within the penis occurring in 1 in 125 boys at birth and is increasing in frequency. While paracrine hedgehog signalling is implicated in the process of urethral closure, how these factors act on a tissue level to execute closure itself is unknown. This study aimed to understand the role of different hedgehog signalling members in urethral closure. The tammar wallaby (Macropus eugenii) provides a unique system to understand urethral closure as it allows direct treatment of developing offspring because mothers give birth to young before urethral closure begins. Wallaby pouch young were treated with vehicle or oestradiol (known to induce hypospadias in males) and samples subjected to RNAseq for differential expression and gene ontology analyses. Localisation of Sonic Hedgehog (SHH) and Indian Hedgehog (IHH), as well as the transcription factor SOX9, were assessed in normal phallus tissue using immunofluorescence. Normal tissue culture explants were treated with SHH or IHH and analysed for AR, ESR1, PTCH1, GLI2, SOX9, IHH and SHH expression by qPCR. Gene ontology analysis showed enrichment for bone differentiation terms in male samples compared with either female samples or males treated with oestradiol. Expression of SHH and IHH localised to specific tissue areas during development, akin to their compartmentalised expression in developing bone. Treatment of phallus explants with SHH or IHH induced factor-specific expression of genes associated with bone differentiation. This reveals a potential developmental interaction involved in urethral closure that mimics bone differentiation and incorporates discrete hedgehog activity within the developing phallus and phallic urethra. Full article
(This article belongs to the Special Issue Hedgehog Signaling in Organogenesis and Tumor Microenvironment)
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11 pages, 4100 KiB  
Communication
Sonic Hedgehog Regulates Bone Fracture Healing
by Hiroaki Takebe, Nazmus Shalehin, Akihiro Hosoya, Tsuyoshi Shimo and Kazuharu Irie
Int. J. Mol. Sci. 2020, 21(2), 677; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21020677 - 20 Jan 2020
Cited by 24 | Viewed by 3665
Abstract
Bone fracture healing involves the combination of intramembranous and endochondral ossification. It is known that Indian hedgehog (Ihh) promotes chondrogenesis during fracture healing. Meanwhile, Sonic hedgehog (Shh), which is involved in ontogeny, has been reported to be involved in fracture healing, but the [...] Read more.
Bone fracture healing involves the combination of intramembranous and endochondral ossification. It is known that Indian hedgehog (Ihh) promotes chondrogenesis during fracture healing. Meanwhile, Sonic hedgehog (Shh), which is involved in ontogeny, has been reported to be involved in fracture healing, but the details had not been clarified. In this study, we demonstrated that Shh participated in fracture healing. Six-week-old Sprague–Dawley rats and Gli-CreERT2; tdTomato mice were used in this study. The right rib bones of experimental animals were fractured. The localization of Shh and Gli1 during fracture healing was examined. The localization of Gli1 progeny cells and osterix (Osx)-positive cells was similar during fracture healing. Runt-related transcription factor 2 (Runx2) and Osx, both of which are osteoblast markers, were observed on the surface of the new bone matrix and chondrocytes on day seven after fracture. Shh and Gli1 were co-localized with Runx2 and Osx. These findings suggest that Shh is involved in intramembranous and endochondral ossification during fracture healing. Full article
(This article belongs to the Special Issue Hedgehog Signaling in Organogenesis and Tumor Microenvironment)
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17 pages, 10597 KiB  
Article
The Role of Sonic Hedgehog Signaling in the Tumor Microenvironment of Oral Squamous Cell Carcinoma
by Kiyofumi Takabatake, Tsuyoshi Shimo, Jun Murakami, Chang Anqi, Hotaka Kawai, Saori Yoshida, May Wathone Oo, Omori Haruka, Shintaro Sukegawa, Hidetsugu Tsujigiwa, Keisuke Nakano and Hitoshi Nagatsuka
Int. J. Mol. Sci. 2019, 20(22), 5779; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20225779 - 17 Nov 2019
Cited by 23 | Viewed by 4041
Abstract
Sonic hedgehog (SHH) and its signaling have been identified in several human cancers, and increased levels of SHH expression appear to correlate with cancer progression. However, the role of SHH in the tumor microenvironment (TME) of oral squamous cell carcinoma (OSCC) is still [...] Read more.
Sonic hedgehog (SHH) and its signaling have been identified in several human cancers, and increased levels of SHH expression appear to correlate with cancer progression. However, the role of SHH in the tumor microenvironment (TME) of oral squamous cell carcinoma (OSCC) is still unclear. No studies have compared the expression of SHH in different subtypes of OSCC and focused on the relationship between the tumor parenchyma and stroma. In this study, we analyzed SHH and expression of its receptor, Patched-1 (PTCH), in the TME of different subtypes of OSCC. Fifteen endophytic-type cases (ED type) and 15 exophytic-type cases (EX type) of OSCC were used. H&E staining, immunohistochemistry (IHC), double IHC, and double-fluorescent IHC were performed on these samples. ED-type parenchyma more strongly expressed both SHH and PTCH than EX-type parenchyma. In OSCC stroma, CD31-positive cancer blood vessels, CD68- and CD11b-positive macrophages, and α-smooth muscle actin-positive cancer-associated fibroblasts partially expressed PTCH. On the other hand, in EX-type stroma, almost no double-positive cells were observed. These results suggest that autocrine effects of SHH induce cancer invasion, and paracrine effects of SHH govern parenchyma-stromal interactions of OSCC. The role of the SHH pathway is to promote growth and invasion. Full article
(This article belongs to the Special Issue Hedgehog Signaling in Organogenesis and Tumor Microenvironment)
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27 pages, 6828 KiB  
Article
Sonic Hedgehog Signaling Is Required for Cyp26 Expression during Embryonic Development
by Maha El Shahawy, Claes-Göran Reibring, Kristina Hallberg, Cynthia L. Neben, Pauline Marangoni, Brian D. Harfe, Ophir D. Klein, Anders Linde and Amel Gritli-Linde
Int. J. Mol. Sci. 2019, 20(9), 2275; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20092275 - 08 May 2019
Cited by 10 | Viewed by 4570
Abstract
Deciphering how signaling pathways interact during development is necessary for understanding the etiopathogenesis of congenital malformations and disease. In several embryonic structures, components of the Hedgehog and retinoic acid pathways, two potent players in development and disease are expressed and operate in the [...] Read more.
Deciphering how signaling pathways interact during development is necessary for understanding the etiopathogenesis of congenital malformations and disease. In several embryonic structures, components of the Hedgehog and retinoic acid pathways, two potent players in development and disease are expressed and operate in the same or adjacent tissues and cells. Yet whether and, if so, how these pathways interact during organogenesis is, to a large extent, unclear. Using genetic and experimental approaches in the mouse, we show that during development of ontogenetically different organs, including the tail, genital tubercle, and secondary palate, Sonic hedgehog (SHH) loss-of-function causes anomalies phenocopying those induced by enhanced retinoic acid signaling and that SHH is required to prevent supraphysiological activation of retinoic signaling through maintenance and reinforcement of expression of the Cyp26 genes. Furthermore, in other tissues and organs, disruptions of the Hedgehog or the retinoic acid pathways during development generate similar phenotypes. These findings reveal that rigidly calibrated Hedgehog and retinoic acid activities are required for normal organogenesis and tissue patterning. Full article
(This article belongs to the Special Issue Hedgehog Signaling in Organogenesis and Tumor Microenvironment)
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Review

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12 pages, 2962 KiB  
Review
Sonic Hedgehog Signaling and Tooth Development
by Akihiro Hosoya, Nazmus Shalehin, Hiroaki Takebe, Tsuyoshi Shimo and Kazuharu Irie
Int. J. Mol. Sci. 2020, 21(5), 1587; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21051587 - 26 Feb 2020
Cited by 54 | Viewed by 8983
Abstract
Sonic hedgehog (Shh) is a secreted protein with important roles in mammalian embryogenesis. During tooth development, Shh is primarily expressed in the dental epithelium, from initiation to the root formation stages. A number of studies have analyzed the function of Shh signaling at [...] Read more.
Sonic hedgehog (Shh) is a secreted protein with important roles in mammalian embryogenesis. During tooth development, Shh is primarily expressed in the dental epithelium, from initiation to the root formation stages. A number of studies have analyzed the function of Shh signaling at different stages of tooth development and have revealed that Shh signaling regulates the formation of various tooth components, including enamel, dentin, cementum, and other soft tissues. In addition, dental mesenchymal cells positive for Gli1, a downstream transcription factor of Shh signaling, have been found to have stem cell properties, including multipotency and the ability to self-renew. Indeed, Gli1-positive cells in mature teeth appear to contribute to the regeneration of dental pulp and periodontal tissues. In this review, we provide an overview of recent advances related to the role of Shh signaling in tooth development, as well as the contribution of this pathway to tooth homeostasis and regeneration. Full article
(This article belongs to the Special Issue Hedgehog Signaling in Organogenesis and Tumor Microenvironment)
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20 pages, 362 KiB  
Review
Sonic Hedgehog Signaling in Organogenesis, Tumors, and Tumor Microenvironments
by Kuo-Shyang Jeng, Chiung-Fang Chang and Shu-Sheng Lin
Int. J. Mol. Sci. 2020, 21(3), 758; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21030758 - 23 Jan 2020
Cited by 115 | Viewed by 10901
Abstract
During mammalian embryonic development, primary cilia transduce and regulate several signaling pathways. Among the various pathways, Sonic hedgehog (SHH) is one of the most significant. SHH signaling remains quiescent in adult mammalian tissues. However, in multiple adult tissues, it becomes active during differentiation, [...] Read more.
During mammalian embryonic development, primary cilia transduce and regulate several signaling pathways. Among the various pathways, Sonic hedgehog (SHH) is one of the most significant. SHH signaling remains quiescent in adult mammalian tissues. However, in multiple adult tissues, it becomes active during differentiation, proliferation, and maintenance. Moreover, aberrant activation of SHH signaling occurs in cancers of the skin, brain, liver, gallbladder, pancreas, stomach, colon, breast, lung, prostate, and hematological malignancies. Recent studies have shown that the tumor microenvironment or stroma could affect tumor development and metastasis. One hypothesis has been proposed, claiming that the pancreatic epithelia secretes SHH that is essential in establishing and regulating the pancreatic tumor microenvironment in promoting cancer progression. The SHH signaling pathway is also activated in the cancer stem cells (CSC) of several neoplasms. The self-renewal of CSC is regulated by the SHH/Smoothened receptor (SMO)/Glioma-associated oncogene homolog I (GLI) signaling pathway. Combined use of SHH signaling inhibitors and chemotherapy/radiation therapy/immunotherapy is therefore key in targeting CSCs. Full article
(This article belongs to the Special Issue Hedgehog Signaling in Organogenesis and Tumor Microenvironment)
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18 pages, 547 KiB  
Review
Hedgehog Signaling for Urogenital Organogenesis and Prostate Cancer: An Implication for the Epithelial–Mesenchyme Interaction (EMI)
by Taiju Hyuga, Mellissa Alcantara, Daiki Kajioka, Ryuma Haraguchi, Kentaro Suzuki, Shinichi Miyagawa, Yoshiyuki Kojima, Yutaro Hayashi and Gen Yamada
Int. J. Mol. Sci. 2020, 21(1), 58; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21010058 - 20 Dec 2019
Cited by 14 | Viewed by 3465
Abstract
Hedgehog (Hh) signaling is an essential growth factor signaling pathway especially in the regulation of epithelial–mesenchymal interactions (EMI) during the development of the urogenital organs such as the bladder and the external genitalia (EXG). The Hh ligands are often expressed in the epithelia, [...] Read more.
Hedgehog (Hh) signaling is an essential growth factor signaling pathway especially in the regulation of epithelial–mesenchymal interactions (EMI) during the development of the urogenital organs such as the bladder and the external genitalia (EXG). The Hh ligands are often expressed in the epithelia, affecting the surrounding mesenchyme, and thus constituting a form of paracrine signaling. The development of the urogenital organ, therefore, provides an intriguing opportunity to study EMI and its relationship with other pathways, such as hormonal signaling. Cellular interactions of prostate cancer (PCa) with its neighboring tissue is also noteworthy. The local microenvironment, including the bone metastatic site, can release cellular signals which can affect the malignant tumors, and vice versa. Thus, it is necessary to compare possible similarities and divergences in Hh signaling functions and its interaction with other local growth factors, such as BMP (bone morphogenetic protein) between organogenesis and tumorigenesis. Additionally, this review will discuss two pertinent research aspects of Hh signaling: (1) the potential signaling crosstalk between Hh and androgen signaling; and (2) the effect of signaling between the epithelia and the mesenchyme on the status of the basement membrane with extracellular matrix structures located on the epithelial–mesenchymal interface. Full article
(This article belongs to the Special Issue Hedgehog Signaling in Organogenesis and Tumor Microenvironment)
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17 pages, 7588 KiB  
Review
The Roles of Indian Hedgehog Signaling in TMJ Formation
by Till E. Bechtold, Naito Kurio, Hyun-Duck Nah, Cheri Saunders, Paul C. Billings and Eiki Koyama
Int. J. Mol. Sci. 2019, 20(24), 6300; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20246300 - 13 Dec 2019
Cited by 21 | Viewed by 5283
Abstract
The temporomandibular joint (TMJ) is an intricate structure composed of the mandibular condyle, articular disc, and glenoid fossa in the temporal bone. Apical condylar cartilage is classified as a secondary cartilage, is fibrocartilaginous in nature, and is structurally distinct from growth plate and [...] Read more.
The temporomandibular joint (TMJ) is an intricate structure composed of the mandibular condyle, articular disc, and glenoid fossa in the temporal bone. Apical condylar cartilage is classified as a secondary cartilage, is fibrocartilaginous in nature, and is structurally distinct from growth plate and articular cartilage in long bones. Condylar cartilage is organized in distinct cellular layers that include a superficial layer that produces lubricants, a polymorphic/progenitor layer that contains stem/progenitor cells, and underlying layers of flattened and hypertrophic chondrocytes. Uniquely, progenitor cells reside near the articular surface, proliferate, undergo chondrogenesis, and mature into hypertrophic chondrocytes. During the past decades, there has been a growing interest in the molecular mechanisms by which the TMJ develops and acquires its unique structural and functional features. Indian hedgehog (Ihh), which regulates skeletal development including synovial joint formation, also plays pivotal roles in TMJ development and postnatal maintenance. This review provides a description of the many important recent advances in Hedgehog (Hh) signaling in TMJ biology. These include studies that used conventional approaches and those that analyzed the phenotype of tissue-specific mouse mutants lacking Ihh or associated molecules. The recent advances in understanding the molecular mechanism regulating TMJ development are impressive and these findings will have major implications for future translational medicine tools to repair and regenerate TMJ congenital anomalies and acquired diseases, such as degenerative damage in TMJ osteoarthritic conditions. Full article
(This article belongs to the Special Issue Hedgehog Signaling in Organogenesis and Tumor Microenvironment)
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20 pages, 1263 KiB  
Review
Recent Insights into Long Bone Development: Central Role of Hedgehog Signaling Pathway in Regulating Growth Plate
by Ryuma Haraguchi, Riko Kitazawa, Yukihiro Kohara, Aoi Ikedo, Yuuki Imai and Sohei Kitazawa
Int. J. Mol. Sci. 2019, 20(23), 5840; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20235840 - 20 Nov 2019
Cited by 26 | Viewed by 6754
Abstract
The longitudinal growth of long bone, regulated by an epiphyseal cartilaginous component known as the “growth plate”, is generated by epiphyseal chondrocytes. The growth plate provides a continuous supply of chondrocytes for endochondral ossification, a sequential bone replacement of cartilaginous tissue, and any [...] Read more.
The longitudinal growth of long bone, regulated by an epiphyseal cartilaginous component known as the “growth plate”, is generated by epiphyseal chondrocytes. The growth plate provides a continuous supply of chondrocytes for endochondral ossification, a sequential bone replacement of cartilaginous tissue, and any failure in this process causes a wide range of skeletal disorders. Therefore, the cellular and molecular characteristics of the growth plate are of interest to many researchers. Hedgehog (Hh), well known as a mitogen and morphogen during development, is one of the best known regulatory signals in the developmental regulation of the growth plate. Numerous animal studies have revealed that signaling through the Hh pathway plays multiple roles in regulating the proliferation, differentiation, and maintenance of growth plate chondrocytes throughout the skeletal growth period. Furthermore, over the past few years, a growing body of evidence has emerged demonstrating that a limited number of growth plate chondrocytes transdifferentiate directly into the full osteogenic and multiple mesenchymal lineages during postnatal bone development and reside in the bone marrow until late adulthood. Current studies with the genetic fate mapping approach have shown that the commitment of growth plate chondrocytes into the skeletal lineage occurs under the influence of epiphyseal chondrocyte-derived Hh signals during endochondral bone formation. Here, we discuss the valuable observations on the role of the Hh signaling pathway in the growth plate based on mouse genetic studies, with some emphasis on recent advances. Full article
(This article belongs to the Special Issue Hedgehog Signaling in Organogenesis and Tumor Microenvironment)
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