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Cells
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Hedgehog Signaling in Development and Cancer 2021
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Hedgehog Signaling in Development and Cancer 2021

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: closed (30 June 2021) | Viewed by 15995

Special Issue Editor

Dr. Xiaoyan Zheng

E-Mail Website
Guest Editor
Department of Anatomy and Cell Biology, The George Washington (GW) Cancer Center, George Washington University School of Medicine and Health Sciences, Washington, DC 20052-20037, USA
Interests: cell signaling; development; cell culture; Drosophila
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The canonical Hh signaling pathway involves binding a secreted molecule (Hedgehog, Hh) to a 12-span-protein receptor (Patched, Ptch). In the absence of the Hh ligands, the Ptch receptor inhibits a seven-span-transmembrane receptor (Smoothened, Smo), while upon ligand binding, Ptch releases Smo from its inhibition, triggering a cascade of signaling, culminating in the activation of a family of zinc-finger transcription factors glioma-associated oncogene (Gli).

The primary cilium plays a central role in the transduction of Hh signals in vertebrates. Hh pathway components continuously traffic through the cilium. In Hh’s absence, the Ptch receptor localizes to the primary cilium, inhibiting Smo activation and preventing Smo accumulation to the cilia. When Hh binds to Ptch, Ptch activity is blocked, leading to the accumulation of Smo in the cilium and activation of downstream signaling pathways.

The Hedgehog pathway represents a key regulator of embryonic development, tissue homeostasis, tissue repair, and stem cell maintenance. Dysregulation of the Hh signaling pathway is associated with developmental anomalies and various cancer types. Mutations leading to cell-autonomous activation of the Hedgehog pathway in primary tumor cells drive tumor growth in a ligand-independent way in familial cancers such as basal cell carcinoma (BCC), medulloblastoma (MB), and rhabdomyosarcoma (RM). In contrast, several recent studies have shown a surprisingly general effect of stromal Hh response in restraining cancer growth and progression, most notably in the bladder, pancreatic, colon, prostate, and lung cancers. 

This Special Issue offers an Open Access forum that aims to bring together a collection of original research articles, reviews, and communications on the function of Hh signaling in development, human cancers, and diseases, as well as on the role of Hh signaling molecules as diagnostic, prognostic, and therapeutic targets.

Dr. Xiaoyan Zheng
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Hedgehog signaling
  • development
  • primary cilium
  • tumor–stroma interaction
  • cancer-promoting effects
  • cancer-restraining effects
  • target therapy

Related Special Issue

Published Papers (4 papers)

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Research

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12 pages, 1570 KiB  
Article
Wnt Inhibitory Factor 1 Binds to and Inhibits the Activity of Sonic Hedgehog
by Krisztina Kerekes, Mária Trexler, László Bányai and László Patthy
Cells 2021, 10(12), 3496; https://doi.org/10.3390/cells10123496 - 10 Dec 2021
Cited by 7 | Viewed by 2481
Abstract
The hedgehog (Hh) and Wnt pathways, crucial for the embryonic development and stem cell proliferation of Metazoa, have long been known to have similarities that argue for their common evolutionary origin. A surprising additional similarity of the two pathways came with the discovery [...] Read more.
The hedgehog (Hh) and Wnt pathways, crucial for the embryonic development and stem cell proliferation of Metazoa, have long been known to have similarities that argue for their common evolutionary origin. A surprising additional similarity of the two pathways came with the discovery that WIF1 proteins are involved in the regulation of both the Wnt and Hh pathways. Originally, WIF1 (Wnt Inhibitory Factor 1) was identified as a Wnt antagonist of vertebrates, but subsequent studies have shown that in Drosophila, the WIF1 ortholog serves primarily to control the distribution of Hh. In the present, work we have characterized the interaction of the human WIF1 protein with human sonic hedgehog (Shh) using Surface Plasmon Resonance spectroscopy and reporter assays monitoring the signaling activity of human Shh. Our studies have shown that human WIF1 protein binds human Shh with high affinity and inhibits its signaling activity efficiently. Our observation that the human WIF1 protein is a potent antagonist of human Shh suggests that the known tumor suppressor activity of WIF1 may not be ascribed only to its role as a Wnt inhibitor. Full article
(This article belongs to the Special Issue Hedgehog Signaling in Development and Cancer 2021)
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Review

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15 pages, 1179 KiB  
Review
Hedgehog Pathway Inhibitors against Tumor Microenvironment
by Silpa Gampala and Jer-Yen Yang
Cells 2021, 10(11), 3135; https://doi.org/10.3390/cells10113135 - 12 Nov 2021
Cited by 19 | Viewed by 4609
Abstract
Targeting the hedgehog (HH) pathway to treat aggressive cancers of the brain, breast, pancreas, and prostate has been ongoing for decades. Gli gene amplifications have been long discovered within malignant glioma patients, and since then, inhibitors against HH pathway-associated molecules have successfully reached [...] Read more.
Targeting the hedgehog (HH) pathway to treat aggressive cancers of the brain, breast, pancreas, and prostate has been ongoing for decades. Gli gene amplifications have been long discovered within malignant glioma patients, and since then, inhibitors against HH pathway-associated molecules have successfully reached the clinical stage where several of them have been approved by the FDA. Albeit this success rate implies suitable progress, clinically used HH pathway inhibitors fail to treat patients with metastatic or recurrent disease. This is mainly due to heterogeneous tumor cells that have acquired resistance to the inhibitors along with the obstacle of effectively targeting the tumor microenvironment (TME). Severe side effects such as hyponatremia, diarrhea, fatigue, amenorrhea, nausea, hair loss, abnormal taste, and weight loss have also been reported. Furthermore, HH signaling is known to be involved in the regulation of immune cell maturation, angiogenesis, inflammation, and polarization of macrophages and myeloid-derived suppressor cells. It is critical to determine key mechanisms that can be targeted at different levels of tumor development and progression to address various clinical issues. Hence current research focus encompasses understanding how HH controls TME to develop TME altering and combinatorial targeting strategies. In this review, we aim to discuss the pros and cons of targeting HH signaling molecules, understand the mechanism involved in treatment resistance, reveal the role of the HH pathway in anti-tumor immune response, and explore the development of potential combination treatment of immune checkpoint inhibitors with HH pathway inhibitors to target HH-driven cancers. Full article
(This article belongs to the Special Issue Hedgehog Signaling in Development and Cancer 2021)
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11 pages, 1039 KiB  
Review
Mechanisms of Smoothened Regulation in Hedgehog Signaling
by Jie Zhang, Zulong Liu and Jianhang Jia
Cells 2021, 10(8), 2138; https://doi.org/10.3390/cells10082138 - 20 Aug 2021
Cited by 17 | Viewed by 5260
Abstract
The seven-transmembrane protein, Smoothened (SMO), has shown to be critical for the hedgehog (HH) signal transduction on the cell membrane (and the cilium in vertebrates). SMO is subjected to multiple types of post-translational regulations, including phosphorylation, ubiquitination, and sumoylation, which alter SMO intracellular [...] Read more.
The seven-transmembrane protein, Smoothened (SMO), has shown to be critical for the hedgehog (HH) signal transduction on the cell membrane (and the cilium in vertebrates). SMO is subjected to multiple types of post-translational regulations, including phosphorylation, ubiquitination, and sumoylation, which alter SMO intracellular trafficking and cell surface accumulation. Recently, SMO is also shown to be regulated by small molecules, such as oxysterol, cholesterol, and phospholipid. The activity of SMO must be very well balanced by these different mechanisms in vivo because the malfunction of SMO will not only cause developmental defects in early stages, but also induce cancers in late stages. Here, we discuss the activation and inactivation of SMO by different mechanisms to better understand how SMO is regulated by the graded HH signaling activity that eventually governs distinct development outcomes. Full article
(This article belongs to the Special Issue Hedgehog Signaling in Development and Cancer 2021)
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10 pages, 1207 KiB  
Review
The Role of the Hedgehog Pathway in Chemoresistance of Gastrointestinal Cancers
by Yabing Liang, Ling Yang and Jingwu Xie
Cells 2021, 10(8), 2030; https://doi.org/10.3390/cells10082030 - 09 Aug 2021
Cited by 17 | Viewed by 2798
Abstract
The hedgehog pathway, which plays a significant role in embryonic development and stem cell regulation, is activated in gastrointestinal cancers. Chemotherapy is widely used in cancer treatment. However, chemoresistance becomes a substantial obstacle in cancer therapy. This review focuses on the recent advances [...] Read more.
The hedgehog pathway, which plays a significant role in embryonic development and stem cell regulation, is activated in gastrointestinal cancers. Chemotherapy is widely used in cancer treatment. However, chemoresistance becomes a substantial obstacle in cancer therapy. This review focuses on the recent advances in the hedgehog pathway’s roles in drug resistance of gastrointestinal cancers and the novel drugs and strategies targeting hedgehog signaling. Full article
(This article belongs to the Special Issue Hedgehog Signaling in Development and Cancer 2021)
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