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Cancers
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Hedgehog Signaling in Cancer
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Hedgehog Signaling in Cancer

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (30 June 2019) | Viewed by 25077

Special Issue Editors

Dr. Francisco Vega

E-Mail Website
Guest Editor
Department of Hematopathology, Unit 72, MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA
Interests: lymphomas; diffuse large cell lymphoma; chemoresistance in lymphomas; hedgehog signaling; smoothened
Dr. Ralf Landgraf

E-Mail Website
Guest Editor
Cancer Biology Graduate Program, University of Miami, Miller School of Medicine, Box 016129 (R-629) Miami, Florida, USA
Interests: receptor signaling in cancer; breast cancer; protein kinases; membrane micro environment; molecular interactions; smoothened

Special Issue Information

Dear Colleagues,

The hedgehog (Hh) signaling pathway is a highly regulated pathway that is important, not only for embryonic development, tissue patterning, and organogenesis, but also for tissue repair and the maintenance of stem cells in adult tissues. Emerging data demonstrate abnormal activation of the Hh signaling components in multiple cancers providing proliferative and survival roles, contributing to maintenance of the cancer stem cell compartment and enhancing tolerance or resistance to chemotherapeutic agents.

The key signal transmission component of Hh signaling is the seven-transmembrane-spanning protein Smoothened (SMO). There is growing evidence supporting that SMO does not act as a mere signal transducer for Hh but may also serve to enhance the activation of several membrane based signaling with importance in cancer biology. SMO signaling is best studied in cilia, a highly specialized surface organelle with a role in developmental signaling. However, loss of cilia assembly has minor phenotypes compared to the loss of SMO signaling components. More importantly, cilia are absent in most cancer cells and still SMO is highly expressed and functional.

In this Special Issue, we would like to focus in these novel potential non-canonical functions of SMO that seems to be relevant in cancer pathobiology. We expect to recollect novel information in the field, that will help us to improve the understanding of this interesting molecule and its cellular role in cancer.

Prof. Dr. Francisco Vega
Dr. Ralf Landgraf
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 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. Cancers 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 2900 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

  • Smoothened
  • non-canonical hedgehog
  • lymphomas
  • cancer
  • chemoresistance
  • cholesterol
  • patched

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Published Papers (3 papers)

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Research

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23 pages, 3158 KiB  
Article
Mesenchymal Cells Support the Oncogenicity and Therapeutic Response of the Hedgehog Pathway in Triple-Negative Breast Cancer
by Ana M. Reyes-Ramos, Karla P. Ramos-Cruz, Nelson J. Rodríguez-Merced, Michelle M. Martínez-Montemayor, Nelson D. Franqui-Ríos, Jan P. Ríos-Grant, Andrea Flores, Gerónimo Maldonado-Martínez, Wandaliz Torres-García and Maribella Domenech
Cancers 2019, 11(10), 1522; https://doi.org/10.3390/cancers11101522 - 10 Oct 2019
Cited by 10 | Viewed by 3981
Abstract
The paracrine interaction between tumor cells and adjacent stroma has been associated with the oncogenic activity of the Hedgehog (Hh) pathway in triple-negative breast tumors. The present study developed a model of paracrine Hh signaling and examined the impact of mesenchymal cell sources [...] Read more.
The paracrine interaction between tumor cells and adjacent stroma has been associated with the oncogenic activity of the Hedgehog (Hh) pathway in triple-negative breast tumors. The present study developed a model of paracrine Hh signaling and examined the impact of mesenchymal cell sources and culture modalities in the oncogenicity of the Hh pathway in breast tumor cells. Studies consisted of tumor cell monocultures and co-cultures with cancer-associated and normal fibroblasts, tumor cells that undergo epithelial–mesenchymal transition (EMT), or adipose-derived mesenchymal stem cells (ADMSCs). Hh ligand and pathway inhibitors, GANT61 and NVP-LDE225 (NVP), were evaluated in both cell cultures and a mouse xenograft model. Results in monocultures show that tumor cell viability and Hh transcriptional activity were not affected by Hh inhibitors. In co-cultures, down-regulation of GLI1, SMO, and PTCH1 in the stroma correlated with reduced tumor growth rates in xenografted tumors and cell cultures, confirming a paracrine interaction. Fibroblasts and EMT cells supported Hh transcriptional activity and enhanced tumor cell growth. Mixed and adjacent culture modalities indicate that tumor growth is supported via fibroblast-secreted soluble factors, whereas enriched tumor stemness requires close proximity between tumor and fibroblasts. Overall this study provides a tumor–mesenchymal model of Hh signaling and highlights the therapeutic value of mesenchymal cells in the oncogenic activity of the Hh pathway. Full article
(This article belongs to the Special Issue Hedgehog Signaling in Cancer)
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17 pages, 2568 KiB  
Article
A Smo/Gli Multitarget Hedgehog Pathway Inhibitor Impairs Tumor Growth
by Ludovica Lospinoso Severini, Deborah Quaglio, Irene Basili, Francesca Ghirga, Francesca Bufalieri, Miriam Caimano, Silvia Balducci, Marta Moretti, Isabella Romeo, Elena Loricchio, Marella Maroder, Bruno Botta, Mattia Mori, Paola Infante and Lucia Di Marcotullio
Cancers 2019, 11(10), 1518; https://doi.org/10.3390/cancers11101518 - 9 Oct 2019
Cited by 40 | Viewed by 4693
Abstract
Pharmacological Hedgehog (Hh) pathway inhibition has emerged as a valuable anticancer strategy. A number of small molecules able to block the pathway at the upstream receptor Smoothened (Smo) or the downstream effector glioma-associated oncogene 1 (Gli1) has been designed and developed. In a [...] Read more.
Pharmacological Hedgehog (Hh) pathway inhibition has emerged as a valuable anticancer strategy. A number of small molecules able to block the pathway at the upstream receptor Smoothened (Smo) or the downstream effector glioma-associated oncogene 1 (Gli1) has been designed and developed. In a recent study, we exploited the high versatility of the natural isoflavone scaffold for targeting the Hh signaling pathway at multiple levels showing that the simultaneous targeting of Smo and Gli1 provided synergistic Hh pathway inhibition stronger than single administration. This approach seems to effectively overcome the drug resistance, particularly at the level of Smo. Here, we combined the pharmacophores targeting Smo and Gli1 into a single and individual isoflavone, compound 22, which inhibits the Hh pathway at both upstream and downstream level. We demonstrate that this multitarget agent suppresses medulloblastoma growth in vitro and in vivo through antagonism of Smo and Gli1, which is a novel mechanism of action in Hh inhibition. Full article
(This article belongs to the Special Issue Hedgehog Signaling in Cancer)
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Review

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13 pages, 917 KiB  
Review
The Hedgehog Signaling Pathway: A Viable Target in Breast Cancer?
by Priyanka Bhateja, Mathew Cherian, Sarmila Majumder and Bhuvaneswari Ramaswamy
Cancers 2019, 11(8), 1126; https://doi.org/10.3390/cancers11081126 - 7 Aug 2019
Cited by 97 | Viewed by 15608
Abstract
The hedgehog (Hh) pathway plays a key role in embryonic development and stem cell programs. 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 [...] Read more.
The hedgehog (Hh) pathway plays a key role in embryonic development and stem cell programs. 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. The Hh pathway is implicated in other malignancies including hormone receptor (HR+) positive and triple negative breast cancer (TNBC). Hh signaling, which is activated in human mammary stem cells, results in activation of glioma-associated oncogene (GLI) transcription factors. High GLI1 expression correlates with worse outcomes in breast cancer. Non-canonical GLI1 activation is one mechanism by which estrogen exposure promotes breast cancer stem cell proliferation and epithelial–mesenchymal transition. Tamoxifen resistant cell lines show aberrant activation of Hh signaling, and knockdown of Hh pathway inhibited growth of tamoxifen resistant cells. As in other cancers Hh signaling is activated by the PI3K/AKT pathway in these endocrine resistant cell lines. Hh pathway activation has also been reported to mediate chemotherapy resistance in TNBC via various mechanisms including paracrine signaling to tumor micro-environment and selective proliferation of cancer stem cells. Co-activation of Hh and Wnt signaling pathways is a poor prognostic marker in TNBC. Early phase clinical trials are evaluating the combination of smoothened (SMO) inhibitors and chemotherapy in TNBC. In addition to SMO inhibitors like vismodegib and sonidegib, which are in clinical use for basal cell carcinoma, GLI1 inhibitors like GANT58 and GANT61 are in preclinical drug development and might be an effective mechanism to overcome drug resistance in breast cancer. Gene signatures predictive of Hh pathway activation could enrich for patients likely to respond to these agents. Full article
(This article belongs to the Special Issue Hedgehog Signaling in Cancer)
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