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Hedgehog Signaling Pathway in Cancer: Smoothened and GLI Take Center...
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Hedgehog Signaling Pathway in Cancer: Smoothened and GLI Take Center Stage

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

Deadline for manuscript submissions: closed (30 June 2015) | Viewed by 128283

Special Issue Editor

Prof. Dr. Hui-Wen Lo

E-Mail Website
Guest Editor
Department of Cancer Biology, Wake Forest University School of Medicine, 4.4056 Hanes Building, Medical Center Blvd., Winston-Salem, NC 27157, USA
Interests: tumor growth; angiogenesis; metastasis; cancer cell signaling; mechanisms for drug resistance

Special Issue Information

Dear Colleagues,

The sonic hedgehog (Shh) pathway plays an important role in mediating normal development, oncogenesis, tumor progression, stem cell biology, and tumor-stroma interactions. Consequently, the Shh pathway is an attractive target for anti-cancer therapy. Although drugs targeting this pathway have produced promising clinical results for basal cell carcinoma (BCC), and despite the fact that some of these drugs are being approved by the FDA for treating BCC patients, hedgehog pathway-targeted therapy has demonstrated limited clinical efficacy against most cancer types. This disappointing outcome highlights the notion that the Shh pathway is highly complex and interactive with other signaling molecules in cells. Consequently, a deeper understanding of the pathway will help lay the foundation for improving the efficacy of Shh inhibitors and for developing novel strategies to circumvent this important pathway. Among the many players within the Shh pathway, the smoothened (SMO) and glioma-associated oncogene homologs (GLI) serve as key positive regulators. Somatic mutations can be detected in SMO and several components of the pathway, including in patched-1 (PTCH) and SUFU (suppressor of fused). In addition to genomic abnormalities, post-translational modifications regulate GLI1 and many components of this important pathway. GLI1 can be regulated by hedgehog ligand-independent, non-canonical pathways. Recently, GLI1 has been recently shown to undergo alternative splicing to yield truncated GLI1 (tGLI1), which behaves as a gain-of-function GLI1, thus promoting tumor invasiveness and angiogenesis. In light of these recent advances, this Special Issue will focus on describing the current landscape of the Shh signaling pathway in a variety of human cancers and on providing an overview of Shh-targeted therapy (with respect to its clinical efficacy and challenges).

Dr. Hui-Wen Lo
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. 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

  • hedgehog signaling
  • smoothened
  • GLI
  • PTCH
  • SUFU
  • oncogenesis
  • stem cells
  • targeted therapy
  • tumor drug resistance
  • tumor-stroma interactions

Published Papers (14 papers)

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503 KiB  
Article
The Hedgehog Inhibitor Cyclopamine Reduces β-Catenin-Tcf Transcriptional Activity, Induces E-Cadherin Expression, and Reduces Invasion in Colorectal Cancer Cells
by David Qualtrough, Phil Rees, Beverley Speight, Ann C. Williams and Christos Paraskeva
Cancers 2015, 7(3), 1885-1899; https://doi.org/10.3390/cancers7030867 - 17 Sep 2015
Cited by 23 | Viewed by 5227
Abstract
Colorectal cancer is a major global health problem resulting in over 600,000 deaths world-wide every year with the majority of these due to metastatic disease. Wnt signalling, and more specifically β-catenin-related transcription, has been shown to drive both tumorigenesis and the metastatic process [...] Read more.
Colorectal cancer is a major global health problem resulting in over 600,000 deaths world-wide every year with the majority of these due to metastatic disease. Wnt signalling, and more specifically β-catenin-related transcription, has been shown to drive both tumorigenesis and the metastatic process in colorectal neoplasia, yet its complex interactions with other key signalling pathways, such as hedgehog, remain to be elucidated. We have previously shown that the Hedgehog (HH) signalling pathway is active in cells from colorectal tumours, and that inhibition of the pathway with cyclopamine induces apoptosis. We now show that cyclopamine treatment reduces β-catenin related transcription in colorectal cancer cell lines, and that this effect can be reversed by addition of Sonic Hedgehog protein. We also show that cyclopamine concomitantly induces expression of the tumour suppressor and prognostic indicator E-cadherin. Consistent with a role for HH in regulating the invasive potential we show that cyclopamine reduces the expression of transcription factors (Slug, Snail and Twist) associated with the epithelial-mesenchymal transition and reduces the invasiveness of colorectal cancer cells in vitro. Taken together, Cancers 2015, 7 1886 these data show that pharmacological inhibition of the hedgehog pathway has therapeutic potential in the treatment of colorectal cancer. Full article
(This article belongs to the Special Issue Hedgehog Signaling Pathway in Cancer: Smoothened and GLI Take Center Stage)
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Review

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647 KiB  
Review
Targeting the Sonic Hedgehog Signaling Pathway: Review of Smoothened and GLI Inhibitors
by Tadas K. Rimkus, Richard L. Carpenter, Shadi Qasem, Michael Chan and Hui-Wen Lo
Cancers 2016, 8(2), 22; https://doi.org/10.3390/cancers8020022 - 15 Feb 2016
Cited by 457 | Viewed by 41443
Abstract
The sonic hedgehog (Shh) signaling pathway is a major regulator of cell differentiation, cell proliferation, and tissue polarity. Aberrant activation of the Shh pathway has been shown in a variety of human cancers, including, basal cell carcinoma, malignant gliomas, medulloblastoma, leukemias, and cancers [...] Read more.
The sonic hedgehog (Shh) signaling pathway is a major regulator of cell differentiation, cell proliferation, and tissue polarity. Aberrant activation of the Shh pathway has been shown in a variety of human cancers, including, basal cell carcinoma, malignant gliomas, medulloblastoma, leukemias, and cancers of the breast, lung, pancreas, and prostate. Tumorigenesis, tumor progression and therapeutic response have all been shown to be impacted by the Shh signaling pathway. Downstream effectors of the Shh pathway include smoothened (SMO) and glioma-associated oncogene homolog (GLI) family of zinc finger transcription factors. Both are regarded as important targets for cancer therapeutics. While most efforts have been devoted towards pharmacologically targeting SMO, developing GLI-targeted approach has its merit because of the fact that GLI proteins can be activated by both Shh ligand-dependent and -independent mechanisms. To date, two SMO inhibitors (LDE225/Sonidegib and GDC-0449/Vismodegib) have received FDA approval for treating basal cell carcinoma while many clinical trials are being conducted to evaluate the efficacy of this exciting class of targeted therapy in a variety of cancers. In this review, we provide an overview of the biology of the Shh pathway and then detail the current landscape of the Shh-SMO-GLI pathway inhibitors including those in preclinical studies and clinical trials. Full article
(This article belongs to the Special Issue Hedgehog Signaling Pathway in Cancer: Smoothened and GLI Take Center Stage)
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993 KiB  
Review
Aberrant GLI1 Activation in DNA Damage Response, Carcinogenesis and Chemoresistance
by Komaraiah Palle, Chinnadurai Mani, Kaushlendra Tripathi and Mohammad Athar
Cancers 2015, 7(4), 2330-2351; https://doi.org/10.3390/cancers7040894 - 27 Nov 2015
Cited by 66 | Viewed by 7503
Abstract
The canonical hedgehog (HH) pathway is a multicomponent signaling cascade (HH, protein patched homolog 1 (PTCH1), smoothened (SMO)) that plays a pivotal role during embryonic development through activation of downstream effector molecules, namely glioma-associated oncogene homolog 1 (GLI1), GLI2 and GLI3. Activation of [...] Read more.
The canonical hedgehog (HH) pathway is a multicomponent signaling cascade (HH, protein patched homolog 1 (PTCH1), smoothened (SMO)) that plays a pivotal role during embryonic development through activation of downstream effector molecules, namely glioma-associated oncogene homolog 1 (GLI1), GLI2 and GLI3. Activation of GLIs must be tightly regulated as they modulate target genes which control tissue patterning, stem cell maintenance, and differentiation during development. However, dysregulation or mutations in HH signaling leads to genomic instability (GI) and various cancers, for example, germline mutation in PTCH1 lead to Gorlin syndrome, a condition where patients develop numerous basal cell carcinomas and rarely rhabdomyosarcoma (RMS). Activating mutations in SMO have also been recognized in sporadic cases of medulloblastoma and SMO is overexpressed in many other cancers. Recently, studies in several human cancers have shown that GLI1 expression is independent from HH ligand and canonical intracellular signaling through PTCH and SMO. In fact, this aberrantly regulated GLI1 has been linked to several non-canonical oncogenic growth signals such as Kirsten rat sarcoma viral oncogene homolog (KRAS), avian myelocytomatosis virus oncogene cellular homolog (C-MYC), transforming growth factor β (TGFβ), wingless-type MMTV integration site family (WNT) and β-catenin. Recent studies from our lab and other independent studies demonstrate that aberrantly expressed GLI1 influences the integrity of several DNA damage response and repair signals, and if altered, these networks can contribute to GI and impact tumor response to chemo- and radiation therapies. Furthermore, the ineffectiveness of SMO inhibitors in clinical studies argues for the development of GLI1-specific inhibitors in order to develop effective therapeutic modalities to treat these tumors. In this review, we focus on summarizing current understanding of the molecular, biochemical and cellular basis for aberrant GLI1 expression and discuss GLI1-mediated HH signaling on DNA damage responses, carcinogenesis and chemoresistance. Full article
(This article belongs to the Special Issue Hedgehog Signaling Pathway in Cancer: Smoothened and GLI Take Center Stage)
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557 KiB  
Review
Targeting the Hedgehog Pathway in Pediatric Medulloblastoma
by Sherri Y. Huang and Jer-Yen Yang
Cancers 2015, 7(4), 2110-2123; https://doi.org/10.3390/cancers7040880 - 23 Oct 2015
Cited by 37 | Viewed by 5460
Abstract
Medulloblastoma (MB), a primitive neuroectomal tumor of the cerebellum, is the most common malignant pediatric brain tumor. The cause of MB is largely unknown, but aberrant activation of Hedgehog (Hh) pathway is responsible for ~30% of MB. Despite aggressive treatment with surgical resection, [...] Read more.
Medulloblastoma (MB), a primitive neuroectomal tumor of the cerebellum, is the most common malignant pediatric brain tumor. The cause of MB is largely unknown, but aberrant activation of Hedgehog (Hh) pathway is responsible for ~30% of MB. Despite aggressive treatment with surgical resection, radiation and chemotherapy, 70%–80% of pediatric medulloblastoma cases can be controlled, but most treated patients suffer devastating side effects. Therefore, developing a new effective treatment strategy is urgently needed. Hh signaling controls transcription of target genes by regulating activities of the three Glioma-associated oncogene (Gli1-3) transcription factors. In this review, we will focus on current clinical treatment options of MB and discuss mechanisms of drug resistance. In addition, we will describe current known molecular pathways which crosstalk with the Hedgehog pathway both in the context of medulloblastoma and non-medulloblastoma cancer development. Finally, we will introduce post-translational modifications that modulate Gli1 activity and summarize the positive and negative regulations of the Hh/Gli1 pathway. Towards developing novel combination therapies for medulloblastoma treatment, current information on interacting pathways and direct regulation of Hh signaling should prove critical Full article
(This article belongs to the Special Issue Hedgehog Signaling Pathway in Cancer: Smoothened and GLI Take Center Stage)
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1181 KiB  
Review
Hedgehog Cholesterolysis: Specialized Gatekeeper to Oncogenic Signaling
by Brian P. Callahan and Chunyu Wang
Cancers 2015, 7(4), 2037-2053; https://doi.org/10.3390/cancers7040875 - 14 Oct 2015
Cited by 16 | Viewed by 5367
Abstract
Discussions of therapeutic suppression of hedgehog (Hh) signaling almost exclusively focus on receptor antagonism; however, hedgehog’s biosynthesis represents a unique and potentially targetable aspect of this oncogenic signaling pathway. Here, we review a key biosynthetic step called cholesterolysis from the perspectives of structure/function [...] Read more.
Discussions of therapeutic suppression of hedgehog (Hh) signaling almost exclusively focus on receptor antagonism; however, hedgehog’s biosynthesis represents a unique and potentially targetable aspect of this oncogenic signaling pathway. Here, we review a key biosynthetic step called cholesterolysis from the perspectives of structure/function and small molecule inhibition. Cholesterolysis, also called cholesteroylation, generates cholesterol-modified Hh ligand via autoprocessing of a hedgehog precursor protein. Post-translational modification by cholesterol appears to be restricted to proteins in the hedgehog family. The transformation is essential for Hh biological activity and upstream of signaling events. Despite its decisive role in generating ligand, cholesterolysis remains conspicuously unexplored as a therapeutic target. Full article
(This article belongs to the Special Issue Hedgehog Signaling Pathway in Cancer: Smoothened and GLI Take Center Stage)
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575 KiB  
Review
The Hedgehog Signalling Pathway in Cell Migration and Guidance: What We Have Learned from Drosophila melanogaster
by Sofia J. Araújo
Cancers 2015, 7(4), 2012-2022; https://doi.org/10.3390/cancers7040873 - 02 Oct 2015
Cited by 10 | Viewed by 5142
Abstract
Cell migration and guidance are complex processes required for morphogenesis, the formation of tumor metastases, and the progression of human cancer. During migration, guidance molecules induce cell directionality and movement through complex intracellular mechanisms. Expression of these molecules has to be tightly regulated [...] Read more.
Cell migration and guidance are complex processes required for morphogenesis, the formation of tumor metastases, and the progression of human cancer. During migration, guidance molecules induce cell directionality and movement through complex intracellular mechanisms. Expression of these molecules has to be tightly regulated and their signals properly interpreted by the receiving cells so as to ensure correct navigation. This molecular control is fundamental for both normal morphogenesis and human disease. The Hedgehog (Hh) signaling pathway is evolutionarily conserved and known to be crucial for normal cellular growth and differentiation throughout the animal kingdom. The relevance of Hh signaling for human disease is emphasized by its activation in many cancers. Here, I review the current knowledge regarding the involvement of the Hh pathway in cell migration and guidance during Drosophila development and discuss its implications for human cancer origin and progression. Full article
(This article belongs to the Special Issue Hedgehog Signaling Pathway in Cancer: Smoothened and GLI Take Center Stage)
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579 KiB  
Review
Clinical Implications of Hedgehog Pathway Signaling in Prostate Cancer
by Daniel L. Suzman and Emmanuel S. Antonarakis
Cancers 2015, 7(4), 1983-1993; https://doi.org/10.3390/cancers7040871 - 29 Sep 2015
Cited by 30 | Viewed by 6086
Abstract
Activity in the Hedgehog pathway, which regulates GLI-mediated transcription, is important in organogenesis and stem cell regulation in self-renewing organs, but is pathologically elevated in many human malignancies. Mutations leading to constitutive activation of the pathway have been implicated in medulloblastoma and basal [...] Read more.
Activity in the Hedgehog pathway, which regulates GLI-mediated transcription, is important in organogenesis and stem cell regulation in self-renewing organs, but is pathologically elevated in many human malignancies. Mutations leading to constitutive activation of the pathway have been implicated in medulloblastoma and basal cell carcinoma, and inhibition of the pathway has demonstrated clinical responses leading to the approval of the Smoothened inhibitor, vismodegib, for the treatment of advanced basal cell carcinoma. Aberrant Hedgehog pathway signaling has also been noted in prostate cancer with evidence suggesting that it may render prostate epithelial cells tumorigenic, drive the epithelial-to-mesenchymal transition, and contribute towards the development of castration-resistance through autocrine and paracrine signaling within the tumor microenvironment and cross-talk with the androgen pathway. In addition, there are emerging clinical data suggesting that inhibition of the Hedgehog pathway may be effective in the treatment of recurrent and metastatic prostate cancer. Here we will review these data and highlight areas of active clinical research as they relate to Hedgehog pathway inhibition in prostate cancer. Full article
(This article belongs to the Special Issue Hedgehog Signaling Pathway in Cancer: Smoothened and GLI Take Center Stage)
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1236 KiB  
Review
The Potential Role of Hedgehog Signaling in the Luminal/Basal Phenotype of Breast Epithelia and in Breast Cancer Invasion and Metastasis
by Arwa Flemban and David Qualtrough
Cancers 2015, 7(3), 1863-1884; https://doi.org/10.3390/cancers7030866 - 16 Sep 2015
Cited by 32 | Viewed by 9383
Abstract
The epithelium of the lactiferous ducts in the breast is comprised of luminal epithelial cells and underlying basal myoepithelial cells. The regulation of cell fate and transit of cells between these two cell types remains poorly understood. This relationship becomes of greater importance [...] Read more.
The epithelium of the lactiferous ducts in the breast is comprised of luminal epithelial cells and underlying basal myoepithelial cells. The regulation of cell fate and transit of cells between these two cell types remains poorly understood. This relationship becomes of greater importance when studying the subtypes of epithelial breast carcinoma, which are categorized according to their expression of luminal or basal markers. The epithelial mesenchymal transition (EMT) is a pivotal event in tumor invasion. It is important to understand mechanisms that regulate this process, which bears relation to the normal dynamic of epithelial/basal phenotype regulation in the mammary gland. Understanding this process could provide answers for the regulation of EMT in breast cancer, and thereby identify potential targets for therapy. Evidence points towards a role for hedgehog signaling in breast tissue homeostasis and also in mammary neoplasia. This review examines our current understanding of role of the hedgehog-signaling (Hh) pathway in breast epithelial cells both during breast development and homeostasis and to assess the potential misappropriation of Hh signals in breast neoplasia, cancer stem cells and tumor metastasis via EMT. Full article
(This article belongs to the Special Issue Hedgehog Signaling Pathway in Cancer: Smoothened and GLI Take Center Stage)
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388 KiB  
Review
Non-Canonical Hh Signaling in Cancer—Current Understanding and Future Directions
by Dongsheng Gu and Jingwu Xie
Cancers 2015, 7(3), 1684-1698; https://doi.org/10.3390/cancers7030857 - 27 Aug 2015
Cited by 51 | Viewed by 5557
Abstract
As a major regulatory pathway for embryonic development and tissue patterning, hedgehog signaling is not active in most adult tissues, but is reactivated in a number of human cancer types. A major milestone in hedgehog signaling in cancer is the Food and Drug [...] Read more.
As a major regulatory pathway for embryonic development and tissue patterning, hedgehog signaling is not active in most adult tissues, but is reactivated in a number of human cancer types. A major milestone in hedgehog signaling in cancer is the Food and Drug Administration (FDA) approval of a smoothened inhibitor Vismodegib for treatment of basal cell carcinomas. Vismodegib can block ligand-mediated hedgehog signaling, but numerous additional clinical trials have failed to show significant improvements in cancer patients. Amounting evidence indicate that ligand-independent hedgehog signaling plays an essential role in cancer. Ligand-independent hedgehog signaling, also named non-canonical hedgehog signaling, generally is not sensitive to smoothened inhibitors. What we know about non-canonical hedgehog signaling in cancer, and how should we prevent its activation? In this review, we will summarize recent development of non-canonical hedgehog signaling in cancer, and will discuss potential ways to prevent this type of hedgehog signaling. Full article
(This article belongs to the Special Issue Hedgehog Signaling Pathway in Cancer: Smoothened and GLI Take Center Stage)
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869 KiB  
Review
The Role of Hedgehog Signaling in Tumor Induced Bone Disease
by Shellese A. Cannonier and Julie A. Sterling
Cancers 2015, 7(3), 1658-1683; https://doi.org/10.3390/cancers7030856 - 26 Aug 2015
Cited by 19 | Viewed by 7829
Abstract
Despite significant progress in cancer treatments, tumor induced bone disease continues to cause significant morbidities. While tumors show distinct mutations and clinical characteristics, they behave similarly once they establish in bone. Tumors can metastasize to bone from distant sites (breast, prostate, lung), directly [...] Read more.
Despite significant progress in cancer treatments, tumor induced bone disease continues to cause significant morbidities. While tumors show distinct mutations and clinical characteristics, they behave similarly once they establish in bone. Tumors can metastasize to bone from distant sites (breast, prostate, lung), directly invade into bone (head and neck) or originate from the bone (melanoma, chondrosarcoma) where they cause pain, fractures, hypercalcemia, and ultimately, poor prognoses and outcomes. Tumors in bone secrete factors (interleukins and parathyroid hormone-related protein) that induce RANKL expression from osteoblasts, causing an increase in osteoclast mediated bone resorption. While the mechanisms involved varies slightly between tumor types, many tumors display an increase in Hedgehog signaling components that lead to increased tumor growth, therapy failure, and metastasis. The work of multiple laboratories has detailed Hh signaling in several tumor types and revealed that tumor establishment in bone can be controlled by both canonical and non-canonical Hh signaling in a cell type specific manner. This review will explore the role of Hh signaling in the modulation of tumor induced bone disease, and will shed insight into possible therapeutic interventions for blocking Hh signaling in these tumors. Full article
(This article belongs to the Special Issue Hedgehog Signaling Pathway in Cancer: Smoothened and GLI Take Center Stage)
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1109 KiB  
Review
Hedgehog Signaling in the Maintenance of Cancer Stem Cells
by Catherine R. Cochrane, Anette Szczepny, D. Neil Watkins and Jason E. Cain
Cancers 2015, 7(3), 1554-1585; https://doi.org/10.3390/cancers7030851 - 11 Aug 2015
Cited by 188 | Viewed by 8281
Abstract
Cancer stem cells (CSCs) represent a rare population of cells with the capacity to self-renew and give rise to heterogeneous cell lineages within a tumour. Whilst the mechanisms underlying the regulation of CSCs are poorly defined, key developmental signaling pathways required for normal [...] Read more.
Cancer stem cells (CSCs) represent a rare population of cells with the capacity to self-renew and give rise to heterogeneous cell lineages within a tumour. Whilst the mechanisms underlying the regulation of CSCs are poorly defined, key developmental signaling pathways required for normal stem and progenitor functions have been strongly implicated. Hedgehog (Hh) signaling is an evolutionarily-conserved pathway essential for self-renewal and cell fate determination. Aberrant Hh signaling is associated with the development and progression of various types of cancer and is implicated in multiple aspects of tumourigenesis, including the maintenance of CSCs. Here, we discuss the mounting evidence suggestive of Hh-driven CSCs in the context of haematological malignancies and solid tumours and the novel strategies that hold the potential to block many aspects of the transformation attributed to the CSC phenotype, including chemotherapeutic resistance, relapse and metastasis. Full article
(This article belongs to the Special Issue Hedgehog Signaling Pathway in Cancer: Smoothened and GLI Take Center Stage)
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482 KiB  
Review
Not so Fast: Co-Requirements for Sonic Hedgehog Induced Brain Tumorigenesis
by Stacey A. Ward and Joshua B. Rubin
Cancers 2015, 7(3), 1484-1498; https://doi.org/10.3390/cancers7030848 - 06 Aug 2015
Cited by 3 | Viewed by 5242
Abstract
The Sonic hedgehog (Shh) pathway plays an integral role in cellular proliferation during normal brain development and also drives growth in a variety of cancers including brain cancer. Clinical trials of Shh pathway inhibitors for brain tumors have yielded disappointing results, indicating a [...] Read more.
The Sonic hedgehog (Shh) pathway plays an integral role in cellular proliferation during normal brain development and also drives growth in a variety of cancers including brain cancer. Clinical trials of Shh pathway inhibitors for brain tumors have yielded disappointing results, indicating a more nuanced role for Shh signaling. We postulate that Shh signaling does not work alone but requires co-activation of other signaling pathways for tumorigenesis and stem cell maintenance. This review will focus on the interplay between the Shh pathway and these pathways to promote tumor growth in brain tumors, presenting opportunities for the study of combinatorial therapies. Full article
(This article belongs to the Special Issue Hedgehog Signaling Pathway in Cancer: Smoothened and GLI Take Center Stage)
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655 KiB  
Review
The Impact of Hedgehog Signaling Pathway on DNA Repair Mechanisms in Human Cancer
by Erhong Meng, Ann Hanna, Rajeev S. Samant and Lalita A. Shevde
Cancers 2015, 7(3), 1333-1348; https://doi.org/10.3390/cancers7030839 - 21 Jul 2015
Cited by 27 | Viewed by 6822
Abstract
Defined cellular mechanisms have evolved that recognize and repair DNA to protect the integrity of its structure and sequence when encountering assaults from endogenous and exogenous sources. There are five major DNA repair pathways: mismatch repair, nucleotide excision repair, direct repair, base excision [...] Read more.
Defined cellular mechanisms have evolved that recognize and repair DNA to protect the integrity of its structure and sequence when encountering assaults from endogenous and exogenous sources. There are five major DNA repair pathways: mismatch repair, nucleotide excision repair, direct repair, base excision repair and DNA double strand break repair (including non-homologous end joining and homologous recombination repair). Aberrant activation of the Hedgehog (Hh) signaling pathway is a feature of many cancer types. The Hh pathway has been documented to be indispensable for epithelial-mesenchymal transition, invasion and metastasis, cancer stemness, and chemoresistance. The functional transcription activators of the Hh pathway include the GLI proteins. Inhibition of the activity of GLI can interfere with almost all DNA repair types in human cancer, indicating that Hh/GLI functions may play an important role in enabling tumor cells to survive lethal types of DNA damage induced by chemotherapy and radiotherapy. Thus, Hh signaling presents an important therapeutic target to overcome DNA repair-enabled multi-drug resistance and consequently increase chemotherapeutic response in the treatment of cancer. Full article
(This article belongs to the Special Issue Hedgehog Signaling Pathway in Cancer: Smoothened and GLI Take Center Stage)
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381 KiB  
Review
Hedgehog Signaling Inhibitors as Anti-Cancer Agents in Osteosarcoma
by Ram Mohan Ram Kumar and Bruno Fuchs
Cancers 2015, 7(2), 784-794; https://doi.org/10.3390/cancers7020784 - 13 May 2015
Cited by 36 | Viewed by 6961
Abstract
Osteosarcoma is a rare type of cancer associated with a poor clinical outcome. Even though the pathologic characteristics of OS are well established, much remains to be understood, particularly at the molecular signaling level. The molecular mechanisms of osteosarcoma progression and metastases have [...] Read more.
Osteosarcoma is a rare type of cancer associated with a poor clinical outcome. Even though the pathologic characteristics of OS are well established, much remains to be understood, particularly at the molecular signaling level. The molecular mechanisms of osteosarcoma progression and metastases have not yet been fully elucidated and several evolutionary signaling pathways have been found to be linked with osteosarcoma pathogenesis, especially the hedgehog signaling (Hh) pathway. The present review will outline the importance and targeting the hedgehog signaling (Hh) pathway in osteosarcoma tumor biology. Available data also suggest that aberrant Hh signaling has pro-migratory effects and leads to the development of osteoblastic osteosarcoma. Activation of Hh signaling has been observed in osteosarcoma cell lines and also in primary human osteosarcoma specimens. Emerging data suggests that interference with Hh signal transduction by inhibitors may reduce osteosarcoma cell proliferation and tumor growth thereby preventing osteosarcomagenesis. From this perspective, we outline the current state of Hh pathway inhibitors in osteosarcoma. In summary, targeting Hh signaling by inhibitors promise to increase the efficacy of osteosarcoma treatment and improve patient outcome. Full article
(This article belongs to the Special Issue Hedgehog Signaling Pathway in Cancer: Smoothened and GLI Take Center Stage)
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