Special Issue "TGF-Beta Signaling in Cancer"

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

Deadline for manuscript submissions: closed (30 April 2018)

Special Issue Editor

Guest Editor
Prof. Dr. Hendrik Ungefroren

First Department of Medicine, University Hospital Schleswig-Holstein (UKSH), Campus Lübeck
Department of General and Thoracic Surgery, University Hospital Schleswig-Holstein (UKSH), Campus Kiel
Website | E-Mail
Interests: pancreatic and breast cancers; tumor microenvironment; growth factor control of cell migration, invasion and metastasis; TGF-beta signaling and signaling crosstalk with small G proteins and G protein-coupled receptors

Special Issue Information

Dear Colleagues,

Transforming growth factor (TGF)-β plays pivotal roles in the control of different cellular processes, including proliferation, cell death, differentiation, and migration during both embryonic development and adulthood. Not surprisingly, dysregulation of its expression and/or altered activation of its intracellular signaling pathways contributes to human diseases, such as tissue fibrosis and cancer. During tumorigenesis, TGF-β may have anticancer activity at early stages, which is mainly due to its strong antiproliferative effect; however, strong evidence suggests that mutational inactivation of the canonical Smad pathway with concurrent overactivation of non-canonical Smad and non-Smad pathways could at later stages contribute to tumor progression by favoring immune suppression, cell invasion, and metastasis. Authors are invited to submit manuscripts that show how these pathways interact (crosstalk) with each other in tumor cells as compared to untransformed cells. The data may provide useful information on how to better and more selectively target TGF-β signaling for inhibition in various types of human cancer with the goal to enhance survival rates of cancer patients.

In this Special Issue, we aim to shed light on the state-of-the-art, as well as novel data, that contribute to increasing our knowledge on the role of TGF-β signaling in the development and progression of human cancer. We welcome experts in the field to contribute research papers and critical reviews on the various facets of TGF-β signaling that either suppress or promote cancer development, as well as on how natural and pharmacological pathway inhibitors for TGF-β signaling may be exploited as tools in anti-cancer therapies.

Prof. Dr. Hendrik Ungefroren
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 papers will be 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 monthly 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 1000 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

  • cancer
  • TGF-beta
  • signaling crosstalk
  • Smad signaling
  • non-Smad signaling
  • TGF-beta receptors
  • TGF-beta signaling inhibitors
  • TGF-beta paradox
  • altered/mutated signaling pathways

Published Papers (7 papers)

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Research

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Open AccessFeature PaperArticle CRISPR-Mediated Reactivation of DKK3 Expression Attenuates TGF-β Signaling in Prostate Cancer
Cancers 2018, 10(6), 165; https://doi.org/10.3390/cancers10060165
Received: 9 May 2018 / Revised: 23 May 2018 / Accepted: 24 May 2018 / Published: 28 May 2018
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Abstract
The DKK3 gene encodes a secreted protein, Dkk-3, that inhibits prostate tumor growth and metastasis. DKK3 is downregulated by promoter methylation in many types of cancer, including prostate cancer. Gene silencing studies have shown that Dkk-3 maintains normal prostate epithelial cell homeostasis by
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The DKK3 gene encodes a secreted protein, Dkk-3, that inhibits prostate tumor growth and metastasis. DKK3 is downregulated by promoter methylation in many types of cancer, including prostate cancer. Gene silencing studies have shown that Dkk-3 maintains normal prostate epithelial cell homeostasis by limiting TGF-β/Smad signaling. While ectopic expression of Dkk-3 leads to prostate cancer cell apoptosis, it is unclear if Dkk-3 has a physiological role in cancer cells. Here, we show that treatment of PC3 prostate cancer cells with the DNA methyltransferase (DNMT) inhibitor decitabine demethylates the DKK3 promoter, induces DKK3 expression, and inhibits TGF-β/Smad-dependent transcriptional activity. Direct induction of DKK3 expression using CRISPR-dCas9-VPR also inhibited TGF-β/Smad-dependent transcription and attenuated PC3 cell migration and proliferation. These effects were not observed in C4-2B cells, which do not respond to TGF-β. TGF-β signals can regulate gene expression directly via SMAD proteins and indirectly by increasing DNMT expression, leading to promoter methylation. Analysis of genes downregulated by promoter methylation and predicted to be regulated by TGF-β found that DKK3 induction increased expression of PTGS2, which encodes cyclooxygenase-2. Together, these observations provide support for using CRISPR-mediated induction of DKK3 as a potential therapeutic approach for prostate cancer and highlight complexities in Dkk-3 regulation of TGF-β signaling. Full article
(This article belongs to the Special Issue TGF-Beta Signaling in Cancer)
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Review

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Open AccessReview The SUMO System and TGFβ Signaling Interplay in Regulation of Epithelial-Mesenchymal Transition: Implications for Cancer Progression
Cancers 2018, 10(8), 264; https://doi.org/10.3390/cancers10080264
Received: 9 July 2018 / Revised: 6 August 2018 / Accepted: 6 August 2018 / Published: 8 August 2018
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Abstract
Protein post-translational modification by the small ubiquitin-like modifier (SUMO), or SUMOylation, can regulate the stability, subcellular localization or interactome of a protein substrate with key consequences for cellular processes including the Epithelial-Mesenchymal Transition (EMT). The secreted protein Transforming Growth Factor beta (TGFβ) is
[...] Read more.
Protein post-translational modification by the small ubiquitin-like modifier (SUMO), or SUMOylation, can regulate the stability, subcellular localization or interactome of a protein substrate with key consequences for cellular processes including the Epithelial-Mesenchymal Transition (EMT). The secreted protein Transforming Growth Factor beta (TGFβ) is a potent inducer of EMT in development and homeostasis. Importantly, the ability of TGFβ to induce EMT has been implicated in promoting cancer invasion and metastasis, resistance to chemo/radio therapy, and maintenance of cancer stem cells. Interestingly, TGFβ-induced EMT and the SUMO system intersect with important implications for cancer formation and progression, and novel therapeutics identification. Full article
(This article belongs to the Special Issue TGF-Beta Signaling in Cancer)
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Open AccessReview TGF-β Sustains Tumor Progression through Biochemical and Mechanical Signal Transduction
Cancers 2018, 10(6), 199; https://doi.org/10.3390/cancers10060199
Received: 24 May 2018 / Revised: 12 June 2018 / Accepted: 12 June 2018 / Published: 14 June 2018
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Abstract
Transforming growth factor β (TGF-β) signaling transduces immunosuppressive biochemical and mechanical signals in the tumor microenvironment. In addition to canonical SMAD transcription factor signaling, TGF-β can promote tumor growth and survival by inhibiting proinflammatory signaling and extracellular matrix (ECM) remodeling. In this article,
[...] Read more.
Transforming growth factor β (TGF-β) signaling transduces immunosuppressive biochemical and mechanical signals in the tumor microenvironment. In addition to canonical SMAD transcription factor signaling, TGF-β can promote tumor growth and survival by inhibiting proinflammatory signaling and extracellular matrix (ECM) remodeling. In this article, we review how TGF-β activated kinase 1 (TAK1) activation lies at the intersection of proinflammatory signaling by immune receptors and anti-inflammatory signaling by TGF-β receptors. Additionally, we discuss the role of TGF-β in the mechanobiology of cancer. Understanding how TGF-β dampens proinflammatory responses and induces pro-survival mechanical signals throughout cancer development is critical for designing therapeutics that inhibit tumor progression while bolstering the immune response. Full article
(This article belongs to the Special Issue TGF-Beta Signaling in Cancer)
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Open AccessReview TGF-β in T Cell Biology: Implications for Cancer Immunotherapy
Cancers 2018, 10(6), 194; https://doi.org/10.3390/cancers10060194
Received: 14 May 2018 / Revised: 7 June 2018 / Accepted: 7 June 2018 / Published: 11 June 2018
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Abstract
Transforming Growth Factor beta (TGF-β) is a pleiotropic cytokine produced in large amounts within cancer microenvironments that will ultimately promote neoplastic progression, notably by suppressing the host’s T-cell immunosurveillance. This effect is mostly due to the well-known inhibitory effect of TGF-β on T
[...] Read more.
Transforming Growth Factor beta (TGF-β) is a pleiotropic cytokine produced in large amounts within cancer microenvironments that will ultimately promote neoplastic progression, notably by suppressing the host’s T-cell immunosurveillance. This effect is mostly due to the well-known inhibitory effect of TGF-β on T cell proliferation, activation, and effector functions. Moreover, TGF-β subverts T cell immunity by favoring regulatory T-cell differentiation, further reinforcing immunosuppression within tumor microenvironments. These findings stimulated the development of many strategies to block TGF-β or its signaling pathways, either as monotherapy or in combination with other therapies, to restore anti-cancer immunity. Paradoxically, recent studies provided evidence that TGF-β can also promote differentiation of certain inflammatory populations of T cells, such as Th17, Th9, and resident-memory T cells (Trm), which have been associated with improved tumor control in several models. Here, we review current advances in our understanding of the many roles of TGF-β in T cell biology in the context of tumor immunity and discuss the possibility to manipulate TGF-β signaling to improve cancer immunotherapy. Full article
(This article belongs to the Special Issue TGF-Beta Signaling in Cancer)
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Open AccessFeature PaperReview Clinico-Pathological Importance of TGF-β/Phospho-Smad Signaling during Human Hepatic Fibrocarcinogenesis
Cancers 2018, 10(6), 183; https://doi.org/10.3390/cancers10060183
Received: 30 April 2018 / Revised: 19 May 2018 / Accepted: 1 June 2018 / Published: 5 June 2018
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Abstract
Chronic viral hepatitis is a global public health problem, with approximately 570 million persons chronically infected. Hepatitis B and C viruses increase the risk of morbidity and mortality from liver cirrhosis, hepatocellular carcinoma (HCC), and extrahepatic complications that develop. Hepatitis virus infection induces
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Chronic viral hepatitis is a global public health problem, with approximately 570 million persons chronically infected. Hepatitis B and C viruses increase the risk of morbidity and mortality from liver cirrhosis, hepatocellular carcinoma (HCC), and extrahepatic complications that develop. Hepatitis virus infection induces transforming growth factor (TGF)-β, which influences microenvironments within the infected liver. TGF-β promotes liver fibrosis by up-regulating extracellular matrix production by hepatic stellate cells. TGF-β is also up-regulated in patients with HCC, in whom it contributes importantly to bringing about a favorable microenvironment for tumor growth. Thus, TGF-β is thought to be a major factor regulating liver fibrosis and carcinogenesis. Since TGF-β carries out regulatory signaling by influencing the phosphorylation of Smads, we have generated several kinds of phospho-specific antibodies to Smad2/3. Using these, we have identified three types of phospohorylated forms: COOH-terminally phosphorylated Smad2/3 (pSmad2C and pSmad3C), linker phosphorylated Smad2/3 (pSmad2L and pSmad3L), and dually phosphorylated Smad3 (pSmad2L/C and pSmad3L/C). TGF-β-mediated pSmad2/3C signaling terminates cell proliferation; on the other hand, cytokine-induced pSmad3L signaling accelerates cell proliferation and promotes fibrogenesis. This review addresses TGF-β/Smad signal transduction in chronic liver injuries and carcinogenic processes. We also discuss the reversibility of Smad signaling after antiviral therapy. Full article
(This article belongs to the Special Issue TGF-Beta Signaling in Cancer)
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Open AccessReview KLF10 as a Tumor Suppressor Gene and Its TGF-β Signaling
Cancers 2018, 10(6), 161; https://doi.org/10.3390/cancers10060161
Received: 25 April 2018 / Revised: 15 May 2018 / Accepted: 23 May 2018 / Published: 25 May 2018
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Abstract
Krüppel-like factor 10 (KLF10), originally named TGF-β (Transforming growth factor beta) inducible early gene 1 (TIEG1), is a DNA-binding transcriptional regulator containing a triple C2H2 zinc finger domain. By binding to Sp1 (specificity protein 1) sites on the DNA and interactions with other
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Krüppel-like factor 10 (KLF10), originally named TGF-β (Transforming growth factor beta) inducible early gene 1 (TIEG1), is a DNA-binding transcriptional regulator containing a triple C2H2 zinc finger domain. By binding to Sp1 (specificity protein 1) sites on the DNA and interactions with other regulatory transcription factors, KLF10 encourages and suppresses the expression of multiple genes in many cell types. Many studies have investigated its signaling cascade, but other than the TGF-β/Smad signaling pathway, these are still not clear. KLF10 plays a role in proliferation, differentiation as well as apoptosis, just like other members of the SP (specificity proteins)/KLF (Krüppel-like Factors). Recently, several studies reported that KLF10 KO (Knock out) is associated with defects in cell and organs such as osteopenia, abnormal tendon or cardiac hypertrophy. Since KLF10 was first discovered, several studies have defined its role in cancer as a tumor suppressor. KLF10 demonstrate anti-proliferative effects and induce apoptosis in various carcinoma cells including pancreatic cancer, leukemia, and osteoporosis. Collectively, these data indicate that KLF10 plays a significant role in various biological processes and diseases, but its role in cancer is still unclear. Therefore, this review was conducted to describe and discuss the role and function of KLF10 in diseases, including cancer, with a special emphasis on its signaling with TGF-β. Full article
(This article belongs to the Special Issue TGF-Beta Signaling in Cancer)
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Open AccessReview Deregulation of Negative Controls on TGF-β1 Signaling in Tumor Progression
Cancers 2018, 10(6), 159; https://doi.org/10.3390/cancers10060159
Received: 2 May 2018 / Revised: 22 May 2018 / Accepted: 23 May 2018 / Published: 25 May 2018
PDF Full-text (979 KB) | HTML Full-text | XML Full-text
Abstract
The multi-functional cytokine transforming growth factor-β1 (TGF-β1) has growth inhibitory and anti-inflammatory roles during homeostasis and the early stages of cancer. Aberrant TGF-β activation in the late-stages of tumorigenesis, however, promotes development of aggressive growth characteristics and metastatic spread. Given the critical importance
[...] Read more.
The multi-functional cytokine transforming growth factor-β1 (TGF-β1) has growth inhibitory and anti-inflammatory roles during homeostasis and the early stages of cancer. Aberrant TGF-β activation in the late-stages of tumorigenesis, however, promotes development of aggressive growth characteristics and metastatic spread. Given the critical importance of this growth factor in fibrotic and neoplastic disorders, the TGF-β1 network is subject to extensive, multi-level negative controls that impact receptor function, mothers against decapentaplegic homolog 2/3 (SMAD2/3) activation, intracellular signal bifurcation into canonical and non-canonical pathways and target gene promotor engagement. Such negative regulators include phosphatase and tensin homologue (PTEN), protein phosphatase magnesium 1A (PPM1A), Klotho, bone morphogenic protein 7 (BMP7), SMAD7, Sloan-Kettering Institute proto-oncogene/ Ski related novel gene (Ski/SnoN), and bone morphogenetic protein and activin membrane-bound Inhibitor (BAMBI). The progression of certain cancers is accompanied by loss of expression, overexpression, mislocalization, mutation or deletion of several endogenous repressors of the TGF-β1 cascade, further modulating signal duration/intensity and phenotypic reprogramming. This review addresses how their aberrant regulation contributes to cellular plasticity, tumor progression/metastasis and reversal of cell cycle arrest and discusses the unexplored therapeutic value of restoring the expression and/or function of these factors as a novel approach to cancer treatment. Full article
(This article belongs to the Special Issue TGF-Beta Signaling in Cancer)
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