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TGF-Beta Signaling in Cancer

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

Deadline for manuscript submissions: closed (30 April 2018) | Viewed by 60029

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Special Issue Editor

Prof. Dr. Hendrik Ungefroren

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Guest Editor

1. First Department of Medicine, Campus Lübeck, University Hospital Schleswig-Holstein (UKSH), Ratzeburger Allee 160, 23538 Lübeck, Germany
2. Department of Surgery, Campus Lübeck, University Hospital Schleswig-Holstein (UKSH), Ratzeburger Allee 160, 23538 Lübeck, Germany
3. Institute of Pathology, Campus Kiel, University Hospital Schleswig-Holstein (UKSH), Arnold-Heller Str. 5, 24105 Kiel, Germany
Interests: TGF-beta signaling and its crosstalk with other signaling pathways; cell migration and invasion; mechanisms of metastasis; tumor biology; pancreatic tumors; small GTPases; neuroendocrine differentiation, epithelial–mesenchymal transition; mesenchymal–epithelial transititon
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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 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

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 (10 papers)

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Editorial

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4 pages, 183 KiB

Open AccessEditorial

TGF-β Signaling in Cancer: Control by Negative Regulators and Crosstalk with Proinflammatory and Fibrogenic Pathways

by Hendrik Ungefroren

Cancers 2019, 11(3), 384; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11030384 - 19 Mar 2019

Cited by 9 | Viewed by 2636

Abstract

The transforming growth factor-β (TGF-β) family of secreted growth factors controls many aspects of cell and tissue physiology in multicellular eukaryotes. Dysregulation of its pathway contributes to a broad variety of pathologies, including fibrosis and cancer. TGF-β acts as a powerful tumor suppressor in epithelial cells but during later stages of tumor development cancer cells eventually respond to this cytokine with epithelial-mesenchymal transition (EMT), invasion, metastasis, and immunosuppression. This collection of articles covers some important aspects of TGF-β signaling in cancer. Two articles focus on the role of TGF-β in tumor immunity and pro- and anti-inflammatory signaling, with one analyzing its impact on T-cell biology and different T-cell subsets, while the other deals with modulation of anti-inflammatory signaling by TGF-β receptors through proinflammatory signaling by immune receptors and the role of mechanotransduction in TGF-β-dependent immunosuppression. Another set of four chapters highlights the fact that context-dependent responsiveness to TGF-β is largely controlled by inputs from negative regulators and cooperation with proinflammatory and proapoptotic pathways. This theme is extended to the regulation of Smad signaling by differential phosphorylation, eventually converting canonical Smad signaling to a mitogenic, fibrogenic and carcinogenic outcome. Last, it is discussed how another posttranslational modification, SUMOylation, can modify protein function and impact TGF-β-induced EMT, invasion and metastasis. Full article

(This article belongs to the Special Issue TGF-Beta Signaling in Cancer)

Research

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12 pages, 2128 KiB

Open AccessArticle

RAC1B Suppresses TGF-β1-Dependent Cell Migration in Pancreatic Carcinoma Cells through Inhibition of the TGF-β Type I Receptor ALK5

by Hendrik Ungefroren, Hannah Otterbein, Christian Fiedler, Koichiro Mihara, Morley D. Hollenberg, Frank Gieseler, Hendrik Lehnert and David Witte

Cancers 2019, 11(5), 691; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11050691 - 17 May 2019

Cited by 17 | Viewed by 3422

Abstract

The small GTPase Ras-related C3 botulinum toxin substrate 1B (RAC1B) has been shown previously by RNA interference-mediated knockdown (KD) to function as a powerful inhibitor of transforming growth factor (TGF)-β1-induced cell migration and epithelial-mesenchymal transition in epithelial cells, but the underlying mechanism has remained enigmatic. Using pancreatic carcinoma cells, we show that both KD and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9-mediated knockout (KO) of RAC1B increased the expression of the TGF-β type I receptor ALK5 (activin receptor-like kinase 5), but this effect was more pronounced in CRISPR-KO cells. Of note, in KO, but not KD cells, ALK5 upregulation was associated with resensitization of TGFBR1 to induction by TGF-β1 stimulation. RAC1B KO also increased TGF-β1-induced C-terminal SMAD3 phosphorylation, SMAD3 transcriptional activity, growth inhibition, and cell migration. The KD of ALK5 expression by RNA interference or inactivation of the ALK5 kinase activity by dominant-negative interference or ATP-competitive inhibition rescued the cells from the RAC1B KD/KO-mediated increase in TGF-β1-induced cell migration, whereas the ectopic expression of kinase-active ALK5 mimicked this RAC1B KD/KO effect. We conclude that RAC1B downregulates the abundance of ALK5 and SMAD3 signaling, thereby attenuating TGF-β/SMAD3-driven cellular responses, such as growth inhibition and cell motility. Full article

(This article belongs to the Special Issue TGF-Beta Signaling in Cancer)

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16 pages, 2296 KiB

Open AccessArticle

Downregulation of TRAIL-Receptor 1 Increases TGFβ Type II Receptor Expression and TGFβ Signalling Via MicroRNA-370-3p in Pancreatic Cancer Cells

by David I. Radke, Qi Ling, Robert Häsler, Gökhan Alp, Hendrik Ungefroren and Anna Trauzold

Cancers 2018, 10(11), 399; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers10110399 - 25 Oct 2018

Cited by 14 | Viewed by 3127

Abstract

The accumulation of perturbations in signalling pathways resulting in an apoptosis-insensitive phenotype is largely responsible for the desperate prognosis of patients with pancreatic ductal adenocarcinoma (PDAC). Accumulating evidence suggests that the death receptors TRAIL-R1 and TRAIL-R2 play important roles in PDAC biology by acting as either tumour suppressors through induction of cell death or tumour promoters through induction of pro-inflammatory signalling, invasion and metastasis. TRAIL-R2 can also associate with nuclear proteins and alter the maturation of micro RNAs (miRs). By genome-wide miR profiling and quantitative PCR analyses we now demonstrate that knockdown of TRAIL-R1 in PDAC cells decreased the level of mature miR-370 and led to an increased abundance of the type II receptor for transforming growth factor β (TGFβ). Transfection of cells with an artificial miR-370-3p decreased the levels of TGFβ-RII. We further show that transient expression of the miR-370 mimic decreased TGFβ1-induced expression of SERPINE1 encoding plasminogen activator-inhibitor 1 and partially relieved TGFβ1-induced growth inhibition. Moreover, stable TRAIL-R1 knockdown in Colo357 cells increased TGFβ1-induced SERPINE1 expression and this effect was partially reversed by transient expression of the miR-370 mimic. Finally, after transient knockdown of TRAIL-R1 in Panc1 cells there was a tendency towards enhanced activation of Smad2 and JNK1/2 signalling by exogenous TGFβ1. Taken together, our study reveals that TRAIL-R1 through regulation of miR-370 can decrease the sensitivity of PDAC cells to TGFβ and therefore represents a potential tumour suppressor in late-stage PDAC. Full article

(This article belongs to the Special Issue TGF-Beta Signaling in Cancer)

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19 pages, 4858 KiB

Open AccessFeature PaperArticle

CRISPR-Mediated Reactivation of DKK3 Expression Attenuates TGF-β Signaling in Prostate Cancer

by Hoda Kardooni, Estela Gonzalez-Gualda, Emmanouil Stylianakis, Sina Saffaran, Jonathan Waxman and Robert M. Kypta

Cancers 2018, 10(6), 165; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers10060165 - 28 May 2018

Cited by 32 | Viewed by 6424

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 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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20 pages, 1694 KiB

Open AccessReview

The SUMO System and TGFβ Signaling Interplay in Regulation of Epithelial-Mesenchymal Transition: Implications for Cancer Progression

by Ayan Chanda, Anusi Sarkar and Shirin Bonni

Cancers 2018, 10(8), 264; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers10080264 - 08 Aug 2018

Cited by 22 | Viewed by 4817

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 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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18 pages, 10279 KiB

Open AccessReview

TGF-β Sustains Tumor Progression through Biochemical and Mechanical Signal Transduction

by Robert L. Furler, Douglas F. Nixon, Christine A. Brantner, Anastas Popratiloff and Christel H. Uittenbogaart

Cancers 2018, 10(6), 199; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers10060199 - 14 Jun 2018

Cited by 32 | Viewed by 6013

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, 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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21 pages, 950 KiB

Open AccessEditor’s ChoiceReview

TGF-β in T Cell Biology: Implications for Cancer Immunotherapy

by Amina Dahmani and Jean-Sébastien Delisle

Cancers 2018, 10(6), 194; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers10060194 - 11 Jun 2018

Cited by 121 | Viewed by 12403

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 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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17 pages, 1227 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Clinico-Pathological Importance of TGF-β/Phospho-Smad Signaling during Human Hepatic Fibrocarcinogenesis

by Katsunori Yoshida, Koichi Matsuzaki, Miki Murata, Takashi Yamaguchi, Kanehiko Suwa and Kazuichi Okazaki

Cancers 2018, 10(6), 183; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers10060183 - 05 Jun 2018

Cited by 58 | Viewed by 7887

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 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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18 pages, 1307 KiB

Open AccessReview

KLF10 as a Tumor Suppressor Gene and Its TGF-β Signaling

by Azra Memon and Woon Kyu Lee

Cancers 2018, 10(6), 161; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers10060161 - 25 May 2018

Cited by 55 | Viewed by 5763

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 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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19 pages, 979 KiB

Open AccessEditor’s ChoiceReview

Deregulation of Negative Controls on TGF-β1 Signaling in Tumor Progression

by Jiaqi Tang, Cody C. Gifford, Rohan Samarakoon and Paul J. Higgins

Cancers 2018, 10(6), 159; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers10060159 - 25 May 2018

Cited by 57 | Viewed by 6048

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 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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