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Cancers
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TGF-β Signaling and Its Roles in Cancers
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TGF-β Signaling and Its Roles in Cancers

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

Deadline for manuscript submissions: closed (15 March 2023) | Viewed by 7105

Special Issue Editor

Dr. Elisabetta Aldieri

E-Mail Website
Guest Editor
Department of Oncology, University of Torino, 10126 Torino, Italy
Interests: molecular cancer biochemistry; mechanisms of tumor transformation and metastasis; epithelial–mesenchymal transition (EMT); oxidative stress and cancer; cancer and tumor microenvironment (TME); research of predictive markers and/or pharmacological targets in cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

it is known that cancer metabolism involves different changes at cellular level, and altered metabolic pathways have been demonstrated to be crucial in tumorigenesis and invasiveness, especially related to accumulated alterations in the signaling pathways that control cellular metabolism. In cancer cells, different cytokines are involved in the development and/or progression of cancer: among these, the transforming growth factor β (TGF-β) is central in tumorigenesis, although depending on the cancer stage. Particularly, in the advanced stage of cancer, TGF-β acts as a driver of tumor progression and metastasis, via some alterations of key components involved in TGF-β signaling and some molecular events associated to the malignant progression of cancer and related to TGF-β pathway, such as Epithelial Mesenchymal Transition (EMT), angiogenesis, inhibition of the immune response and various aspects concerning the tumor microenvironment (TME).  

Based on these considerations, this Special Issue will be addressed to focus and identify those targets in the TGF-β signaling pathway that could be significant for improving the preventive and therapeutic approach to cancer. Therefore, we are pleased to invite you to contribute, with original research articles and/or reviews, to this Special Issue, with the aim of clarifying and deepening current knowledge, and for proposing further new research perspectives in the field of cancer at the molecular level.

I look forward to receiving your contributions.

Dr. Elisabetta Aldieri
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

  • TGF-β
  • cancer
  • tumorigenesis
  • metastasis
  • Epithelial Mesenchymal Transition (EMT)
  • tumor microenvironment (TME)

Published Papers (4 papers)

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Research

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14 pages, 2252 KiB  
Article
TAp73 Inhibits EMT and Cell Migration in Pancreatic Cancer Cells through Promoting SMAD4 Expression and SMAD4-Dependent Inhibition of ERK Activation
by Hendrik Ungefroren, Björn Konukiewitz, Rüdiger Braun, Ulrich Friedrich Wellner, Hendrik Lehnert and Jens-Uwe Marquardt
Cancers 2023, 15(15), 3791; https://doi.org/10.3390/cancers15153791 - 26 Jul 2023
Cited by 1 | Viewed by 1013
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease due to early metastatic spread, late diagnosis and the lack of efficient therapies. A major driver of cancer progression and hurdle to successful treatment is transforming growth factor (TGF)-β. Recent data from pancreatic cancer mouse [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease due to early metastatic spread, late diagnosis and the lack of efficient therapies. A major driver of cancer progression and hurdle to successful treatment is transforming growth factor (TGF)-β. Recent data from pancreatic cancer mouse models showed that transcriptionally active p73 (TAp73), a p53 family member, inhibits tumor progression through promoting tumor suppressive canonical TGF-β/Smad signaling, while preventing non-canonical TGF-β signaling through extracellular signal-regulated kinases (ERK)1/2. Here, we studied whether this mechanism also operates in human PDAC. Using the PDAC-derived tumor cell lines PANC-1, HPAFII and L3.6pl, we showed that TAp73 induces the expression of the epithelial marker and invasion suppressor E-cadherin and the common-mediator Smad, SMAD4, while at the same time suppressing expression of the EMT master regulator SNAIL and basal and TGF-β1-induced activation of ERK1 and ERK2. Using dominant-negative and RNA interference-based inhibition of SMAD4 function, we went on to show that inhibition of ERK activation by TAp73 is mediated through SMAD4. Intriguingly, both SMAD4 and the α isoform of TAp73—but not the β isoform—interfered with cell migration, as shown by xCELLigence technology. Our findings highlighted the role of TAp73-SMAD4 signaling in tumor suppression of human PDAC and identified direct inhibition of basal and TGF-β-stimulated pro-invasive ERK activation as an underlying mechanism. Full article
(This article belongs to the Special Issue TGF-β Signaling and Its Roles in Cancers)
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18 pages, 6327 KiB  
Article
A CRISPR/Cas9-Based Assay for High-Throughput Studies of Cancer-Induced Innervation
by Sapthala Loku Galappaththi, Brenna Katz, Patrick H. Howze IV, Gregory Hoover and Simon Grelet
Cancers 2023, 15(7), 2026; https://doi.org/10.3390/cancers15072026 - 29 Mar 2023
Viewed by 1687
Abstract
The aggressive nature of certain cancers and their adverse effects on patient outcomes have been linked to cancer innervation, where neurons infiltrate and differentiate within the cancer stroma. Recently we demonstrated how cancer plasticity and TGFβ signaling could promote breast cancer innervation that [...] Read more.
The aggressive nature of certain cancers and their adverse effects on patient outcomes have been linked to cancer innervation, where neurons infiltrate and differentiate within the cancer stroma. Recently we demonstrated how cancer plasticity and TGFβ signaling could promote breast cancer innervation that is associated with increased cancer aggressivity. Despite the promising potential of cancer innervation as a target for anti-cancer therapies, there is currently a significant lack of effective methods to study cancer-induced neuronal differentiation, hindering the development of high-throughput approaches for identifying new targets or pharmacological inhibitors against cancer innervation. To overcome this challenge, we used CRISPR-based endogenous labeling of the neuronal marker β3-tubulin in neuronal precursors to investigate cancer-induced neuronal differentiation in nerve-cancer cocultures and provide a tool that allows for better standardization and reproducibility of studies about cancer-induced innervation. Our approach demonstrated that β3-tubulin gene editing did not affect neuronal behavior and enabled accurate reporting of cancer-induced neuronal differentiation dynamics in high-throughput settings, which makes this approach suitable for screening large cohorts of cells or testing various biological contexts. In a more context-based approach, by combining this method with a cell model of breast cancer epithelial-mesenchymal transition, we revealed the role of cancer cell plasticity in promoting neuronal differentiation, suggesting that cancer innervation represents an underexplored path for epithelial-mesenchymal transition-mediated cancer aggressivity. Full article
(This article belongs to the Special Issue TGF-β Signaling and Its Roles in Cancers)
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23 pages, 6122 KiB  
Article
Silibinin Overcomes EMT-Driven Lung Cancer Resistance to New-Generation ALK Inhibitors
by Sara Verdura, Jose Antonio Encinar, Eduard Teixidor, Antonio Segura-Carretero, Vicente Micol, Elisabet Cuyàs, Joaquim Bosch-Barrera and Javier A. Menendez
Cancers 2022, 14(24), 6101; https://doi.org/10.3390/cancers14246101 - 11 Dec 2022
Cited by 4 | Viewed by 2025
Abstract
Epithelial-to-mesenchymal transition (EMT) may drive the escape of ALK-rearranged non-small-cell lung cancer (NSCLC) tumors from ALK-tyrosine kinase inhibitors (TKIs). We investigated whether first-generation ALK–TKI therapy-induced EMT promotes cross-resistance to new-generation ALK–TKIs and whether this could be circumvented by the flavonolignan silibinin, an EMT [...] Read more.
Epithelial-to-mesenchymal transition (EMT) may drive the escape of ALK-rearranged non-small-cell lung cancer (NSCLC) tumors from ALK-tyrosine kinase inhibitors (TKIs). We investigated whether first-generation ALK–TKI therapy-induced EMT promotes cross-resistance to new-generation ALK–TKIs and whether this could be circumvented by the flavonolignan silibinin, an EMT inhibitor. ALK-rearranged NSCLC cells acquiring a bona fide EMT phenotype upon chronic exposure to the first-generation ALK–TKI crizotinib exhibited increased resistance to second-generation brigatinib and were fully refractory to third-generation lorlatinib. Such cross-resistance to new-generation ALK–TKIs, which was partially recapitulated upon chronic TGFβ stimulation, was less pronounced in ALK-rearranged NSCLC cells solely acquiring a partial/hybrid E/M transition state. Silibinin overcame EMT-induced resistance to brigatinib and lorlatinib and restored their efficacy involving the transforming growth factor-beta (TGFβ)/SMAD signaling pathway. Silibinin deactivated TGFβ-regulated SMAD2/3 phosphorylation and suppressed the transcriptional activation of genes under the control of SMAD binding elements. Computational modeling studies and kinase binding assays predicted a targeted inhibitory binding of silibinin to the ATP-binding pocket of TGFβ type-1 receptor 1 (TGFBR1) and TGFBR2 but solely at the two-digit micromolar range. A secretome profiling confirmed the ability of silibinin to normalize the augmented release of TGFβ into the extracellular fluid of ALK–TKIs-resistant NSCLC cells and reduce constitutive and inducible SMAD2/3 phosphorylation occurring in the presence of ALK–TKIs. In summary, the ab initio plasticity along the EMT spectrum may explain the propensity of ALK-rearranged NSCLC cells to acquire resistance to new-generation ALK–TKIs, a phenomenon that could be abrogated by the silibinin-driven attenuation of the TGFβ/SMAD signaling axis in mesenchymal ALK-rearranged NSCLC cells. Full article
(This article belongs to the Special Issue TGF-β Signaling and Its Roles in Cancers)
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Review

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15 pages, 2988 KiB  
Review
TGF-β as Predictive Marker and Pharmacological Target in Lung Cancer Approach
by Valeria Ramundo, Maria Luisa Palazzo and Elisabetta Aldieri
Cancers 2023, 15(8), 2295; https://doi.org/10.3390/cancers15082295 - 14 Apr 2023
Cited by 3 | Viewed by 1877
Abstract
Lung cancer (LC) represents the leading cause of cancer incidence and mortality worldwide. LC onset is strongly related to genetic mutations and environmental interactions, such as tobacco smoking, or pathological conditions, such as chronic inflammation. Despite advancement in knowledge of the molecular mechanisms [...] Read more.
Lung cancer (LC) represents the leading cause of cancer incidence and mortality worldwide. LC onset is strongly related to genetic mutations and environmental interactions, such as tobacco smoking, or pathological conditions, such as chronic inflammation. Despite advancement in knowledge of the molecular mechanisms involved in LC, this tumor is still characterized by an unfavorable prognosis, and the current therapeutic options are unsatisfactory. TGF-β is a cytokine that regulates different biological processes, particularly at the pulmonary level, and its alteration has been demonstrated to be associated with LC progression. Moreover, TGF-β is involved in promoting invasiveness and metastasis, via epithelial to mesenchymal transition (EMT) induction, where TGF-β is the major driver. Thus, a TGF-β-EMT signature may be considered a potential predictive marker in LC prognosis, and TGF-β-EMT inhibition has been demonstrated to prevent metastasis in various animal models. Concerning a LC therapeutic approach, some TGF-β and TGF-β-EMT inhibitors could be used in combination with chemo- and immunotherapy without major side effects, thereby improving cancer therapy. Overall, targeting TGF-β may be a valid possibility to fight LC, both in improving LC prognosis and cancer therapy, via a novel approach that could open up new effective strategies against this aggressive cancer. Full article
(This article belongs to the Special Issue TGF-β Signaling and Its Roles in Cancers)
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