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Cells
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Cancer-Related Signaling Cascades: Current Knowledge and Potential Therapeutic Targets
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Cancer-Related Signaling Cascades: Current Knowledge and Potential Therapeutic Targets

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: 30 September 2024 | Viewed by 4258

Special Issue Editors

Dr. Takatsune Shimizu

E-Mail Website
Guest Editor
Department of Pathophysiology, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan
Interests: osteosarcoma; preclinical models of osteosarcoma; metastasis; tumor microenvironment; tumor immunology
Special Issues, Collections and Topics in MDPI journals
Dr. Hideyuki Takeshima

E-Mail Website
Guest Editor
Department of Epigenomics, Institute for Advanced Life Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan
Interests: cancer epigenetics; cancer therapy; synthetic lethality

Special Issue Information

Dear Colleagues,

Cancer cells acquire the ability of infinite proliferation, and this ability ultimately leads to the death of individuals. ‘The hallmarks of cancer’ required for this fatal process have been clarified thus far; unlimited cell division, ligand-independent activation of growth signaling, resistance to anti-growth signals, apoptosis evasion, tissue invasion/metastasis, evasion from anti-tumor immune response, and enhancement of angiogenesis. These cancer hallmarks are attributable to the alterations of various intracellular signaling cascades caused by cell-intrinsic oncogenic mutations and microenvironmental stimuli. Therefore, altered cancer-associated signaling cascades have been utilized for the development of pharmacological cancer therapy.

Different cancer signaling cascades are altered based on cancer types and individual patients. Some cancers are addicted to a single cascade, and easily therapeutically targeted. In contrast, many other cancers are endowed with complex networks of altered cascades, and the determination of appropriate therapeutic targets is very difficult. Furthermore, crossover between multiple signaling cascades is a major cause of the resistance of the current targeted therapy.

To overcome this serious problem, this Special Issue offers an open access forum that aims to bring together a collection of original research and review articles addressing the expanding field of cancer-associated signaling cascades and their potential for cancer therapy. 

We hope to provide a stimulating resource for the fascinating subject of cancer signaling cascades and their therapeutic implications.

Dr. Takatsune Shimizu
Dr. Hideyuki Takeshima
Guest Editors

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. Cells 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 2700 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 signaling
  • crosstalk of signaling pathway
  • oncogenic activation
  • genetic alterations
  • epigenetic alterations
  • tumor microenvironment
  • therapeutic resistance

Published Papers (5 papers)

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Research

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20 pages, 2602 KiB  
Article
Comprehensive Analysis of CXCR4, JUNB, and PD-L1 Expression in Circulating Tumor Cells (CTCs) from Prostate Cancer Patients
by Argyro Roumeliotou, Areti Strati, Foteini Chamchougia, Anastasia Xagara, Victoria Tserpeli, Stavroula Smilkou, Elina Lagopodi, Athina Christopoulou, Emmanouil Kontopodis, Ioannis Drositis, Nikolaos Androulakis, Vassilis Georgoulias, Filippos Koinis, Athanasios Kotsakis, Evi Lianidou and Galatea Kallergi
Cells 2024, 13(9), 782; https://doi.org/10.3390/cells13090782 - 3 May 2024
Viewed by 407
Abstract
CXCR4, JUNB and PD-L1 are implicated in cancer progression and metastasis. The current study investigated these biomarkers in CTCs isolated from metastatic prostate cancer (mPCa) patients at the RNA and protein levels. CTCs were isolated from 48 mPCa patients using the Ficoll density [...] Read more.
CXCR4, JUNB and PD-L1 are implicated in cancer progression and metastasis. The current study investigated these biomarkers in CTCs isolated from metastatic prostate cancer (mPCa) patients at the RNA and protein levels. CTCs were isolated from 48 mPCa patients using the Ficoll density gradient and ISET system (17 out of 48). The (CK/PD-L1/CD45) and (CK/CXCR4/JUNB) phenotypes were identified using two triple immunofluorescence stainings followed by VyCAP platform analysis. Molecular analysis was conducted with an EpCAM-dependent method for 25/48 patients. CK-8, CK-18, CK-19, JUNB, CXCR4, PD-L1, and B2M (reference gene) were analyzed with RT-qPCR. The (CK+/PD-L1+/CD45-) and the (CK+/CXCR4+/JUNB+) were the most frequent phenotypes (61.1% and 62.5%, respectively). Furthermore, the (CK+/CXCR4+/JUNB-) phenotype was correlated with poorer progression-free survival [(PFS), HR: 2.5, p = 0.049], while the (CK+/PD-L1+/CD45-) phenotype was linked to decreased overall survival [(OS), HR: 262.7, p = 0.007]. Molecular analysis revealed that 76.0% of the samples were positive for CK-8,18, and 19, while 28.0% were positive for JUNB, 44.0% for CXCR4, and 48.0% for PD-L1. Conclusively, CXCR4, JUNB, and PD-L1 were highly expressed in CTCs from mPCa patients. The CXCR4 protein expression was associated with poorer PFS, while PD-L1 was correlated with decreased OS, providing new biomarkers with potential clinical relevance. Full article
(This article belongs to the Special Issue Cancer-Related Signaling Cascades: Current Knowledge and Potential Therapeutic Targets)
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21 pages, 7404 KiB  
Article
GW501516-Mediated Targeting of Tetraspanin 15 Regulates ADAM10-Dependent N-Cadherin Cleavage in Invasive Bladder Cancer Cells
by Alexandre Barbaud, Isabelle Lascombe, Adeline Péchery, Sergen Arslan, François Kleinclauss and Sylvie Fauconnet
Cells 2024, 13(8), 708; https://doi.org/10.3390/cells13080708 - 19 Apr 2024
Viewed by 579
Abstract
Bladder cancer aggressiveness is correlated with abnormal N-cadherin transmembrane glycoprotein expression. This protein is cleaved by the metalloprotease ADAM10 and the γ-secretase complex releasing a pro-angiogenic N-terminal fragment (NTF) and a proliferation-activating soluble C-terminal fragment (CTF2). Tetraspanin 15 (Tspan15) is identified as an [...] Read more.
Bladder cancer aggressiveness is correlated with abnormal N-cadherin transmembrane glycoprotein expression. This protein is cleaved by the metalloprotease ADAM10 and the γ-secretase complex releasing a pro-angiogenic N-terminal fragment (NTF) and a proliferation-activating soluble C-terminal fragment (CTF2). Tetraspanin 15 (Tspan15) is identified as an ADAM10-interacting protein to induce selective N-cadherin cleavage. We first demonstrated, in invasive T24 bladder cancer cells, that N-cadherin was cleaved by ADAM10 generating NTF in the extracellular environment and leaving a membrane-anchored CTF1 fragment and that Tspan15 is required for ADAM10 to induce the selective N-cadherin cleavage. Targeting N-cadherin function in cancer is relevant to preventing tumor progression and metastases. For antitumor molecules to inhibit N-cadherin function, they should be complete and not cleaved. We first showed that the GW501516, an agonist of the nuclear receptor PPARβ/δ, decreased Tspan15 and prevented N-cadherin cleavage thus decreasing NTF. Interestingly, the drug did not modify ADAM10 expression, which was important because it could limit side effects since ADAM10 cleaves numerous substrates. By targeting Tspan15 to block ADAM10 activity on N-cadherin, GW501516 could prevent NTF pro-tumoral effects and be a promising molecule to treat bladder cancer. More interestingly, it could optimize the effects of the N-cadherin antagonists those such as ADH-1 that target the N-cadherin ectodomain. Full article
(This article belongs to the Special Issue Cancer-Related Signaling Cascades: Current Knowledge and Potential Therapeutic Targets)
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15 pages, 10517 KiB  
Article
Sertoli Cell-Specific Activation of Transforming Growth Factor Beta Receptor 1 Leads to Testicular Granulosa Cell Tumor Formation
by Xin Fang, Linfeng Nie, Satwikreddy Putluri, Nan Ni, Laurent Bartholin and Qinglei Li
Cells 2023, 12(23), 2717; https://doi.org/10.3390/cells12232717 - 27 Nov 2023
Viewed by 1090
Abstract
The transforming growth factor β (TGFβ) superfamily, consisting of protein ligands, receptors, and intracellular SMAD transducers, regulates fundamental biological processes and cancer development. Our previous study has shown that sustained activation of TGFβ receptor 1 (TGFBR1) driven by anti-Mullerian hormone receptor type 2 [...] Read more.
The transforming growth factor β (TGFβ) superfamily, consisting of protein ligands, receptors, and intracellular SMAD transducers, regulates fundamental biological processes and cancer development. Our previous study has shown that sustained activation of TGFβ receptor 1 (TGFBR1) driven by anti-Mullerian hormone receptor type 2 (Amhr2)-Cre in the mouse testis induces the formation of testicular granulosa cell tumors (TGCTs). As Amhr2-Cre is expressed in both Sertoli cells and Leydig cells, it remains unclear whether the activation of TGFBR1 in Sertoli cells alone is sufficient to induce TGCT formation. Therefore, the objective of this study was to determine whether Sertoli cell-activation of TGFBR1 drives oncogenesis in the testis. Our hypothesis was that overactivation of TGFBR1 in Sertoli cells would promote their transdifferentiation into granulosa-like cells and the formation of TGCTs. To test this hypothesis, we generated mice harboring constitutive activation of TGFBR1 in Sertoli cells using anti-Mullerian hormone (Amh)-Cre. Disorganized seminiferous tubules and tumor nodules were found in TGFBR1CA; Amh-Cre mice. A histological analysis showed that Sertoli cell-specific activation of TGFBR1 led to the development of neoplasms resembling granulosa cell tumors, which derailed spermatogenesis. Moreover, TGCTs expressed granulosa cell markers including FOXL2, FOXO1, and INHA. Using a dual fluorescence reporter line, the membrane-targeted tdTomato (mT)/membrane-targeted EGFP (mG) mouse, we provided evidence that Sertoli cells transdifferentiated toward a granulosa cell fate during tumorigenesis. Thus, our findings indicate that Sertoli cell-specific activation of TGFBR1 leads to the formation of TGCTs, supporting a key contribution of Sertoli cell reprogramming to the development of this testicular malignancy in our model. Full article
(This article belongs to the Special Issue Cancer-Related Signaling Cascades: Current Knowledge and Potential Therapeutic Targets)
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23 pages, 7211 KiB  
Article
Unraveling the Role of Hepatic PGC1α in Breast Cancer Invasion: A New Target for Therapeutic Intervention?
by Kumar Ganesan, Cong Xu, Qingqing Liu, Yue Sui and Jianping Chen
Cells 2023, 12(18), 2311; https://doi.org/10.3390/cells12182311 - 19 Sep 2023
Cited by 3 | Viewed by 982
Abstract
Breast cancer (BC) is the most common cancer among women worldwide and the main cause of cancer deaths in women. Metabolic components are key risk factors for the development of non-alcoholic fatty liver disease (NAFLD), which may promote BC. Studies have reported that [...] Read more.
Breast cancer (BC) is the most common cancer among women worldwide and the main cause of cancer deaths in women. Metabolic components are key risk factors for the development of non-alcoholic fatty liver disease (NAFLD), which may promote BC. Studies have reported that increasing PGC1α levels increases mitochondrial biogenesis, thereby increasing cell proliferation and metastasis. Moreover, the PGC1α/ERRα axis is a crucial regulator of cellular metabolism in various tissues, including BC. However, it remains unclear whether NAFLD is closely associated with the risk of BC. Therefore, the present study aimed to determine whether hepatic PGC1α promotes BC cell invasion via ERRα. Various assays, including ELISA, western blotting, and immunoprecipitation, have been employed to explore these mechanisms. According to the KM plot and TCGA data, elevated PGC1α expression was highly associated with a shorter overall survival time in patients with BC. High concentrations of palmitic acid (PA) promoted PGC1α expression, lipogenesis, and inflammatory processes in hepatocytes. Conditioned medium obtained from PA-treated hepatocytes significantly increased BC cell proliferation. Similarly, recombinant PGC1α in E0771 and MCF7 cells promoted cell proliferation, migration, and invasion in vitro. However, silencing PGC1α in both BC cell lines resulted in a decrease in this trend. As determined by immunoprecipitation assay, PCG1a interacted with ERRα, thereby facilitating the proliferation of BC cells. This outcome recognizes the importance of further investigations in exploring the full potential of hepatic PGC1α as a prognostic marker for BC development. Full article
(This article belongs to the Special Issue Cancer-Related Signaling Cascades: Current Knowledge and Potential Therapeutic Targets)
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Review

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26 pages, 2423 KiB  
Review
Protein Stability Regulation in Osteosarcoma: The Ubiquitin-like Modifications and Glycosylation as Mediators of Tumor Growth and as Targets for Therapy
by Jacopo Di Gregorio, Laura Di Giuseppe, Sara Terreri, Michela Rossi, Giulia Battafarano, Olivia Pagliarosi, Vincenzo Flati and Andrea Del Fattore
Cells 2024, 13(6), 537; https://doi.org/10.3390/cells13060537 - 18 Mar 2024
Viewed by 853
Abstract
The identification of new therapeutic targets and the development of innovative therapeutic approaches are the most important challenges for osteosarcoma treatment. In fact, despite being relatively rare, recurrence and metastatic potential, particularly to the lungs, make osteosarcoma a deadly form of cancer. In [...] Read more.
The identification of new therapeutic targets and the development of innovative therapeutic approaches are the most important challenges for osteosarcoma treatment. In fact, despite being relatively rare, recurrence and metastatic potential, particularly to the lungs, make osteosarcoma a deadly form of cancer. In fact, although current treatments, including surgery and chemotherapy, have improved survival rates, the disease’s recurrence and metastasis are still unresolved complications. Insights for analyzing the still unclear molecular mechanisms of osteosarcoma development, and for finding new therapeutic targets, may arise from the study of post-translational protein modifications. Indeed, they can influence and alter protein structure, stability and function, and cellular interactions. Among all the post-translational modifications, ubiquitin-like modifications (ubiquitination, deubiquitination, SUMOylation, and NEDDylation), as well as glycosylation, are the most important for regulating protein stability, which is frequently altered in cancers including osteosarcoma. This review summarizes the relevance of ubiquitin-like modifications and glycosylation in osteosarcoma progression, providing an overview of protein stability regulation, as well as highlighting the molecular mediators of these processes in the context of osteosarcoma and their possible targeting for much-needed novel therapy. Full article
(This article belongs to the Special Issue Cancer-Related Signaling Cascades: Current Knowledge and Potential Therapeutic Targets)
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