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Cancers
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Mechanism Underlying Tumor Relapse and Targeted Treatment Strategies
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Mechanism Underlying Tumor Relapse and Targeted Treatment Strategies

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (15 August 2022) | Viewed by 22109

Special Issue Editor

Dr. Neha Kaushik

E-Mail Website
Guest Editor
Department of Biotechnology17, Bongdam-eup, Hwaseong-si, Gyeonggi-do, University of Suwon, 18323, Korea
Interests: tumor microenvironment; plasma medicine; tumor oncology; cancer metastasis and stem cells; cancer biomarkers; nanotechnology; molecular biochemistry

Special Issue Information

Dear colleagues,

Tumorigenesis is a multistep process and these steps reveal genetic modifications that drive the progressive transformation of normal human cells into highly malignant cells. Pathological analyses of various organ sites reveal lesions that seem to represent the intermediate steps in a process through which cells grow progressively from a normal state, through a series of premalignant states, into an invasive cancer state. Metastatic relapse is responsible for approximately 85–90% of cancer-related deaths, and involves a sequence of events, called “invasion-metastasis cascade”. The use of anticancer agents targeted to each of the hallmark capabilities of cancer, used alone or in appropriate combinations, to identify entire stages of disease progression, to prevent initial cancers from developing, and cure preexisting cancers, remain important goals at present. In this Special Issue, experts in this field will review the modern and novel approaches for the management of metastasis cancers with future prospective treatment.

Dr. Neha Kaushik
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

  • Epithelial–mesenchymal Transition
  • Cancer stem cells
  • Metabolic regulation
  • Plasma medicine
  • Anticancer agents
  • Apoptosis and autophagy cell death
  • Cancer-selective vulnerabilities
  • Oncogenes

Published Papers (6 papers)

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Research

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19 pages, 2847 KiB  
Article
Bak and Bcl-xL Participate in Regulating Sensitivity of Solid Tumor Derived Cell Lines to Mcl-1 Inhibitors
by Viacheslav V. Senichkin, Nikolay V. Pervushin, Alexey V. Zamaraev, Elena V. Sazonova, Anton P. Zuev, Alena Y. Streletskaia, Tatiana A. Prikazchikova, Timofei S. Zatsepin, Olga V. Kovaleva, Elena M. Tchevkina, Boris Zhivotovsky and Gelina S. Kopeina
Cancers 2022, 14(1), 181; https://doi.org/10.3390/cancers14010181 - 30 Dec 2021
Cited by 4 | Viewed by 3030
Abstract
BH3 mimetics represent a promising tool in cancer treatment. Recently, the drugs targeting the Mcl-1 protein progressed into clinical trials, and numerous studies are focused on the investigation of their activity in various preclinical models. We investigated two BH3 mimetics to Mcl-1, A1210477 [...] Read more.
BH3 mimetics represent a promising tool in cancer treatment. Recently, the drugs targeting the Mcl-1 protein progressed into clinical trials, and numerous studies are focused on the investigation of their activity in various preclinical models. We investigated two BH3 mimetics to Mcl-1, A1210477 and S63845, and found their different efficacies in on-target doses, despite the fact that both agents interacted with the target. Thus, S63845 induced apoptosis more effectively through a Bak-dependent mechanism. There was an increase in the level of Bcl-xL protein in cells with acquired resistance to Mcl-1 inhibition. Cell lines sensitive to S63845 demonstrated low expression of Bcl-xL. Tumor tissues from patients with lung adenocarcinoma were characterized by decreased Bcl-xL and increased Bak levels of both mRNA and proteins. Concomitant inhibition of Bcl-xL and Mcl-1 demonstrated dramatic cytotoxicity in six of seven studied cell lines. We proposed that co-targeting Bcl-xL and Mcl-1 might lead to a release of Bak, which cannot be neutralized by other anti-apoptotic proteins. Surprisingly, in Bak-knockout cells, inhibition of Mcl-1 and Bcl-xL still resulted in pronounced cell death, arguing against a sole role of Bak in the studied phenomenon. We demonstrate that Bak and Bcl-xL are co-factors for, respectively, sensitivity and resistance to Mcl-1 inhibition. Full article
(This article belongs to the Special Issue Mechanism Underlying Tumor Relapse and Targeted Treatment Strategies)
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25 pages, 7073 KiB  
Article
Chaperonin-Containing TCP-1 Promotes Cancer Chemoresistance and Metastasis through the AKT-GSK3β-β-Catenin and XIAP-Survivin Pathways
by Yun-Xun Chang, Yuan-Feng Lin, Chi-Long Chen, Ming-Shyan Huang, Michael Hsiao and Po-Huang Liang
Cancers 2020, 12(12), 3865; https://doi.org/10.3390/cancers12123865 - 21 Dec 2020
Cited by 16 | Viewed by 3429
Abstract
Chaperonin-containing TCP-1 (CCT) is a chaperonin composed of eight subunits that participates in intracellular protein folding. Here, we showed that increased levels of subunits of CCT, particularly CCT-β, were significantly correlated with lower survival rates for cancer patients. Endogenously high expression of CCT-β [...] Read more.
Chaperonin-containing TCP-1 (CCT) is a chaperonin composed of eight subunits that participates in intracellular protein folding. Here, we showed that increased levels of subunits of CCT, particularly CCT-β, were significantly correlated with lower survival rates for cancer patients. Endogenously high expression of CCT-β was found in cancer cell lines, such as the triple-negative breast cancer cell line MDA-MB-231 and the highly metastatic non-small-cell lung cancer cell line CL1-5. Knocking down CCT-β in these cancer cells led to decreased levels of anti-apoptotic proteins, such as XIAP, as well as inhibited phosphorylation of Ser473-AKT and GSK3, resulting in decrease of the nucleus-entering form of β-catenin; these changes reduced the chemoresistance and migration/invasion of the cells. Conversely, overexpression of CCT-β recovered the chemoresistance and cell migration/invasion by promoting the AKT-GSK3β-β-catenin and XIAP-Survivin pathways. Coimmunoprecipitation data revealed that the CCT complex might directly bind and stabilize XIAP and β-catenin. This study not only elucidates the roles of CCT in chemoresistance and metastasis, which are two major obstacles for current cancer therapy, but also provides a possible therapeutic strategy against cancers with overexpressed CCT-β. Full article
(This article belongs to the Special Issue Mechanism Underlying Tumor Relapse and Targeted Treatment Strategies)
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17 pages, 1840 KiB  
Article
Liposome-Encapsulated Bacillus Calmette–Guérin Cell Wall Skeleton Enhances Antitumor Efficiency for Bladder Cancer In Vitro and In Vivo via Induction of AMP-Activated Protein Kinase
by Young Mi Whang, Da Hyeon Yoon, Gwang Yong Hwang, Hoyub Yoon, Serk In Park, Young Wook Choi and In Ho Chang
Cancers 2020, 12(12), 3679; https://doi.org/10.3390/cancers12123679 - 8 Dec 2020
Cited by 18 | Viewed by 3130
Abstract
The Mycobacterium Bacillus Calmette-Guérin cell wall skeleton (BCG-CWS), the main immune active center of BCG, is a potent candidate non-infectious immunotherapeutic drug and an alternative to live BCG for use against urothelial carcinoma. However, its application in anticancer therapy is limited, as BCG-CWS [...] Read more.
The Mycobacterium Bacillus Calmette-Guérin cell wall skeleton (BCG-CWS), the main immune active center of BCG, is a potent candidate non-infectious immunotherapeutic drug and an alternative to live BCG for use against urothelial carcinoma. However, its application in anticancer therapy is limited, as BCG-CWS tends to aggregate in both aqueous and non-aqueous solvents. To improve the internalization of BCG-CWS into bladder cancer cells without aggregation, BCG-CWS was nanoparticulated at a 180 nm size in methylene chloride and subsequently encapsulated with conventional liposomes (CWS-Nano-CL) using an emulsified lipid (LEEL) method. In vitro cell proliferation assays showed that CWS-Nano-CL was more effective at suppressing bladder cancer cell growth compared to nonenveloped BCG-CWS. In an orthotopic implantation model of luciferase-tagged MBT2 bladder cancer cells, encapsulated BCG-CWS nanoparticles could enhance the delivery of BCG-CWS into the bladder and suppress tumor growth. Treatment with CWS-Nano-CL induced the inhibition of the mammalian target of rapamycin (mTOR) pathway and the activation of AMP-activated protein kinase (AMPK) phosphorylation, leading to apoptosis, both in vitro and in vivo. Furthermore, the antitumor activity of CWS-Nano-CL was mediated predominantly by reactive oxygen species (ROS) generation and AMPK activation, which induced endoplasmic reticulum (ER) stress, followed by c-Jun N-terminal kinase (JNK) signaling-mediated apoptosis. Therefore, our data suggest that the intravesical instillation of liposome-encapsulated BCG-CWS nanoparticles can facilitate BCG-CW cellular endocytosis and provide a promising drug-delivery system as a therapeutic strategy for BCG-mediated bladder cancer treatment. Full article
(This article belongs to the Special Issue Mechanism Underlying Tumor Relapse and Targeted Treatment Strategies)
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26 pages, 1135 KiB  
Article
How Different Are the Molecular Mechanisms of Nodal and Distant Metastasis in Luminal A Breast Cancer?
by Petr Lapcik, Anna Pospisilova, Lucia Janacova, Peter Grell, Pavel Fabian and Pavel Bouchal
Cancers 2020, 12(9), 2638; https://doi.org/10.3390/cancers12092638 - 16 Sep 2020
Cited by 4 | Viewed by 3179
Abstract
Lymph node status is one of the best prognostic factors in breast cancer, however, its association with distant metastasis is not straightforward. Here we compare molecular mechanisms of nodal and distant metastasis in molecular subtypes of breast cancer, with major focus on luminal [...] Read more.
Lymph node status is one of the best prognostic factors in breast cancer, however, its association with distant metastasis is not straightforward. Here we compare molecular mechanisms of nodal and distant metastasis in molecular subtypes of breast cancer, with major focus on luminal A patients. We analyze a new cohort of 706 patients (MMCI_706) as well as an independent cohort of 836 primary tumors with full gene expression information (SUPERTAM_HGU133A). We evaluate the risk of distant metastasis, analyze targetable molecular mechanisms in Gene Set Enrichment Analysis and identify relevant inhibitors. Lymph node positivity is generally associated with NF-κB and Src pathways and is related to high risk (OR: 5.062 and 2.401 in MMCI_706 and SUPERTAM_HGU133A, respectively, p < 0.05) of distant metastasis in luminal A patients. However, a part (≤15%) of lymph node negative tumors at the diagnosis develop the distant metastasis which is related to cell proliferation control and thrombolysis. Distant metastasis of lymph node positive patients is mostly associated with immune response. These pro-metastatic mechanisms further vary in other molecular subtypes. Our data indicate that the management of breast cancer and prevention of distant metastasis requires stratified approach based on targeted strategies. Full article
(This article belongs to the Special Issue Mechanism Underlying Tumor Relapse and Targeted Treatment Strategies)
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Review

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49 pages, 8716 KiB  
Review
Targeted Cancer Therapy Using Compounds Activated by Light
by Petra Dunkel and Janez Ilaš
Cancers 2021, 13(13), 3237; https://doi.org/10.3390/cancers13133237 - 29 Jun 2021
Cited by 29 | Viewed by 4898
Abstract
Cancer chemotherapy is affected by a modest selectivity and toxic side effects of pharmacological interventions. Among novel approaches to overcome this limitation and to bring to therapy more potent and selective agents is the use of light for selective activation of anticancer compounds. [...] Read more.
Cancer chemotherapy is affected by a modest selectivity and toxic side effects of pharmacological interventions. Among novel approaches to overcome this limitation and to bring to therapy more potent and selective agents is the use of light for selective activation of anticancer compounds. In this review, we focus on the anticancer applications of two light-activated approaches still in the experimental phase: photoremovable protecting groups (“photocages”) and photoswitches. We describe the structural considerations behind the development of novel compounds and the plethora of assays used to confirm whether the photochemical and pharmacological properties are meeting the stringent criteria for an efficient in vivo light-dependent activation. Despite its immense potential, light activation brings many challenges, and the complexity of the task is very demanding. Currently, we are still deeply in the phase of pharmacological tools, but the vivid research and rapid development bring the light of hope for potential clinical use. Full article
(This article belongs to the Special Issue Mechanism Underlying Tumor Relapse and Targeted Treatment Strategies)
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14 pages, 1128 KiB  
Review
Small Molecules in the Treatment of Squamous Cell Carcinomas: Focus on Indirubins
by Mirijam Schäfer, Marie Luise Semmler, Thoralf Bernhardt, Tobias Fischer, Vinodh Kakkassery, Robert Ramer, Martin Hein, Sander Bekeschus, Peter Langer, Burkhard Hinz, Steffen Emmert and Lars Boeckmann
Cancers 2021, 13(8), 1770; https://doi.org/10.3390/cancers13081770 - 7 Apr 2021
Cited by 17 | Viewed by 3467
Abstract
Skin cancers are the most common malignancies in the world. Among the most frequent skin cancer entities, squamous cell carcinoma (SCC) ranks second (~20%) after basal cell carcinoma (~77%). In early stages, a complete surgical removal of the affected tissue is carried out [...] Read more.
Skin cancers are the most common malignancies in the world. Among the most frequent skin cancer entities, squamous cell carcinoma (SCC) ranks second (~20%) after basal cell carcinoma (~77%). In early stages, a complete surgical removal of the affected tissue is carried out as standard therapy. To treat advanced and metastatic cancers, targeted therapies with small molecule inhibitors are gaining increasing attention. Small molecules are a heterogeneous group of protein regulators, which are produced by chemical synthesis or fermentation. The majority of them belong to the group of receptor tyrosine kinase inhibitors (RTKIs), which specifically bind to certain RTKs and directly influence the respective signaling pathway. Knowledge of characteristic molecular alterations in certain cancer entities, such as SCC, can help identify tumor-specific substances for targeted therapies. Most frequently, altered genes in SCC include TP53, NOTCH, EGFR, and CCND1. For example, the gene CCND1, which codes for cyclin D1 protein, is upregulated in nearly half of SCC cases and promotes proliferation of affected cells. A treatment with the small molecule 5′-nitroindirubin-monoxime (INO) leads to inhibition of cyclin D1 and thus inhibition of proliferation. As a component of Danggui Longhui Wan, a traditional Chinese medicine, indirubins are used to treat chronic diseases and have been shown to inhibit inflammatory reactions. Indirubins are pharmacologically relevant small molecules with proapoptotic and antiproliferative activity. In this review, we discuss the current literature on indirubin-based small molecules in cancer treatment. A special focus is on the molecular biology of squamous cell carcinomas, their alterations, and how these are rendered susceptible to indirubin-based small molecule inhibitors. The potential molecular mechanisms of the efficacy of indirubins in killing SCC cells will be discussed as well. Full article
(This article belongs to the Special Issue Mechanism Underlying Tumor Relapse and Targeted Treatment Strategies)
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