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Cancers
Special Issues
Cancer Therapy-Induced Senescence: The Good, the Bad and the Ugly
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Cancer Therapy-Induced Senescence: The Good, the Bad and the Ugly

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Immunology and Immunotherapy".

Deadline for manuscript submissions: closed (15 December 2020) | Viewed by 26616

Special Issue Editor

Dr. Beshay Zordoky

E-Mail Website
Guest Editor
Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, SE Minneapolis, MN, USA
Interests: Cardio-oncology, Cardiovascular Pharmacology and Toxicology

Special Issue Information

Dear Colleagues,

Cellular senescence is classically defined as an irreversible cell cycle arrest, often accompanied by a senescence-associated secretory phenotype (SASP). Although senescence is a physiological tumor-suppressing mechanism, SASP can also promote tumor progression and enhance cancer cell proliferation. Therefore, cellular senescence is commonly described as a double-edged sword, and whether it has a beneficial or detrimental role is highly context-dependent. Several chemotherapeutic agents induce cellular senescence, including doxorubicin, cyclophosphamide, etoposide, and cisplatin. Additionally, radiation therapy can also induce cellular senescence. Although therapy-induced senescence (TIS) can limit tumor progression, tumor cells may escape therapy-induced senescence-like arrest, leading to disease recurrence. Moreover, TIS can result in the accumulation of senescent cells in normal organs, leading to a number of cancer treatment-induced specific organ toxicities (e.g., cardiovascular toxicity). TIS can also result in an accelerated aging phenotype commonly seen in cancer survivors. Indeed, clearance of senescent cells after doxorubicin treatment in mice has been recently shown to prevent a number of doxorubicin-induced adverse effects, including cardiac dysfunction, secondary malignancy, and fatigue.

For this Special Issue on Cancer Therapy-induced Senescence, we invite original research and reviews that focus on the following topics:

  • Mechanisms and biological effects of therapy-induced senescence.
  • The role of therapy-induced senescence in cancer treatment-related toxicity.
  • The potential use of senotherapeutics in cancer treatment.
  • Cancer treatment-induced accelerated aging in cancer survivors.

Dr. Beshay Zordoky
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

  • Chemotherapy
  • Radiation Therapy
  • Cellular Senescence
  • Senotherapeutics

Published Papers (6 papers)

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Research

Jump to: Review

24 pages, 3610 KiB  
Article
Chromatin-Directed Proteomics Identifies ZNF84 as a p53-Independent Regulator of p21 in Genotoxic Stress Response
by Anna Strzeszewska-Potyrała, Karolina Staniak, Joanna Czarnecka-Herok, Mahmoud-Reza Rafiee, Marcin Herok, Grażyna Mosieniak, Jeroen Krijgsveld and Ewa Sikora
Cancers 2021, 13(9), 2115; https://doi.org/10.3390/cancers13092115 - 27 Apr 2021
Cited by 10 | Viewed by 2498
Abstract
The p21WAF1/Cip1 protein, encoded by CDKN1A, plays a vital role in senescence, and its transcriptional control by the tumour suppressor p53 is well-established. However, p21 can also be regulated in a p53-independent manner, by mechanisms that still remain less understood. We [...] Read more.
The p21WAF1/Cip1 protein, encoded by CDKN1A, plays a vital role in senescence, and its transcriptional control by the tumour suppressor p53 is well-established. However, p21 can also be regulated in a p53-independent manner, by mechanisms that still remain less understood. We aimed to expand the knowledge about p53-independent senescence by looking for novel players involved in CDKN1A regulation. We used a chromatin-directed proteomic approach and identified ZNF84 as a novel regulator of p21 in various p53-deficient cell lines treated with cytostatic dose of doxorubicin. Knock-down of ZNF84, an as-yet un-characterized protein, inhibited p21 gene and protein expression in response to doxorubicin, it attenuated senescence and was associated with enhanced proliferation, indicating that ZNF84-deficiency can favor senescence bypass. ZNF84 deficiency was also associated with transcriptomic changes in genes governing various cancer-relevant processes e.g., mitosis. In cells with ZNF84 knock-down we discovered significantly lower level of H2AX Ser139 phosphorylation (γH2AX), which is triggered by DNA double strand breaks. Intriguingly, we observed a reverse correlation between the level of ZNF84 expression and survival rate of colon cancer patients. In conclusion, ZNF84, whose function was previously not recognized, was identified here as a critical p53-independent regulator of senescence, opening possibilities for its targeting in novel therapies of p53-null cancers. Full article
(This article belongs to the Special Issue Cancer Therapy-Induced Senescence: The Good, the Bad and the Ugly)
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15 pages, 3560 KiB  
Article
FAK Inhibition Induces Glioblastoma Cell Senescence-Like State through p62 and p27
by Lía Alza, Mireia Nàger, Anna Visa, Carles Cantí and Judit Herreros
Cancers 2020, 12(5), 1086; https://doi.org/10.3390/cancers12051086 - 27 Apr 2020
Cited by 18 | Viewed by 3820
Abstract
Focal adhesion kinase (FAK) is a central component of focal adhesions that regulate cancer cell proliferation and migration. Here, we studied the effects of FAK inhibition in glioblastoma (GBM), a fast growing brain tumor that has a poor prognosis. Treating GBM cells with [...] Read more.
Focal adhesion kinase (FAK) is a central component of focal adhesions that regulate cancer cell proliferation and migration. Here, we studied the effects of FAK inhibition in glioblastoma (GBM), a fast growing brain tumor that has a poor prognosis. Treating GBM cells with the FAK inhibitor PF-573228 induced a proliferative arrest and increased cell size. PF-573228 also reduced the growth of GBM neurospheres. These effects were associated with increased p27/CDKN1B levels and β-galactosidase activity, compatible with acquisition of senescence. Interestingly, FAK inhibition repressed the expression of the autophagy cargo receptor p62/SQSTM-1. Moreover, depleting p62 in GBM cells also induced a senescent-like phenotype through transcriptional upregulation of p27. Our results indicate that FAK inhibition arrests GBM cell proliferation, resulting in cell senescence, and pinpoint p62 as being key to this process. These findings highlight the possible therapeutic value of targeting FAK in GBM. Full article
(This article belongs to the Special Issue Cancer Therapy-Induced Senescence: The Good, the Bad and the Ugly)
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Review

Jump to: Research

19 pages, 1474 KiB  
Review
The Role of Senescent Cells in Acquired Drug Resistance and Secondary Cancer in BRAFi-Treated Melanoma
by Elizabeth L. Thompson, Jiayi J. Hu and Laura J. Niedernhofer
Cancers 2021, 13(9), 2241; https://doi.org/10.3390/cancers13092241 - 7 May 2021
Cited by 7 | Viewed by 3545
Abstract
BRAF is the most common gene mutated in malignant melanoma, and predominately it is a missense mutation of codon 600 in the kinase domain. This oncogenic BRAF missense mutation results in constitutive activation of the mitogen-activate protein kinase (MAPK) pro-survival pathway. Several BRAF [...] Read more.
BRAF is the most common gene mutated in malignant melanoma, and predominately it is a missense mutation of codon 600 in the kinase domain. This oncogenic BRAF missense mutation results in constitutive activation of the mitogen-activate protein kinase (MAPK) pro-survival pathway. Several BRAF inhibitors (BRAFi) have been developed to specifically inhibit BRAFV600 mutations that improve melanoma survival, but resistance and secondary cancer often occur. Causal mechanisms of BRAFi-induced secondary cancer and resistance have been identified through upregulation of MAPK and alternate pro-survival pathways. In addition, overriding of cellular senescence is observed throughout the progression of disease from benign nevi to malignant melanoma. In this review, we discuss melanoma BRAF mutations, the genetic mechanism of BRAFi resistance, and the evidence supporting the role of senescent cells in melanoma disease progression, drug resistance and secondary cancer. We further highlight the potential benefit of targeting senescent cells with senotherapeutics as adjuvant therapy in combating melanoma. Full article
(This article belongs to the Special Issue Cancer Therapy-Induced Senescence: The Good, the Bad and the Ugly)
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24 pages, 1366 KiB  
Review
Senolytics for Cancer Therapy: Is All that Glitters Really Gold?
by Valerie J. Carpenter, Tareq Saleh and David A. Gewirtz
Cancers 2021, 13(4), 723; https://doi.org/10.3390/cancers13040723 - 10 Feb 2021
Cited by 67 | Viewed by 6756
Abstract
Senolytics represent a group of mechanistically diverse drugs that can eliminate senescent cells, both in tumors and in several aging-related pathologies. Consequently, senolytic use has been proposed as a potential adjuvant approach to improve the response to senescence-inducing conventional and targeted cancer therapies. [...] Read more.
Senolytics represent a group of mechanistically diverse drugs that can eliminate senescent cells, both in tumors and in several aging-related pathologies. Consequently, senolytic use has been proposed as a potential adjuvant approach to improve the response to senescence-inducing conventional and targeted cancer therapies. Despite the unequivocal promise of senolytics, issues of universality, selectivity, resistance, and toxicity remain to be further clarified. In this review, we attempt to summarize and analyze the current preclinical literature involving the use of senolytics in senescent tumor cell models, and to propose tenable solutions and future directions to improve the understanding and use of this novel class of drugs. Full article
(This article belongs to the Special Issue Cancer Therapy-Induced Senescence: The Good, the Bad and the Ugly)
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16 pages, 7187 KiB  
Review
Cancer Response to Therapy-Induced Senescence: A Matter of Dose and Timing
by Maria Patrizia Mongiardi, Manuela Pellegrini, Roberto Pallini, Andrea Levi and Maria Laura Falchetti
Cancers 2021, 13(3), 484; https://doi.org/10.3390/cancers13030484 - 27 Jan 2021
Cited by 30 | Viewed by 3579
Abstract
Cellular senescence participates to fundamental processes like tissue remodeling in embryo development, wound healing and inhibition of preneoplastic cell growth. Most senescent cells display common hallmarks, among which the most characteristic is a permanent (or long lasting) arrest of cell division. However, upon [...] Read more.
Cellular senescence participates to fundamental processes like tissue remodeling in embryo development, wound healing and inhibition of preneoplastic cell growth. Most senescent cells display common hallmarks, among which the most characteristic is a permanent (or long lasting) arrest of cell division. However, upon senescence, different cell types acquire distinct phenotypes, which also depend on the specific inducing stimuli. Senescent cells are metabolically active and secrete a collection of growth factors, cytokines, proteases, and matrix-remodeling proteins collectively defined as senescence-associated secretory phenotype, SASP. Through SASP, senescent cells modify their microenvironment and engage in a dynamic dialog with neighbor cells. Senescence of neoplastic cells, at least temporarily, reduces tumor expansion, but SASP of senescent cancer cells as well as SASP of senescent stromal cells in the tumor microenvironment may promote the growth of more aggressive cancer subclones. Here, we will review recent data on the mechanisms and the consequences of cancer-therapy induced senescence, enlightening the potentiality and the risk of senescence inducing treatments. Full article
(This article belongs to the Special Issue Cancer Therapy-Induced Senescence: The Good, the Bad and the Ugly)
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15 pages, 1008 KiB  
Review
Cancer Treatment-Induced Accelerated Aging in Cancer Survivors: Biology and Assessment
by Shuo Wang, Anna Prizment, Bharat Thyagarajan and Anne Blaes
Cancers 2021, 13(3), 427; https://doi.org/10.3390/cancers13030427 - 23 Jan 2021
Cited by 46 | Viewed by 5513
Abstract
Rapid improvements in cancer survival led to the realization that many modalities used to treat or control cancer may cause accelerated aging in cancer survivors. Clinically, “accelerated aging” phenotypes in cancer survivors include secondary cancers, frailty, chronic organ dysfunction, and cognitive impairment, all [...] Read more.
Rapid improvements in cancer survival led to the realization that many modalities used to treat or control cancer may cause accelerated aging in cancer survivors. Clinically, “accelerated aging” phenotypes in cancer survivors include secondary cancers, frailty, chronic organ dysfunction, and cognitive impairment, all of which can impact long-term health and quality of life in cancer survivors. The treatment-induced accelerated aging in cancer survivors could be explained by telomere attrition, cellular senescence, stem cell exhaustion, DNA damage, and epigenetic alterations. Several aging clocks and biomarkers of aging have been proposed to be potentially useful in estimating biological age, which can provide specific information about how old an individual is biologically independent of chronological age. Measuring biological age in cancer survivors may be important for two reasons. First, it can better predict the risk of cancer treatment-related comorbidities than chronological age. Second, biological age may provide additional value in evaluating the effects of treatments and personalizing cancer therapies to maximize efficacy of treatment. A deeper understanding of treatment-induced accelerated aging in individuals with cancer may lead to novel strategies that reduce the accelerated aging and improve the quality of life in cancer survivors. Full article
(This article belongs to the Special Issue Cancer Therapy-Induced Senescence: The Good, the Bad and the Ugly)
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