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The Bright and Dark Sides of Apoptosis and Other Modes of Cell “Death” in Cancer Therapy

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

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 22349

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Special Issue Editor

Prof. Dr. Razmik Mirzayans

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Guest Editor

Department of Oncology, University of Alberta, Cross Cancer Institute, Edmonton, AB T6G 1Z2, Canada
Interests: DNA damage response; p53 signaling; senescence; polyploidy; multinucleation; radioresistance; chemoresistance; Li-Fraumeni syndrome
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Stress-induced programmed cell death (e.g., through apoptosis) and “functional death” (e.g., dormancy through premature senescence) in cancer cells have long been regarded as favorable outcomes in cancer therapy. In the past decade, however, it has become evident that while these responses are essential for initial tumor control, they can also contribute to disease relapse, at least in solid tumors. Apoptotic cancer cells, for example, not only secrete tumor-promoting factors but can also undergo a reversal process (through anastasis), giving rise to tumor repopulating progeny. Reversal of a subset of apoptotic/dormant cancer cells contributes to intratumor heterogeneity, which poses a major challenge in treating cancer patients with metastatic disease. Unfortunately, intratumor heterogeneity is overlooked in most preclinical methods used in anticancer studies.

The purpose of this Special Issue is to provide a comprehensive update on molecular events that underlie intratumor heterogeneity in the context of cancer therapy. Reviews and original articles addressing the dark side of stress-induced apoptosis and senescence in solid tumors are particularly welcomed.

Prof. Dr. Razmik Mirzayans
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

intratumor heterogeneity
single-cell analysis
senescence
senotherapeutics
apoptosis and tumorigenicity
anastasis
cell fusion
novel therapeutic strategies targeting dormant cancer cells

Published Papers (6 papers)

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Research

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14 pages, 2325 KiB

Open AccessCommunication

Profiling Anti-Apoptotic BCL-xL Protein Expression in Glioblastoma Tumorspheres

by Deborah Fanfone, Ahmed Idbaih, Jade Mammi, Mathieu Gabut and Gabriel Ichim

Cancers 2020, 12(10), 2853; https://doi.org/10.3390/cancers12102853 - 02 Oct 2020

Cited by 15 | Viewed by 3167

Abstract

Glioblastoma (GBM) is one of the cancers with the worst prognosis, despite huge efforts to understand its unusual heterogeneity and aggressiveness. This is mainly due to glioblastoma stem cells (GSCs), which are also responsible for the frequent tumor recurrence following surgery, chemotherapy or radiotherapy. In this study, we investigate the expression pattern of the anti-apoptotic BCL-xL protein in several GBM cell lines and the role it might play in GSC-enriched tumorspheres. We report that several GBM cell lines have an increased BCL-xL expression in tumorspheres compared to differentiated cells. Moreover, by artificially modulating BCL-xL expression, we unravel a correlation between BCL-xL and tumorsphere size. In addition, BCL-xL upregulation appears to sensitize GBM tumorspheres to newly developed BH3 mimetics, opening promising therapeutic perspectives for treating GBM patients. Full article

(This article belongs to the Special Issue The Bright and Dark Sides of Apoptosis and Other Modes of Cell “Death” in Cancer Therapy)

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Review

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24 pages, 2425 KiB

Open AccessReview

Cell-Cell Fusion Mediated by Viruses and HERV-Derived Fusogens in Cancer Initiation and Progression

by Thomas Dittmar, Julian Weiler, Tianjiao Luo and Ralf Hass

Cancers 2021, 13(21), 5363; https://doi.org/10.3390/cancers13215363 - 26 Oct 2021

Cited by 20 | Viewed by 3499

Abstract

Cell fusion is a well-known, but still scarcely understood biological phenomenon, which might play a role in cancer initiation, progression and formation of metastases. Although the merging of two (cancer) cells appears simple, the entire process is highly complex, energy-dependent and tightly regulated. Among cell fusion-inducing and -regulating factors, so-called fusogens have been identified as a specific type of proteins that are indispensable for overcoming fusion-associated energetic barriers and final merging of plasma membranes. About 8% of the human genome is of retroviral origin and some well-known fusogens, such as syncytin-1, are expressed by human (cancer) cells. Likewise, enveloped viruses can enable and facilitate cell fusion due to evolutionarily optimized fusogens, and are also capable to induce bi- and multinucleation underlining their fusion capacity. Moreover, multinucleated giant cancer cells have been found in tumors derived from oncogenic viruses. Accordingly, a potential correlation between viruses and fusogens of human endogenous retroviral origin in cancer cell fusion will be summarized in this review. Full article

(This article belongs to the Special Issue The Bright and Dark Sides of Apoptosis and Other Modes of Cell “Death” in Cancer Therapy)

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20 pages, 1654 KiB

Open AccessReview

Cancer Cell Fusion and Post-Hybrid Selection Process (PHSP)

by Ralf Hass, Juliane von der Ohe and Thomas Dittmar

Cancers 2021, 13(18), 4636; https://doi.org/10.3390/cancers13184636 - 16 Sep 2021

Cited by 13 | Viewed by 3960

Abstract

Fusion of cancer cells either with other cancer cells (homotypic fusion) in local vicinity of the tumor tissue or with other cell types (e.g., macrophages, cancer-associated fibroblasts (CAFs), mesenchymal stromal-/stem-like cells (MSC)) (heterotypic fusion) represents a rare event. Accordingly, the clinical relevance of cancer-cell fusion events appears questionable. However, enhanced tumor growth and/or development of certain metastases can originate from cancer-cell fusion. Formation of hybrid cells after cancer-cell fusion requires a post-hybrid selection process (PHSP) to cope with genomic instability of the parental nuclei and reorganize survival and metabolic functionality. The present review dissects mechanisms that contribute to a PHSP and resulting functional alterations of the cancer hybrids. Based upon new properties of cancer hybrid cells, the arising clinical consequences of the subsequent tumor heterogeneity after cancer-cell fusion represent a major therapeutic challenge. However, cellular partners during cancer-cell fusion such as MSC within the tumor microenvironment or MSC-derived exosomes may provide a suitable vehicle to specifically address and deliver anti-tumor cargo to cancer cells. Full article

(This article belongs to the Special Issue The Bright and Dark Sides of Apoptosis and Other Modes of Cell “Death” in Cancer Therapy)

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21 pages, 1609 KiB

Open AccessFeature PaperReview

Hybrid Formation and Fusion of Cancer Cells In Vitro and In Vivo

by Ralf Hass, Juliane von der Ohe and Thomas Dittmar

Cancers 2021, 13(17), 4496; https://doi.org/10.3390/cancers13174496 - 06 Sep 2021

Cited by 18 | Viewed by 3362

Abstract

The generation of cancer hybrid cells by intra-tumoral cell fusion opens new avenues for tumor plasticity to develop cancer stem cells with altered properties, to escape from immune surveillance, to change metastatic behavior, and to broaden drug responsiveness/resistance. Genomic instability and chromosomal rearrangements in bi- or multinucleated aneuploid cancer hybrid cells contribute to these new functions. However, the significance of cell fusion in tumorigenesis is controversial with respect to the low frequency of cancer cell fusion events and a clonal advantage of surviving cancer hybrid cells following a post-hybrid selection process. This review highlights alternative processes of cancer hybrid cell development such as entosis, emperipolesis, cannibalism, therapy-induced polyploidization/endoreduplication, horizontal or lateral gene transfer, and focusses on the predominant mechanisms of cell fusion. Based upon new properties of cancer hybrid cells the arising clinical consequences of the subsequent tumor heterogeneity after cancer cell fusion represent a major therapeutic challenge. Full article

(This article belongs to the Special Issue The Bright and Dark Sides of Apoptosis and Other Modes of Cell “Death” in Cancer Therapy)

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18 pages, 1264 KiB

Open AccessReview

Anastasis: Return Journey from Cell Death

by Victoria Zaitceva, Gelina S. Kopeina and Boris Zhivotovsky

Cancers 2021, 13(15), 3671; https://doi.org/10.3390/cancers13153671 - 22 Jul 2021

Cited by 19 | Viewed by 3809

Abstract

For over 20 years, it has been a dogma that once the integrity of mitochondria is disrupted and proapoptotic proteins that are normally located in the intermembrane space of mitochondria appeared in the cytoplasm, the process of cell death becomes inevitable. However, it has been recently shown that upon removal of the death signal, even at the stage of disturbance in the mitochondria, cells can recover and continue to grow. This phenomenon was named anastasis. Here, we will critically discuss the present knowledge concerning the mechanisms of cell death reversal, or development of anastasis, methods for its detection, and what role signaling from different intracellular compartments plays in anastasis stimulation. Full article

(This article belongs to the Special Issue The Bright and Dark Sides of Apoptosis and Other Modes of Cell “Death” in Cancer Therapy)

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15 pages, 638 KiB

Open AccessReview

Senescent Tumor CD8⁺ T Cells: Mechanisms of Induction and Challenges to Immunotherapy

by Wei Liu, Paweł Stachura, Haifeng C. Xu, Sanil Bhatia, Arndt Borkhardt, Philipp A. Lang and Aleksandra A. Pandyra

Cancers 2020, 12(10), 2828; https://doi.org/10.3390/cancers12102828 - 30 Sep 2020

Cited by 9 | Viewed by 3427

Abstract

The inability of tumor-infiltrating T lymphocytes to eradicate tumor cells within the tumor microenvironment (TME) is a major obstacle to successful immunotherapeutic treatments. Understanding the immunosuppressive mechanisms within the TME is paramount to overcoming these obstacles. T cell senescence is a critical dysfunctional state present in the TME that differs from T cell exhaustion currently targeted by many immunotherapies. This review focuses on the physiological, molecular, metabolic and cellular processes that drive CD8⁺ T cell senescence. Evidence showing that senescent T cells hinder immunotherapies is discussed, as are therapeutic options to reverse T cell senescence. Full article

(This article belongs to the Special Issue The Bright and Dark Sides of Apoptosis and Other Modes of Cell “Death” in Cancer Therapy)

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