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Cancers
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Cell Death in Cancer
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Cell Death in Cancer

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

Deadline for manuscript submissions: closed (30 November 2019) | Viewed by 72600

Special Issue Editors

Prof. Dr. Rudolf Oehler

E-Mail Website
Guest Editor
Surgical Research Laboratories, Department of Surgery, Medical University of Vienna, 1090 Vienna, Austria
Interests: Colorectal cancer; breast cancer; tumor immunology; neutrophils; macrophages; apoptosis; efferocytosis
Prof. Ronit Pinkas-Kramarski

E-Mail Website
Guest Editor
Department of Neurobiology, Tel Aviv University, Tel Aviv, Israel
Interests: autophagy; mitophagy; signal transduction; receptor tyrosine kinases; Ras; Beclin 1; Bcl2 proteins

Special Issue Information

Dear Colleagues,

Cancer development is often characterized by the deregulation of normal growth and decreased ability to eliminate abnormal cells. The escape of cancer cells from death enables their survival under adverse conditions, leading to aberrant growth. In spite of this resilience, pathologists observe individual disintegrated dead tumor cells in almost all cancer tissues, suggesting a constant release of pro-inflammatory damage associated molecular patterns (DAMPs). The initial type of cell death pathway responsible for this effect may differ between cancers. To escape the elimination by a consequently activated immune system, cancer cells establish an immunosuppressive microenvironment.

Chemotherapies, radiotherapies, and many targeted therapies aim to overcome the anti-apoptotic capacity of tumor cells. However, increasing evidence indicates that these therapies can also induce other types of cell death including necroptosis, ferroptosis, pyroptosis, autophagy-dependent, and immunogenic cell death—each with a distinct underlying molecular mechanism. Of note, autophagy may have other effects on tumor cell growth. Immunomodulatory therapies such as immune checkpoint inhibitors help to release the break on the immune system. These are very successful in specific cancers, but only patients with highly immune cell infiltrated tumors profit from the treatment. Ongoing clinical trials explore the possibilities of increasing the response rate by combining immune checkpoint inhibitors with cell death-inducing therapies. However, recent research indicates that the immunostimulating effect differs between the various cell death pathways, which might affect the success of the treatment strategy.

This Special Issue will review the complexity of cell death pathways in cancer and highlight the role of novel pathways.

Dr. Rudolf Oehler
Prof. Ronit Pinkas-Kramarski
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. 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

  • regulated cell death
  • apoptosis
  • necroptosis
  • autophagy
  • ferroptosis
  • pyroptosis
  • immunogenicity of cell death

Published Papers (10 papers)

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Research

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15 pages, 4154 KiB  
Article
Molecular Engineering Strategies Tailoring the Apoptotic Response to a MET Therapeutic Antibody
by Chiara Modica, Simona Gallo, Cristina Chiriaco, Martina Spilinga, Paolo Maria Comoglio, Tiziana Crepaldi, Cristina Basilico and Elisa Vigna
Cancers 2020, 12(3), 741; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12030741 - 21 Mar 2020
Cited by 3 | Viewed by 2670
Abstract
The MET oncogene encodes a tyrosine kinase receptor involved in the control of a complex network of biological responses that include protection from apoptosis and stimulation of cell growth during embryogenesis, tissue regeneration, and cancer progression. We previously developed an antagonist antibody (DN30) [...] Read more.
The MET oncogene encodes a tyrosine kinase receptor involved in the control of a complex network of biological responses that include protection from apoptosis and stimulation of cell growth during embryogenesis, tissue regeneration, and cancer progression. We previously developed an antagonist antibody (DN30) inducing the physical removal of the receptor from the cell surface and resulting in suppression of the biological responses to MET. In its bivalent form, the antibody displayed a residual agonist activity, due to dimerization of the lingering receptors, and partial activation of the downstream signaling cascade. The balance between the two opposing activities is variable in different biological systems and is hardly predictable. In this study, we generated and characterized two single-chain antibody fragments derived from DN30, sharing the same variable regions but including linkers different in length and composition. The two engineered molecules bind MET with high affinity but induce different biological responses. One behaves as a MET-antagonist, promoting programmed cell death in MET “addicted” cancer cells. The other acts as a hepatocyte growth factor (HGF)-mimetic, protecting normal cells from doxorubicin-induced apoptosis. Thus, by engineering the same receptor antibody, it is possible to generate molecules enhancing or inhibiting apoptosis either to kill cancer cells or to protect healthy tissues from the injuries of chemotherapy. Full article
(This article belongs to the Special Issue Cell Death in Cancer)
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16 pages, 3851 KiB  
Article
Hispidulin Enhances TRAIL-Mediated Apoptosis via CaMKKβ/AMPK/USP51 Axis-Mediated Bim Stabilization
by Seon Min Woo, Seung Un Seo, Sang Hyun Kim, Ju-Ock Nam, Shin Kim, Jong-Wook Park, Kyoung-jin Min and Taeg Kyu Kwon
Cancers 2019, 11(12), 1960; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11121960 - 06 Dec 2019
Cited by 13 | Viewed by 3156
Abstract
Hispidulin, a natural compound present in herbs, has anti-cancer effects. Here, we investigated whether hispidulin sensitizes human carcinoma cells to apoptosis induced by TRAIL. Sub-lethal dosages of TRAIL alone and hispidulin alone does not increase apoptosis, but hispidulin increases sensitivity to TRAIL, resulting [...] Read more.
Hispidulin, a natural compound present in herbs, has anti-cancer effects. Here, we investigated whether hispidulin sensitizes human carcinoma cells to apoptosis induced by TRAIL. Sub-lethal dosages of TRAIL alone and hispidulin alone does not increase apoptosis, but hispidulin increases sensitivity to TRAIL, resulting in induction of apoptosis in hispidulin plus TRAIL-treated cancer cells. In addition, combined treatment with hispidulin and TRAIL also reduced tumor growth and increased apoptosis in xenograft models. However, hispidulin did not alter cell viability in human renal normal mesangial cells and human skin fibroblast. Hispidulin markedly increased the BH3-only proteins Bim at the post-translational levels. Depletion of Bim with siRNA significantly blocked hispidulin plus TRAIL-induced apoptosis. Furthermore, we found that activation of AMPK by hispidulin has a crucial role in Bim proteins stability through up-regulation of USP51 expression. Our findings suggest that USP51-dependent stabilization of Bim by AMPK activation plays a critical role in hispidulin-mediated sensitization of cancer cells to apoptosis induced by TRAIL. Full article
(This article belongs to the Special Issue Cell Death in Cancer)
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17 pages, 2379 KiB  
Article
LdrB Toxin with In Vitro and In Vivo Antitumor Activity as a Potential Tool for Cancer Gene Therapy
by Yaiza Jiménez-Martínez, Carmen Griñán-Lisón, Hoda Khaldy, Ana Martín, Alba Cambrils, Andrea Ibáñez Grau, Gema Jiménez, Juan A. Marchal and Houria Boulaiz
Cancers 2019, 11(7), 1016; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11071016 - 20 Jul 2019
Cited by 4 | Viewed by 4320
Abstract
Due to the high prevalence of cancer in recent years, it is necessary to develop new and more effective therapies that produce fewer side effects. Development of gene therapy for cancer based on the use of suicide genes that can damage the tumor [...] Read more.
Due to the high prevalence of cancer in recent years, it is necessary to develop new and more effective therapies that produce fewer side effects. Development of gene therapy for cancer based on the use of suicide genes that can damage the tumor cell, without requiring a prodrug for its lethal effect, is one of the recent foci of gene therapy strategies. We evaluated the cytotoxic impact of the LdrB toxin from Escherichia coli k12 as a possible tool for cancer gene therapy. For that, colorectal and breast cancer cells were transfected under the control of a TRE3G promoter inducible by doxycycline. Our results showed that ldrB gene expression induced a drastic inhibition of proliferation in vitro, in both 2D and 3D experimental models. Moreover, unlike conventional chemotherapy, the ldrB gene induced a severe loss of proliferation in vivo without any side effects in our animal model. This antitumor outcome was modulated by cell cycle arrest in the G0/G1 phase and apoptotic death. Scanning electronic microscopy demonstrates that the LdrB toxin conserves its pore-forming ability in HCT-116 cells as in E. coli k12. Taken together, our results provide, for the first time, a proof of concept of the antitumor capacity of the ldrB gene in colorectal and breast cancer. Full article
(This article belongs to the Special Issue Cell Death in Cancer)
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18 pages, 2428 KiB  
Article
Docosahexaenoic Acid Enhances Oxaliplatin-Induced Autophagic Cell Death via the ER Stress/Sesn2 Pathway in Colorectal Cancer
by Soyeon Jeong, Dae Yeong Kim, Sang Hee Kang, Hye Kyeong Yun, Jung Lim Kim, Bo Ram Kim, Seong Hye Park, Yoo Jin Na, Min Jee Jo, Yoon A. Jeong, Bu Gyeom Kim, Dae-Hee Lee and Sang Cheul Oh
Cancers 2019, 11(7), 982; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11070982 - 14 Jul 2019
Cited by 35 | Viewed by 6951
Abstract
Oxaliplatin is an anticancer drug administered to colorectal cancer (CRC) patients in combination with 5-fluorouracil and antibodies (bevacizumab and cetuximab), thereby significantly improving the survival rate of CRC. However, due to various side effects associated with the above treatment strategy, the need for [...] Read more.
Oxaliplatin is an anticancer drug administered to colorectal cancer (CRC) patients in combination with 5-fluorouracil and antibodies (bevacizumab and cetuximab), thereby significantly improving the survival rate of CRC. However, due to various side effects associated with the above treatment strategy, the need for combinatorial therapeutic strategies has emerged. Based on the demand for new combinatorial therapies and the known antitumor effects of the omega-3 polyunsaturated fatty acid, docosahexaenoic acid (DHA), we investigated the Oxaliplatin and DHA combination for its effect. Our results indicated that DHA further enhanced Oxaliplatin-induced cell viability and autophagic cell death, in vitro and in vivo. Oxaliplatin and DHA also increased the expression of Sestrin 2 (SESN2) and endoplasmic reticulum (ER) stress related C/EBP homologous protein (CHOP). Additionally, treatment with Oxaliplatin and DHA enhanced the binding of CHOP to the promotor region of SESN2, increasing SESN2 expression. These results suggested that DHA enhanced Oxaliplatin-induced reduction in cell viability and increase in autophagy via activating SESN2 and increasing ER stress. Thus, SESN2 may be an effective preclinical target for CRC treatment. Full article
(This article belongs to the Special Issue Cell Death in Cancer)
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24 pages, 1129 KiB  
Review
Ferroptosis in Cancer Cell Biology
by Christina M. Bebber, Fabienne Müller, Laura Prieto Clemente, Josephine Weber and Silvia von Karstedt
Cancers 2020, 12(1), 164; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12010164 - 09 Jan 2020
Cited by 212 | Viewed by 18839
Abstract
A major hallmark of cancer is successful evasion of regulated forms of cell death. Ferroptosis is a recently discovered type of regulated necrosis which, unlike apoptosis or necroptosis, is independent of caspase activity and receptor-interacting protein 1 (RIPK1) kinase activity. Instead, ferroptotic cells [...] Read more.
A major hallmark of cancer is successful evasion of regulated forms of cell death. Ferroptosis is a recently discovered type of regulated necrosis which, unlike apoptosis or necroptosis, is independent of caspase activity and receptor-interacting protein 1 (RIPK1) kinase activity. Instead, ferroptotic cells die following iron-dependent lipid peroxidation, a process which is antagonised by glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1). Importantly, tumour cells escaping other forms of cell death have been suggested to maintain or acquire sensitivity to ferroptosis. Therefore, therapeutic exploitation of ferroptosis in cancer has received increasing attention. Here, we systematically review current literature on ferroptosis signalling, cross-signalling to cellular metabolism in cancer and a potential role for ferroptosis in tumour suppression and tumour immunology. By summarising current findings on cell biology relevant to ferroptosis in cancer, we aim to point out new conceptual avenues for utilising ferroptosis in systemic treatment approaches for cancer. Full article
(This article belongs to the Special Issue Cell Death in Cancer)
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20 pages, 1524 KiB  
Review
Targeting Non-Oncogene Addiction: Focus on Thyroid Cancer
by Maria Chiara Anania, Tiziana Di Marco, Mara Mazzoni and Angela Greco
Cancers 2020, 12(1), 129; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12010129 - 04 Jan 2020
Cited by 6 | Viewed by 5045
Abstract
Thyroid carcinoma (TC) is the most common malignancy of endocrine organs with an increasing incidence in industrialized countries. The majority of TC are characterized by a good prognosis, even though cases with aggressive forms not cured by standard therapies are also present. Moreover, [...] Read more.
Thyroid carcinoma (TC) is the most common malignancy of endocrine organs with an increasing incidence in industrialized countries. The majority of TC are characterized by a good prognosis, even though cases with aggressive forms not cured by standard therapies are also present. Moreover, target therapies have led to low rates of partial response and prompted the emergence of resistance, indicating that new therapies are needed. In this review, we summarize current literature about the non-oncogene addiction (NOA) concept, which indicates that cancer cells, at variance with normal cells, rely on the activity of genes, usually not mutated or aberrantly expressed, essential for coping with the transformed phenotype. We highlight the potential of non-oncogenes as a point of intervention for cancer therapy in general, and present evidence for new putative non-oncogenes that are essential for TC survival and that may constitute attractive new therapeutic targets. Full article
(This article belongs to the Special Issue Cell Death in Cancer)
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33 pages, 7533 KiB  
Review
Radiotherapy as a Backbone for Novel Concepts in Cancer Immunotherapy
by Julijan Kabiljo, Felix Harpain, Sebastian Carotta and Michael Bergmann
Cancers 2020, 12(1), 79; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12010079 - 29 Dec 2019
Cited by 31 | Viewed by 4884
Abstract
Radiation-induced immunogenic cell death has been described to contribute to the efficacy of external beam radiotherapy in local treatment of solid tumors. It is well established that radiation therapy can induce immunogenic cell death in cancer cells under certain conditions. Initial clinical studies [...] Read more.
Radiation-induced immunogenic cell death has been described to contribute to the efficacy of external beam radiotherapy in local treatment of solid tumors. It is well established that radiation therapy can induce immunogenic cell death in cancer cells under certain conditions. Initial clinical studies combining radiotherapy with immunotherapies suggest a synergistic potential of this approach. Improving our understanding of how radiation reconditions the tumor immune microenvironment should pave the way for designing rational and robust combinations with immunotherapeutic drugs that enhance both local and systemic anti-cancer immune effects. In this review, we summarize irradiation-induced types of immunogenic cell death and their effects on the tumor microenvironment. We discuss preclinical insights on mechanisms and benefits of combining radiotherapy with immunotherapy, focusing on immune checkpoint inhibitors. In addition, we elaborate how these observations were translated into clinical studies and which parameters may be optimized to achieve best results in future clinical trials. Full article
(This article belongs to the Special Issue Cell Death in Cancer)
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14 pages, 2555 KiB  
Review
p53-Mediated Tumor Suppression: DNA-Damage Response and Alternative Mechanisms
by Consuelo Pitolli, Ying Wang, Eleonora Candi, Yufang Shi, Gerry Melino and Ivano Amelio
Cancers 2019, 11(12), 1983; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11121983 - 09 Dec 2019
Cited by 53 | Viewed by 15846
Abstract
The tumor suppressor p53 regulates different cellular pathways involved in cell survival, DNA repair, apoptosis, and senescence. However, according to an increasing number of studies, the p53-mediated canonical DNA damage response is dispensable for tumor suppression. p53 is involved in mechanisms regulating many [...] Read more.
The tumor suppressor p53 regulates different cellular pathways involved in cell survival, DNA repair, apoptosis, and senescence. However, according to an increasing number of studies, the p53-mediated canonical DNA damage response is dispensable for tumor suppression. p53 is involved in mechanisms regulating many other cellular processes, including metabolism, autophagy, and cell migration and invasion, and these pathways might crucially contribute to its tumor suppressor function. In this review we summarize the canonical and non-canonical functions of p53 in an attempt to provide an overview of the potentially crucial aspects related to its tumor suppressor activity. Full article
(This article belongs to the Special Issue Cell Death in Cancer)
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24 pages, 1707 KiB  
Review
Cancer Treatment Goes Viral: Using Viral Proteins to Induce Tumour-Specific Cell Death
by Jasmine Wyatt, Manuel M. Müller and Mahvash Tavassoli
Cancers 2019, 11(12), 1975; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11121975 - 07 Dec 2019
Cited by 10 | Viewed by 3934
Abstract
Cell death is a tightly regulated process which can be exploited in cancer treatment to drive the killing of the tumour. Several conventional cancer therapies including chemotherapeutic agents target pathways involved in cell death, yet they often fail due to the lack of [...] Read more.
Cell death is a tightly regulated process which can be exploited in cancer treatment to drive the killing of the tumour. Several conventional cancer therapies including chemotherapeutic agents target pathways involved in cell death, yet they often fail due to the lack of selectivity they have for tumour cells over healthy cells. Over the past decade, research has demonstrated the existence of numerous proteins which have an intrinsic tumour-specific toxicity, several of which originate from viruses. These tumour-selective viral proteins, although from distinct backgrounds, have several similar and interesting properties. Though the mechanism(s) of action of these proteins are not fully understood, it is possible that they can manipulate several cell death modes in cancer exemplifying the intricate interplay between these pathways. This review will discuss our current knowledge on the topic and outstanding questions, as well as deliberate the potential for viral proteins to progress into the clinic as successful cancer therapeutics. Full article
(This article belongs to the Special Issue Cell Death in Cancer)
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26 pages, 2571 KiB  
Review
The Multifaceted Roles of Pyroptotic Cell Death Pathways in Cancer
by Man Wang, Shuai Jiang, Yinfeng Zhang, Peifeng Li and Kun Wang
Cancers 2019, 11(9), 1313; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11091313 - 05 Sep 2019
Cited by 47 | Viewed by 6007
Abstract
Cancer is a category of diseases involving abnormal cell growth with the potential to invade other parts of the body. Chemotherapy is the most widely used first-line treatment for multiple forms of cancer. Chemotherapeutic agents act via targeting the cellular apoptotic pathway. However, [...] Read more.
Cancer is a category of diseases involving abnormal cell growth with the potential to invade other parts of the body. Chemotherapy is the most widely used first-line treatment for multiple forms of cancer. Chemotherapeutic agents act via targeting the cellular apoptotic pathway. However, cancer cells usually acquire chemoresistance, leading to poor outcomes in cancer patients. For that reason, it is imperative to discover other cell death pathways for improved cancer intervention. Pyroptosis is a new form of programmed cell death that commonly occurs upon pathogen invasion. Pyroptosis is marked by cell swelling and plasma membrane rupture, which results in the release of cytosolic contents into the extracellular space. Currently, pyroptosis is proposed to be an alternative mode of cell death in cancer treatment. Accumulating evidence shows that the key components of pyroptotic cell death pathways, including inflammasomes, gasdermins and pro-inflammatory cytokines, are involved in the initiation and progression of cancer. Interfering with pyroptotic cell death pathways may represent a promising therapeutic option for cancer management. In this review, we describe the current knowledge regarding the biological significance of pyroptotic cell death pathways in cancer pathogenesis and also discuss their potential therapeutic utility. Full article
(This article belongs to the Special Issue Cell Death in Cancer)
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