Special Issue "Cellular Stress in Cancer Progression, Drug Resistance and Treatment"

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

Deadline for manuscript submissions: closed (30 November 2018)

Special Issue Editors

Guest Editor
Dr. Denis Collins

Cancer Biotherapeutics, National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland
Website | E-Mail
Interests: signal transduction in cancer; tumour-immune interactions; the mechanisms of resistance to small molecules; monoclonal antibody (mAb)-targeted therapies in cancer; the impact of somatic mutations on targeted therapy responses; immune-modulatory therapies and stress-related cell signaling pathways
Guest Editor
Dr. Eva Szegezdi

Apoptosis Research Centre, School of Natural Sciences, National University of Ireland, Galway; Biomedical Sciences, Dangan, Galway, Ireland
Website | E-Mail
Phone: +353-9149-5037
Interests: death receptors, apoptosis, cell death signalling, leukemia, leukemic stem cells, tumour-microenvironment interaction, drug resistance

Special Issue Information

Dear Colleagues,

Cellular stress is an inherent feature of carcinogenesis, from the start of malignant transformation throughout tumour progression to drug resistance. The normal cell stress response engages a number of checkpoints that can: 1) arrest the cell cycle temporarily to allow repair; 2) permanently arrest the cell cycle (senescence); or 3) initiate cell death. Correct functioning of these responses is essential for tumour suppression, meaning they are often aberrant in cancer.

Cellular stress pathways are triggered in malignant cells both by inherent processes in the malignant cells, such as oncogenic stress, insufficient nutrient and oxygen supply, DNA damage and endoplasmic reticulum stress due to, for example, accumulating mutant proteins as well as by extrinsic factors, such as chemotherapeutics. The cellular stress response of the tumour cells can also impact on the tumour microenvironment, including the residing the immune response against the tumour and inflammation, an area that is now at the forefront in anti-cancer therapeutic strategies.

The importance of these cell stress pathways in cancer is increasingly recognized in recent research, both as a driver of carcinogenesis and as a target for therapy. The aim of this Special Issue is to provide an updated overview of the current progress in the field and highlight perspectives and challenges for the future and invites contributions from all areas related to cellular stress pathways in cancer development, how they impact on drug resistance and may be exploited for therapy.

Dr. Denis Collins
Dr. Eva Szegezdi
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 papers will be 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 monthly 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 1800 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.

Published Papers (9 papers)

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Research

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Open AccessArticle Combination Therapy of Chloroquine and C2-Ceramide Enhances Cytotoxicity in Lung Cancer H460 and H1299 Cells
Cancers 2019, 11(3), 370; https://doi.org/10.3390/cancers11030370
Received: 11 November 2018 / Revised: 27 February 2019 / Accepted: 7 March 2019 / Published: 15 March 2019
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Abstract
Non-small cell lung cancer (NSCLC) is a type of malignant cancer, and 85% of metastatic NSCLC patients have a poor prognosis. C2-ceramide induces G2/M phase arrest and cytotoxicity in NSCLC cells. In this study, the autophagy-inducing effect of C2-ceramide [...] Read more.
Non-small cell lung cancer (NSCLC) is a type of malignant cancer, and 85% of metastatic NSCLC patients have a poor prognosis. C2-ceramide induces G2/M phase arrest and cytotoxicity in NSCLC cells. In this study, the autophagy-inducing effect of C2-ceramide was demonstrated, and cotreatment with the autophagy inhibitor chloroquine (CQ) was investigated in NSCLC H460 and H1299 cells. The results suggested that C2-ceramide exhibited dose-dependent anticancer effects in H460 and H1299 cells and autophagy induction. Zebrafish-based acridine orange staining confirmed the combined effects in vivo. Importantly, the combination of a sublethal dose of C2-ceramide and CQ resulted in additive cytotoxicity and autophagy in both cell lines. Alterations of related signaling factors, including Src and SIRT1 inhibition and activation of the autophagic regulators LAMP2 and LC3-I/II, contributed to the autophagy-dependent apoptosis. We found that C2-ceramide continuously initiated autophagy; however, CQ inhibited autophagosome maturation and degradation during autophagy progression. Accumulated and non-degraded autophagosomes increased NSCLC cell stress, eventually leading to cell death. This study sheds light on improvements to NSCLC chemotherapy to reduce the chemotherapy dose and NSCLC patient burden. Full article
(This article belongs to the Special Issue Cellular Stress in Cancer Progression, Drug Resistance and Treatment)
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Open AccessArticle HER2-Targeted Tyrosine Kinase Inhibitors Cause Therapy-Induced-Senescence in Breast Cancer Cells
Cancers 2019, 11(2), 197; https://doi.org/10.3390/cancers11020197
Received: 15 January 2019 / Accepted: 1 February 2019 / Published: 8 February 2019
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Abstract
Prolonged treatment of HER2 positive breast cancer cells with tyrosine kinase inhibitors (TKIs) leads to the emergence of acquired resistance. However, the effects of continuous TKI exposure on cell fate, and the steps leading to the acquisition of a resistant phenotype are poorly [...] Read more.
Prolonged treatment of HER2 positive breast cancer cells with tyrosine kinase inhibitors (TKIs) leads to the emergence of acquired resistance. However, the effects of continuous TKI exposure on cell fate, and the steps leading to the acquisition of a resistant phenotype are poorly understood. To explore this, we exposed five HER2 positive cells lines to HER2 targeted therapies for periods of up to 4 weeks and examined senescence associated β-galactosidase (SA-β-gal) activity together with additional markers of senescence. We found that lapatinib treatment resulted in phenotypic alterations consistent with a senescent phenotype and strong SA-β-gal activity in HER2-positive cell lines. Lapatinib-induced senescence was associated with elevated levels of p15 and p27 but was not dependent on the expression of p16 or p21. Restoring wild type p53 activity either by transfection or by treatment with APR-246, a molecule which reactivates mutant p53, blocked lapatinib-induced senescence and caused increased cell death. In contrast to lapatinib, SA-β-gal activity was not induced by exposing the cells to trastuzumab as a single agent but co-administration of lapatinib and trastuzumab induced senescence, as did treatment of the cells with the irreversible HER2 TKIs neratinib and afatinib. Neratinib- and afatinib-induced senescence was not reversed by removing the drug whereas lapatinib-induced senescence was reversible. In summary, therapy-induced senescence represents a novel mechanism of action of HER2 targeting agents and may be a potential pathway for the emergence of resistance. Full article
(This article belongs to the Special Issue Cellular Stress in Cancer Progression, Drug Resistance and Treatment)
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Open AccessArticle High-Throughput Screening Identified Compounds Sensitizing Tumor Cells to Glucose Starvation in Culture and VEGF Inhibitors In Vivo
Cancers 2019, 11(2), 156; https://doi.org/10.3390/cancers11020156
Received: 27 December 2018 / Revised: 17 January 2019 / Accepted: 28 January 2019 / Published: 30 January 2019
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Abstract
Tumor cells utilize glucose to fuel their anabolic needs, including rapid proliferation. However, due to defective vasculature and increased glucose uptake, tumor cells must overcome glucose deprivation. Accordingly, tumor cells depend on cellular pathways promoting survival under such conditions. Targeting these survival mechanisms [...] Read more.
Tumor cells utilize glucose to fuel their anabolic needs, including rapid proliferation. However, due to defective vasculature and increased glucose uptake, tumor cells must overcome glucose deprivation. Accordingly, tumor cells depend on cellular pathways promoting survival under such conditions. Targeting these survival mechanisms can thus serve as a new therapeutic strategy in oncology. As such, we sought to identify small-molecule inhibitors which sensitize tumor cells to glucose starvation by high-throughput drug screening in vitro. Specifically, we searched for inhibitors that selectively killed tumor cells growing in glucose-free but not in normal medium. This phenotypic drug screen of 7000 agents with MCF7 cells led to the identification of 67 potential candidates, 31 of which were validated individually. Among the identified compounds, we found a high number of compounds known to target mitochondria. The efficacies of two of the identified compounds, QNZ (EVP4593) and papaverine, were validated in four different tumor cell lines. We found that these agents inhibited the mTOR(Mechamistic\Mammilian Target of Rapamycin) pathway in tumor cells growing under glucose starvation, but not under normal conditions. The results were validated and confirmed in vivo, with QNZ and papaverine exhibiting superior antitumor activity in a tumor xenograft model when combined with the VEGF inhibitor bevacizumab (avastin). Administering these drug combinations (i.e., avastin and papaverine, and avastin and QNZ) led to significant reductions in proliferation and mTOR activity of the aggressive DLD1 colon cell line in mice. Given our findings, we propose that compounds targeting metabolically challenged tumors, such as inhibitors of mitochondrial activity, be considered as a therapeutic strategy in cancer. Full article
(This article belongs to the Special Issue Cellular Stress in Cancer Progression, Drug Resistance and Treatment)
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Open AccessArticle The PERK Branch of the Unfolded Protein Response Promotes DLL4 Expression by Activating an Alternative Translation Mechanism
Cancers 2019, 11(2), 142; https://doi.org/10.3390/cancers11020142
Received: 3 December 2018 / Revised: 15 January 2019 / Accepted: 22 January 2019 / Published: 25 January 2019
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Abstract
Delta-like 4 (DLL4) is a pivotal endothelium specific Notch ligand that has been shown to function as a regulating factor during physiological and pathological angiogenesis. DLL4 functions as a negative regulator of angiogenic branching and sprouting. Interestingly, Dll4 is with Vegf-a one of [...] Read more.
Delta-like 4 (DLL4) is a pivotal endothelium specific Notch ligand that has been shown to function as a regulating factor during physiological and pathological angiogenesis. DLL4 functions as a negative regulator of angiogenic branching and sprouting. Interestingly, Dll4 is with Vegf-a one of the few examples of haplo-insufficiency, resulting in obvious vascular abnormalities and in embryonic lethality. These striking phenotypes are a proof of concept of the crucial role played by the bioavailability of VEGF and DLL4 during vessel patterning and that there must be a very fine-tuning of DLL4 expression level. However, to date the expression regulation of this factor was poorly studied. In this study, we showed that the DLL4 5′-UTR harbors an Internal Ribosomal Entry Site (IRES) that, in contrast to cap-dependent translation, was efficiently utilized in cells subjected to several stresses including hypoxia and endoplasmic reticulum stress (ER stress). We identified PERK, a kinase activated by ER stress, as the driver of DLL4 IRES-mediated translation, and hnRNP-A1 as an IRES-Trans-Acting Factor (ITAF) participating in the IRES-dependent translation of DLL4 during endoplasmic reticulum stress. The presence of a stress responsive internal ribosome entry site in the DLL4 msRNA suggests that the process of alternative translation initiation, by controlling the expression of this factor, could have a crucial role in the control of endothelial tip cell function. Full article
(This article belongs to the Special Issue Cellular Stress in Cancer Progression, Drug Resistance and Treatment)
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Open AccessArticle Fenofibrate Augments the Sensitivity of Drug-Resistant Prostate Cancer Cells to Docetaxel
Received: 29 November 2018 / Revised: 31 December 2018 / Accepted: 8 January 2019 / Published: 11 January 2019
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Abstract
Metronomic agents reduce the effective doses and adverse effects of cytostatics in cancer chemotherapy. Therefore, they can enhance the treatment efficiency of drug-resistant cancers. Cytostatic and anti-angiogenic effects of fenofibrate (FF) suggest that it can be used for the metronomic chemotherapy of drug-resistant [...] Read more.
Metronomic agents reduce the effective doses and adverse effects of cytostatics in cancer chemotherapy. Therefore, they can enhance the treatment efficiency of drug-resistant cancers. Cytostatic and anti-angiogenic effects of fenofibrate (FF) suggest that it can be used for the metronomic chemotherapy of drug-resistant prostate tumors. To estimate the effect of FF on the drug-resistance of prostate cancer cells, we compared the reactions of naïve and drug-resistant cells to the combined treatment with docetaxel (DCX)/mitoxantrone (MTX) and FF. FF sensitized drug-resistant DU145 and PC3 cells to DCX and MTX, as illustrated by their reduced viability and invasive potential observed in the presence of DCX/MTX and FF. The synergy of the cytostatic activities of both agents was accompanied by the inactivation of P-gp-dependent efflux, dysfunction of the microtubular system, and induction of polyploidy in DCX-resistant cells. Chemical inhibition of PPARα- and reactive oxygen species (ROS)-dependent pathways by GW6471 and N-acetyl-L-cysteine, respectively, had no effect on cell sensitivity to combined DCX/FF treatment. Instead, we observed the signs of adenosine triphosphate (ATP) deficit and autophagy in DCX/FF-treated drug-resistant cells. Furthermore, the cells that had been permanently propagated under DCX- and DCX/FF-induced stress did not acquire DCX/FF-resistance. Instead, relatively slow proliferation of DCX-resistant cells was efficiently inhibited by FF. Collectively, our observations show that FF reduces the effective doses of DCX by interfering with the drug resistance and energy metabolism of prostate cancer cells. Concomitantly, it impairs the chemotherapy-induced microevolution and expansion of DCX/FF-resistant cells. Therefore, FF can be applied as a metronomic agent to enhance the efficiency of palliative chemotherapy of prostate cancer. Full article
(This article belongs to the Special Issue Cellular Stress in Cancer Progression, Drug Resistance and Treatment)
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Review

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Open AccessReview Acquired Resistance to Antibody-Drug Conjugates
Cancers 2019, 11(3), 394; https://doi.org/10.3390/cancers11030394
Received: 22 February 2019 / Revised: 15 March 2019 / Accepted: 15 March 2019 / Published: 20 March 2019
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Abstract
Antibody-drug conjugates (ADCs) combine the tumor selectivity of antibodies with the potency of cytotoxic small molecules thereby constituting antibody-mediated chemotherapy. As this inherently limits the adverse effects of the chemotherapeutic, such approaches are heavily pursued by pharma and biotech companies and have resulted [...] Read more.
Antibody-drug conjugates (ADCs) combine the tumor selectivity of antibodies with the potency of cytotoxic small molecules thereby constituting antibody-mediated chemotherapy. As this inherently limits the adverse effects of the chemotherapeutic, such approaches are heavily pursued by pharma and biotech companies and have resulted in four FDA (Food and Drug Administration)-approved ADCs. However, as with other cancer therapies, durable responses are limited by the fact that under cell stress exerted by these drugs, tumors can acquire mechanisms of escape. Resistance can develop against the antibody component of ADCs by down-regulation/mutation of the targeted cell surface antigen or against payload toxicity by up-regulation of drug efflux transporters. Unique resistance mechanisms specific for the mode of action of ADCs have also emerged, like altered internalization or cell surface recycling of the targeted tumor antigen, changes in the intracellular routing or processing of ADCs, and impaired release of the toxic payload into the cytosol. These evasive changes are tailored to the specific nature and interplay of the three ADC constituents: the antibody, the linker, and the payload. Hence, they do not necessarily endow broad resistance to ADC therapy. This review summarizes preclinical and clinical findings that shed light on the mechanisms of acquired resistance to ADC therapies. Full article
(This article belongs to the Special Issue Cellular Stress in Cancer Progression, Drug Resistance and Treatment)
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Open AccessReview Role of Extracellular Vesicles (EVs) in Cell Stress Response and Resistance to Cancer Therapy
Cancers 2019, 11(2), 136; https://doi.org/10.3390/cancers11020136
Received: 20 December 2018 / Revised: 16 January 2019 / Accepted: 22 January 2019 / Published: 24 January 2019
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Abstract
Extracellular vesicles (EVs) are nanosized particles released by all cells that have been heralded as novel regulators of cell-to-cell communication. It is becoming increasingly clear that in response to a variety of stress conditions, cells employ EV-mediated intercellular communication to transmit a pro-survival [...] Read more.
Extracellular vesicles (EVs) are nanosized particles released by all cells that have been heralded as novel regulators of cell-to-cell communication. It is becoming increasingly clear that in response to a variety of stress conditions, cells employ EV-mediated intercellular communication to transmit a pro-survival message in the tumor microenvironment and beyond, supporting evasion of cell death and transmitting resistance to therapy. Understanding changes in EV cargo and secretion pattern during cell stress may uncover novel, targetable mechanisms underlying disease progression, metastasis and resistance to therapy. Further, the profile of EVs released into the circulation may provide a circulating biomarker predictive of response to therapy and indicative of microenvironmental conditions linked to disease progression, such as hypoxia. Continued progress in this exciting and rapidly expanding field of research will be dependent upon widespread adoption of transparent reporting standards and implementation of guidelines to establish a consensus on methods of EV isolation, characterisation and nomenclature employed. Full article
(This article belongs to the Special Issue Cellular Stress in Cancer Progression, Drug Resistance and Treatment)
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Open AccessReview Targeting Proteotoxic Stress in Cancer: A Review of the Role that Protein Quality Control Pathways Play in Oncogenesis
Received: 2 November 2018 / Revised: 24 November 2018 / Accepted: 7 December 2018 / Published: 9 January 2019
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Abstract
Despite significant advances in cancer diagnostics and therapeutics the majority of cancer unfortunately remains incurable, which has led to continued research to better understand its exceptionally diverse biology. As a result of genomic instability, cancer cells typically have elevated proteotoxic stress. Recent appreciation [...] Read more.
Despite significant advances in cancer diagnostics and therapeutics the majority of cancer unfortunately remains incurable, which has led to continued research to better understand its exceptionally diverse biology. As a result of genomic instability, cancer cells typically have elevated proteotoxic stress. Recent appreciation of this functional link between the two secondary hallmarks of cancer: aneuploidy (oxidative stress) and proteotoxic stress, has therefore led to the development of new anticancer therapies targeting this emerging “Achilles heel” of malignancy. This review highlights the importance of managing proteotoxic stress for cancer cell survival and provides an overview of the integral role proteostasis pathways play in the maintenance of protein homeostasis. We further review the efforts undertaken to exploit proteotoxic stress in multiple myeloma (as an example of a hematologic malignancy) and triple negative breast cancer (as an example of a solid tumor), and give examples of: (1) FDA-approved therapies in routine clinical use; and (2) promising therapies currently in clinical trials. Finally, we provide new insights gleaned from the use of emerging technologies to disrupt the protein secretory pathway and repurpose E3 ligases to achieve targeted protein degradation. Full article
(This article belongs to the Special Issue Cellular Stress in Cancer Progression, Drug Resistance and Treatment)
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Open AccessFeature PaperReview The Unfolded Protein Response in Breast Cancer
Cancers 2018, 10(10), 344; https://doi.org/10.3390/cancers10100344
Received: 3 August 2018 / Revised: 12 September 2018 / Accepted: 18 September 2018 / Published: 21 September 2018
Cited by 3 | PDF Full-text (1351 KB) | HTML Full-text | XML Full-text
Abstract
In 2018, in the US alone, it is estimated that 268,670 people will be diagnosed with breast cancer, and that 41,400 will die from it. Since breast cancers often become resistant to therapies, and certain breast cancers lack therapeutic targets, new approaches are [...] Read more.
In 2018, in the US alone, it is estimated that 268,670 people will be diagnosed with breast cancer, and that 41,400 will die from it. Since breast cancers often become resistant to therapies, and certain breast cancers lack therapeutic targets, new approaches are urgently required. A cell-stress response pathway, the unfolded protein response (UPR), has emerged as a promising target for the development of novel breast cancer treatments. This pathway is activated in response to a disturbance in endoplasmic reticulum (ER) homeostasis but has diverse physiological and disease-specific functions. In breast cancer, UPR signalling promotes a malignant phenotype and can confer tumours with resistance to widely used therapies. Here, we review several roles for UPR signalling in breast cancer, highlighting UPR-mediated therapy resistance and the potential for targeting the UPR alone or in combination with existing therapies. Full article
(This article belongs to the Special Issue Cellular Stress in Cancer Progression, Drug Resistance and Treatment)
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