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Apoptosis and Autophagy: The Double Edge in Cancer Development and Progression and in Other Human Diseases 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 September 2020) | Viewed by 46404

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Prof. Dr. Michele Caraglia

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Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
Interests: noncoding RNAs; micro-RNAs; prostate cancer; nanotechnological delivery of anticancer drugs and nucleic acids; diagnostic markers in cancer; Urotensin II receptor; next-generation sequencing; predictive markers of response; circulating tumor cells
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Prof. Dr. Maria Luisa Balestrieri

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Department of Biochemistry, Biophysics and General Pathology, School of Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy
Interests: aging; oxidative stress; nitric oxide; endothelial cells; endothelial progenitor cells; angiogenesis; inflammation; cell senescence; apoptosis; atherosclerosis; diabetes, endothelial dysfunction, sirtuins and cardiovascular disease; natural products; betaines; health; bioactive compounds; free radicals; antioxidants; ergothioneine; cell cycle; cancer-related biochemical pathways; cell proliferation; senescence; cancer cell death; epigenetic regulation; sirtuins and cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

We are pleased to announced the continuation of our Special Issue “Apoptosis and Autophagy: The Double Edge in Cancer Development and Progression and in Other Human Diseases”, with a second edition.

The mechanisms of cell death have a pivotal role in the determination of the fate of normal and cancer cells in a multicellular organism. The disruption of these mechanisms is at the core of the development of inflammatory and tumor diseases, and knowledge of the molecular components altered in specific illnesses can be useful in the design of new therapeutic strategies for the treatment of human cancers as well as of inflammatory diseases. Two of the most known cell death mechanisms are apoptosis and autophagy, which are differently-involved in the regulation of tumor cell proliferation and metastasization. These mechanisms are often opposite, and autophagy is described as an escape mechanism from apoptotic occurrence, representing a protective effect of tumor cells to anti-cancer agents or hypoxic conditions, both of which are deleterious for cancer progression. On the other hand, some anti-cancer agents can induce autophagy during the repression of tumor proliferation. In this way, autophagy can become a marker of cancer response to treatment. The existence of specific tumor conditions can determine the functional role of autophagy in cancer tissues. The interaction between autophagy and apoptosis occurs through the cross-talk of the respective molecular mechanisms that are able to influence each other in a tunable way. A role for apoptosis and autophagy in the regulation of normal tissue development and differentiation is also emerging. Therefore, apoptosis and autophagy also regulate the physiological mechanisms of several organs (i.e., liver and ovary), and are involved in the occurrence of several diseases, based on either a development defect or a chronic inflammatory status. The intervention on the programmed cell death with specific agents can be a new strategy for the treatment of these kinds of diseases.

This Issue of the International Journal of Molecular Sciences will focus on the recent advances in “Apoptosis and Autophagy: The Double Edge in Cancer Development and Progression and in Other Human Diseases 2.0”, including new insights into the molecular mechanisms of apoptosis, autophagy, and other programmed cell death mechanisms (i.e., senescence), and their correlations with the control of cancer growth, metastasization, tissue development, and inflammation. Moreover, emerging data on the natural or synthetic modulators of apoptosis and autophagy in relation to new therapeutic strategies are welcome.

Prof. Dr. Michele Caraglia
Prof. Dr. Maria Luisa Balestrieri
Guest Editors

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Keywords

apoptosis
autophagy
cancer
miRNA
long non-coding RNAs
senescence
inflammation
therapeutics

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Published Papers (11 papers)

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Research

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14 pages, 4435 KiB

Open AccessArticle

Contribution of Autophagy-Notch1-Mediated NLRP3 Inflammasome Activation to Chronic Inflammation and Fibrosis in Keloid Fibroblasts

by Seongju Lee, Sun Kyeon Kim, Hyungsun Park, Yu Jin Lee, Song Hee Park, Kyung Jae Lee, Dong Geon Lee, Hoon Kang and Jung Eun Kim

Int. J. Mol. Sci. 2020, 21(21), 8050; https://doi.org/10.3390/ijms21218050 - 28 Oct 2020

Cited by 39 | Viewed by 2968

Abstract

Keloid is a representative chronic fibroproliferative condition that occurs after tissue injury. Emerging evidence showed that activation of NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome is involved in the pro-inflammatory response in injured tissues. However, the role of NLRP3 inflammasome in keloid progression remains unclear. Notch signaling, which activates NLRP3 inflammasome, is known to contribute to scar formation in keloid, but the cause of enhanced Notch signaling in keloid is not clear. We sought to investigate whether autophagy regulates Notch1 signaling in keloid fibroblasts and determine whether Notch1 signaling might regulate NLRP3 inflammasomes and myofibroblast differentiation. An in vitro model of keloid was established by culturing primary keloid fibroblasts from patients. Expression levels of Notch1, NLRP3 inflammasome proteins, pro-inflammatory cytokines, and myofibroblast markers in keloid fibroblasts were examined and compared with those in normal fibroblasts. Autophagy known to mediate Notch1 degradation was also monitored in fibroblasts. Small interfering RNA (siRNA) targeting Notch1 was used to transfect keloid fibroblasts to further examine the role of Notch signaling in NLRP3 inflammasome activation. Expression levels of Notch1 and NLRP3 inflammasome in keloid fibroblasts increased compared to those in normal fibroblasts. Such increases were accompanied by increased LC3 levels and reduced autophagic flux. Notch1 silencing in keloid fibroblasts by siRNA transfection significantly suppressed increased levels of overall NLRP3 inflammasome complex proteins, NF-kB, and α-smooth muscle actin. Autophagy induction by rapamycin treatment in keloid fibroblasts effectively suppressed expression levels of Notch1 and NLRP3 inflammasome proteins. Decreased autophagy activity in keloid can result in Notch1-mediated myofibroblast activation and NLRP3 inflammasome signaling activation which is critical for chronic inflammation. Collectively, these results identify Notch1 as a novel activator of NLRP3 inflammasome signaling leading to chronic tissue damage and myofibroblast differentiation in keloid progression. Full article

(This article belongs to the Special Issue Apoptosis and Autophagy: The Double Edge in Cancer Development and Progression and in Other Human Diseases 2.0)

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14 pages, 1751 KiB

Open AccessArticle

Transcriptomic Profiling for the Autophagy Pathway in Colorectal Cancer

by Justyna Gil, Paweł Karpiński and Maria M. Sąsiadek

Int. J. Mol. Sci. 2020, 21(19), 7101; https://doi.org/10.3390/ijms21197101 - 26 Sep 2020

Cited by 7 | Viewed by 2553

Abstract

The role of autophagy in colorectal cancer (CRC) pathogenesis appears to be crucial. Autophagy acts both as a tumor suppressor, by removing redundant cellular material, and a tumor-promoting factor, by providing access to components necessary for growth, metabolism, and proliferation. To date, little is known about the expression of genes that play a basal role in the autophagy in CRC. In this study, we aimed to compare the expression levels of 46 genes involved in the autophagy pathway between tumor-adjacent and tumor tissue, employing large RNA sequencing (RNA-seq) and microarray datasets. Additionally, we verified our results using data on 38 CRC cell lines. Gene set enrichment analysis revealed a significant deregulation of autophagy-related gene sets in CRC. The unsupervised clustering of tumors using the mRNA levels of autophagy-related genes revealed the existence of two major clusters: microsatellite instability (MSI)-enriched and -depleted. In cluster 1 (MSI-depleted), ATG9B and LAMP1 genes were the most prominently expressed, whereas cluster 2 (MSI-enriched) was characterized by DRAM1 upregulation. CRC cell lines were also clustered according to MSI-enriched/-depleted subgroups. The moderate deregulation of autophagy-related genes in cancer tissue, as compared to adjacent tissue, suggests a prominent field cancerization or early disruption of autophagy. Genes differentiating these clusters are promising candidates for CRC targeting therapy worthy of further investigation. Full article

(This article belongs to the Special Issue Apoptosis and Autophagy: The Double Edge in Cancer Development and Progression and in Other Human Diseases 2.0)

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13 pages, 3413 KiB

Open AccessArticle

Stress Granule Formation Attenuates RACK1-Mediated Apoptotic Cell Death Induced by Morusin

by Ye-Jin Park, Dong Wook Choi, Sang Woo Cho, Jaeseok Han, Siyoung Yang and Cheol Yong Choi

Int. J. Mol. Sci. 2020, 21(15), 5360; https://doi.org/10.3390/ijms21155360 - 28 Jul 2020

Cited by 22 | Viewed by 4869

Abstract

Stress granules are membraneless organelles composed of numerous components including ribonucleoproteins. The stress granules are characterized by a dynamic complex assembly in response to various environmental stressors, which has been implicated in the coordinated regulation of diverse biological pathways, to exert a protective role against stress-induced cell death. Here, we show that stress granule formation is induced by morusin, a novel phytochemical displaying antitumor capacity through barely known mechanisms. Morusin-mediated induction of stress granules requires activation of protein kinase R (PKR) and subsequent eIF2α phosphorylation. Notably, genetic inactivation of stress granule formation mediated by G3BP1 knockout sensitized cancer cells to morusin treatment. This protective function against morusin-mediated cell death can be attributed at least in part to the sequestration of receptors for activated C kinase-1 (RACK1) within the stress granules, which reduces caspase-3 activation. Collectively, our study provides biochemical evidence for the role of stress granules in suppressing the antitumor capacity of morusin, proposing that morusin treatment, together with pharmacological inhibition of stress granules, could be an efficient strategy for targeting cancer. Full article

(This article belongs to the Special Issue Apoptosis and Autophagy: The Double Edge in Cancer Development and Progression and in Other Human Diseases 2.0)

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14 pages, 3968 KiB

Open AccessCommunication

Human NANOS1 Represses Apoptosis by Downregulating Pro-Apoptotic Genes in the Male Germ Cell Line

by Damian M. Janecki, Erkut Ilaslan, Maciej J. Smialek, Marcin P. Sajek, Maciej Kotecki, Barbara Ginter-Matuszewska, Patryk Krainski, Jadwiga Jaruzelska and Kamila Kusz-Zamelczyk

Int. J. Mol. Sci. 2020, 21(8), 3009; https://doi.org/10.3390/ijms21083009 - 24 Apr 2020

Cited by 6 | Viewed by 3638

Abstract

While two mouse NANOS paralogues, NANOS2 and NANOS3, are crucial for maintenance of germ cells by suppression of apoptosis, the mouse NANOS1 paralogue does not seem to regulate these processes. Previously, we described a human NANOS1 p.[(Pro34Thr);(Ser83del)] mutation associated with the absence of germ cells in seminiferous tubules of infertile patients, which might suggest an anti-apoptotic role of human NANOS1. In this study, we aimed to determine a potential influence of human NANOS1 on the maintenance of TCam-2 model germ cells by investigating proliferation, cell cycle, and apoptosis. Constructs encoding wild-type or mutated human NANOS1 were used for transfection of TCam-2 cells, in order to investigate the effect of NANOS1 on cell proliferation, which was studied using a colorimetric assay, as well as apoptosis and the cell cycle, which were measured by flow cytometry. RNA-Seq (RNA sequencing) analysis followed by RT-qPCR (reverse transcription and quantitative polymerase chain reaction) was conducted for identifying pro-apoptotic genes repressed by NANOS1. Here, we show that overexpression of NANOS1 downregulates apoptosis in TCam-2 cells. Moreover, we found that NANOS1 represses a set of pro-apoptotic genes at the mRNA level. We also found that the infertility-associated p.[(Pro34Thr);(Ser83del)] mutation causes NANOS1 to functionally switch from being anti-apoptotic to pro-apoptotic in the human male germ cell line. Thus, this report is the first to show an anti-apoptotic role of NANOS1 exerted by negative regulation of mRNAs of pro-apoptotic genes. Full article

(This article belongs to the Special Issue Apoptosis and Autophagy: The Double Edge in Cancer Development and Progression and in Other Human Diseases 2.0)

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14 pages, 2564 KiB

Open AccessArticle

TLR3 Expression Induces Apoptosis in Human Non-Small-Cell Lung Cancer

by Francesca Bianchi, Spyridon Alexiadis, Chiara Camisaschi, Mauro Truini, Giovanni Centonze, Massimo Milione, Andrea Balsari, Elda Tagliabue and Lucia Sfondrini

Int. J. Mol. Sci. 2020, 21(4), 1440; https://doi.org/10.3390/ijms21041440 - 20 Feb 2020

Cited by 34 | Viewed by 3908

Abstract

The prognostic value of Toll-like receptor 3 (TLR3) is debated in cancer, differing between tumor types, methods, and cell types. We recently showed for the first time that TLR3 expression on early stage non-small-cell lung cancer (NSCLC) results associated with a good prognosis. Here, we provide experimental evidences explaining the molecular reason behind TLR3’s favorable prognostic role. We demonstrated that TLR3 activation in vitro induces apoptosis in lung cancer cell lines and, accordingly, that TLR3 expression is associated with caspase-3 activation in adenocarcinoma NSCLC specimens, both evaluated by immunohistochemistry. Moreover, we showed that TLR3 expression on cancer cells contributes to activate the CD103+ lung dendritic cell subset, that is specifically associated with processing of antigens derived from apoptotic cells and their presentation to CD8+ T lymphocytes. These findings point to the relevant role of TLR3 expression on lung cancer cells and support the use of TLR3 agonists in NSCLC patients to re-activate local innate immune response. Full article

(This article belongs to the Special Issue Apoptosis and Autophagy: The Double Edge in Cancer Development and Progression and in Other Human Diseases 2.0)

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10 pages, 3400 KiB

Open AccessCommunication

Anti-Apoptotic and Anti-Oxidant Proteins in Glioblastomas: Immunohistochemical Expression of Beclin and DJ-1 and Its Correlation with Prognosis

by Elia Guadagno, Giorgio Borrelli, Sara Pignatiello, Annalidia Donato, Ivan Presta, Biagio Arcidiacono, Natalia Malara, Domenico Solari, Teresa Somma, Paolo Cappabianca, Giuseppe Donato and Marialaura Del Basso De Caro

Int. J. Mol. Sci. 2019, 20(16), 4066; https://doi.org/10.3390/ijms20164066 - 20 Aug 2019

Cited by 5 | Viewed by 2938

Abstract

DJ-1 deglycase is a protein with anti-oxidative and anti-apoptotic properties and its role in oncogenesis is controversial. Indeed in primary breast cancer and non-small-cell lung carcinoma, its higher expression was shown in more aggressive tumors while in other neoplasms (e.g., pancreatic adenocarcinoma), higher expression was related to better prognosis. Beclin has a relevant role in autophagy and cellular death regulation, processes that are well known to be impaired in neoplastic cells. DJ-1 shows the ability to modulate signal transduction. It can modulate autophagy through many signaling pathways, a process that can mediate either cell survival or cell death depending on the circumstances. Previously, it has been suggested that the involvement of DJ-1 in autophagy regulation may play a role in tumorigenesis. The aim of our study was to investigate the link between DJ-1 and Beclin-1 in glioblastoma through the immunohistochemical expression of such proteins and to correlate the data obtained with prognosis. Protein expression was assessed by immunohistochemistry and the immunoscores were correlated with clinicopathologic parameters. Kaplan–Meier survival curves were generated. A statistically significant association between DJ-1 score and recurrence (p = 0.0189) and between the former and Isocitrate Dehydrogenase 1 (IDH1) mutation (p = 0.0072) was observed. Kaplan–Meier survival curve analysis revealed that a higher DJ-1 score was associated with longer overall survival (p = 0.0253, ĸ2 = 5.005). Furthermore, an unexpected direct correlation (p = 0.0424, r = 0.4009) between DJ-1 and Beclin score was evident. The most significant result of the present study was the evidence of high DJ-1 expression in IDH-mutant tumors and in cases with longer overall survival. This finding could aid, together with IDH1, in the identification of glioblastomas with better prognosis. Full article

(This article belongs to the Special Issue Apoptosis and Autophagy: The Double Edge in Cancer Development and Progression and in Other Human Diseases 2.0)

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14 pages, 1419 KiB

Open AccessArticle

A Hydroquinone-Based Derivative Elicits Apoptosis and Autophagy via Activating a ROS-Dependent Unfolded Protein Response in Human Glioblastoma

by Silvia Zappavigna, Alessia Maria Cossu, Marianna Abate, Gabriella Misso, Angela Lombardi, Michele Caraglia and Rosanna Filosa

Int. J. Mol. Sci. 2019, 20(15), 3836; https://doi.org/10.3390/ijms20153836 - 06 Aug 2019

Cited by 9 | Viewed by 4408

Abstract

5-Lipoxygenase (5-LO) has been reported to be highly expressed in brain tumors and to promote glioma cell proliferation. Therefore, we investigated the anticancer activity of the novel 5-LO inhibitor derivative 3-tridecyl-4,5-dimethoxybenzene-1,2-diol hydroquinone (EA-100C red) on glioblastoma (GBM) cell growth. Cell viability was evaluated by MTT assay. The effects of the compound on apoptosis, oxidative stress and autophagy were assessed by flow cytometry (FACS). The mode of action was confirmed by Taqman apoptosis array, Real Time qPCR, confocal microscopy analysis and the western blotting technique. Our results showed that EA-100C Red had a higher anti-proliferative effect on LN229 as compared to U87MG cells. The compound induced a significant increase of apoptosis and autophagy and up-regulated pro-apoptotic genes (Bcl3, BNIP3L, and NFKBIA) in both GBM cell lines. In this light, we studied the effects of EA-100C red on the expression of CHOP and XBP1, that are implicated in ER-stress-mediated cell death. In summary, our findings revealed that EA-100C red induced ER stress-mediated apoptosis associated to autophagy in GBM cells through CHOP and Beclin1 up-regulation and activation of caspases 3, 9, JNK and NF-kappaB pathway. On these bases, EA-100C red could represent a promising compound for anti-cancer treatment. Full article

(This article belongs to the Special Issue Apoptosis and Autophagy: The Double Edge in Cancer Development and Progression and in Other Human Diseases 2.0)

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Review

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14 pages, 746 KiB

Open AccessReview

The Role of Cell Cycle Regulators in Cell Survival—Dual Functions of Cyclin-Dependent Kinase 20 and p21^Cip1/Waf1

by Lo Lai, Ga Yoon Shin and Hongyu Qiu

Int. J. Mol. Sci. 2020, 21(22), 8504; https://doi.org/10.3390/ijms21228504 - 12 Nov 2020

Cited by 32 | Viewed by 3602

Abstract

The mammalian cell cycle is important in controlling normal cell proliferation and the development of various diseases. Cell cycle checkpoints are well regulated by both activators and inhibitors to avoid cell growth disorder and cancerogenesis. Cyclin dependent kinase 20 (CDK20) and p21^Cip1/Waf1 are widely recognized as key regulators of cell cycle checkpoints controlling cell proliferation/growth and involving in developing multiple cancers. Emerging evidence demonstrates that these two cell cycle regulators also play an essential role in promoting cell survival independent of the cell cycle, particularly in those cells with a limited capability of proliferation, such as cardiomyocytes. These findings bring new insights into understanding cytoprotection in these tissues. Here, we summarize the new progress of the studies on these two molecules in regulating cell cycle/growth, and their new roles in cell survival by inhibiting various cell death mechanisms. We also outline their potential implications in cancerogenesis and protection in heart diseases. This information renews the knowledge in molecular natures and cellular functions of these regulators, leading to a better understanding of the pathogenesis of the associated diseases and the discovery of new therapeutic strategies. Full article

(This article belongs to the Special Issue Apoptosis and Autophagy: The Double Edge in Cancer Development and Progression and in Other Human Diseases 2.0)

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21 pages, 1196 KiB

Open AccessReview

Targeting Autophagy in Breast Cancer

by Stefania Cocco, Alessandra Leone, Michela Piezzo, Roberta Caputo, Vincenzo Di Lauro, Francesca Di Rella, Giuseppina Fusco, Monica Capozzi, Germira di Gioia, Alfredo Budillon and Michelino De Laurentiis

Int. J. Mol. Sci. 2020, 21(21), 7836; https://doi.org/10.3390/ijms21217836 - 22 Oct 2020

Cited by 55 | Viewed by 6240

Abstract

Breast cancer is a heterogeneous disease consisting of different biological subtypes, with differences in terms of incidence, response to diverse treatments, risk of disease progression, and sites of metastases. In the last years, several molecular targets have emerged and new drugs, targeting PI3K/Akt/mTOR and cyclinD/CDK/pRb pathways and tumor microenvironment have been integrated into clinical practice. However, it is clear now that breast cancer is able to develop resistance to these drugs and the identification of the underlying molecular mechanisms is paramount to drive further drug development. Autophagy is a highly conserved homeostatic process that can be activated in response to antineoplastic agents as a cytoprotective mechanism. Inhibition of autophagy could enhance tumor cell death by diverse anti-cancer therapies, representing an attractive approach to control mechanisms of drug resistance. In this manuscript, we present a review of autophagy focusing on its interplay with targeted drugs used for breast cancer treatment. Full article

(This article belongs to the Special Issue Apoptosis and Autophagy: The Double Edge in Cancer Development and Progression and in Other Human Diseases 2.0)

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11 pages, 1004 KiB

Open AccessReview

Anticancer Strategy Targeting Cell Death Regulators: Switching the Mechanism of Anticancer Floxuridine-Induced Cell Death from Necrosis to Apoptosis

by Akira Sato, Akiko Hiramoto, Hye-Sook Kim and Yusuke Wataya

Int. J. Mol. Sci. 2020, 21(16), 5876; https://doi.org/10.3390/ijms21165876 - 16 Aug 2020

Cited by 15 | Viewed by 2800

Abstract

Cell death can be broadly characterized as either necrosis or apoptosis, depending on the morphological and biochemical features of the cell itself. We have previously reported that the treatment of mouse mammary carcinoma FM3A cells with the anticancer drug floxuridine (FUdR) induces necrosis in the original clone F28-7 but apoptosis in the variant F28-7-A. We have identified regulators, including heat shock protein 90, lamin-B1, cytokeratin-19, and activating transcription factor 3, of cell death mechanisms by using comprehensive gene and protein expression analyses and a phenotype-screening approach. We also observed that the individual inhibition or knockdown of the identified regulators in F28-7 results in a shift from necrotic to apoptotic morphology. Furthermore, we investigated microRNA (miRNA, miR) expression profiles in sister cell strains F28-7 and F28-7-A using miRNA microarray analyses. We found that several unique miRNAs, miR-351-5p and miR-743a-3p, were expressed at higher levels in F28-7-A than in F28-7. Higher expression of these miRNAs in F28-7 induced by transfecting miR mimics resulted in a switch in the mode of cell death from necrosis to apoptosis. Our findings suggest that the identified cell death regulators may play key roles in the decision of cell death mechanism: necrosis or apoptosis. Full article

(This article belongs to the Special Issue Apoptosis and Autophagy: The Double Edge in Cancer Development and Progression and in Other Human Diseases 2.0)

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28 pages, 2295 KiB

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The Role of Autophagy for the Regeneration of the Aging Liver

by Fengming Xu, Chuanfeng Hua, Hans-Michael Tautenhahn, Olaf Dirsch and Uta Dahmen

Int. J. Mol. Sci. 2020, 21(10), 3606; https://doi.org/10.3390/ijms21103606 - 20 May 2020

Cited by 30 | Viewed by 7750

Abstract

Age is one of the key risk factors to develop malignant diseases leading to a high incidence of hepatic tumors in the elderly population. The only curative treatment for hepatic tumors is surgical removal, which initiates liver regeneration. However, liver regeneration is impaired with aging, leading to an increased surgical risk for the elderly patient. Due to the increased risk, those patients are potentially excluded from curative surgery. Aging impairs autophagy via lipofuscin accumulation and inhibition of autophagosome formation. Autophagy is a recycling mechanism for eukaryotic cells to maintain homeostasis. Its principal function is to degrade endogenous bio-macromolecules for recycling cellular substances. A number of recent studies have shown that the reduced regenerative capacity of the aged remnant liver can be restored by promoting autophagy. Autophagy can be activated via multiple mTOR-dependent and mTOR-independent pathways. However, inducing autophagy through the mTOR-dependent pathway alone severely impairs liver regeneration. In contrast, recent observations suggest that inducing autophagy via mTOR-independent pathways might be promising in promoting liver regeneration. Conclusion: Activation of autophagy via an mTOR-independent autophagy inducer is a potential therapy for promoting liver regeneration, especially in the elderly patients at risk. Full article

(This article belongs to the Special Issue Apoptosis and Autophagy: The Double Edge in Cancer Development and Progression and in Other Human Diseases 2.0)

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