Cancers

2023

Jump to: 2021, 2020, 2019

13 pages, 1963 KiB

Open AccessArticle

Inhibition of DHODH Enhances Replication-Associated Genomic Instability and Promotes Sensitivity in Endometrial Cancer

by Shengyuan Zhao, Aaliyah Francois and Dawit Kidane

Cancers 2023, 15(24), 5727; https://doi.org/10.3390/cancers15245727 - 6 Dec 2023

Cited by 2 | Viewed by 1395

Abstract

Endometrial carcinoma (EC) is the most common gynecological malignancy in the United States. De novo pyrimidine synthesis pathways generate nucleotides that are required for DNA synthesis. Approximately 38% of human endometrial tumors present with an overexpression of human dihydroorotate dehydrogenase (DHODH). However, the [...] Read more.

Endometrial carcinoma (EC) is the most common gynecological malignancy in the United States. De novo pyrimidine synthesis pathways generate nucleotides that are required for DNA synthesis. Approximately 38% of human endometrial tumors present with an overexpression of human dihydroorotate dehydrogenase (DHODH). However, the role of DHODH in cancer cell DNA replication and its impact on modulating a treatment response is currently unknown. Here, we report that endometrial tumors with overexpression of DHODH are associated with a high mutation count and chromosomal instability. Furthermore, tumors with an overexpression of DHODH show significant co-occurrence with mutations in DNA replication polymerases, which result in a histologically high-grade endometrial tumor. An in vitro experiment demonstrated that the inhibition of DHODH in endometrial cancer cell lines significantly induced replication-associated DNA damage and hindered replication fork progression. Furthermore, endometrial cancer cells were sensitive to the DHODH inhibitor either alone or in combination with the Poly (ADP-ribose) polymerase 1 inhibitor. Our findings may have important clinical implications for utilizing DHODH as a potential target to enhance cytotoxicity in high-grade endometrial tumors. Full article

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2021

Jump to: 2023, 2020, 2019

15 pages, 4737 KiB

Open AccessFeature PaperArticle

Vascular Damage in the Aorta of Wild-Type Mice Exposed to Ionizing Radiation: Sparing and Enhancing Effects of Dose Protraction

by Nobuyuki Hamada, Ki-ichiro Kawano, Takaharu Nomura, Kyoji Furukawa, Farina Mohamad Yusoff, Tatsuya Maruhashi, Makoto Maeda, Ayumu Nakashima and Yukihito Higashi

Cancers 2021, 13(21), 5344; https://doi.org/10.3390/cancers13215344 - 25 Oct 2021

Cited by 11 | Viewed by 2551

Abstract

During medical (therapeutic or diagnostic) procedures or in other settings, the circulatory system receives ionizing radiation at various dose rates. Here, we analyzed prelesional changes in the circulatory system of wild-type mice at six months after starting acute, intermittent, or continuous irradiation with [...] Read more.

During medical (therapeutic or diagnostic) procedures or in other settings, the circulatory system receives ionizing radiation at various dose rates. Here, we analyzed prelesional changes in the circulatory system of wild-type mice at six months after starting acute, intermittent, or continuous irradiation with 5 Gy of photons. Independent of irradiation regimens, irradiation had little impact on left ventricular function, heart weight, and kidney weight. In the aorta, a single acute exposure delivered in 10 minutes led to structural disorganizations and detachment of the aortic endothelium, and intima-media thickening. These morphological changes were accompanied by increases in markers for profibrosis (TGF-β1), fibrosis (collagen fibers), proinflammation (TNF-α), and macrophages (F4/80 and CD68), with concurrent decreases in markers for cell adhesion (CD31 and VE-cadherin) and vascular functionality (eNOS) in the aortic endothelium. Compared with acute exposure, the magnitude of such aortic changes was overall greater when the same dose was delivered in 25 fractions spread over 6 weeks, smaller in 100 fractions over 5 months, and much smaller in chronic exposure over 5 months. These findings suggest that dose protraction alters vascular damage in the aorta, but in a way that is not a simple function of dose rate. Full article

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16 pages, 2577 KiB

Open AccessReview

Mitochondrial Control of Genomic Instability in Cancer

by Massimo Bonora, Sonia Missiroli, Mariasole Perrone, Francesco Fiorica, Paolo Pinton and Carlotta Giorgi

Cancers 2021, 13(8), 1914; https://doi.org/10.3390/cancers13081914 - 15 Apr 2021

Cited by 20 | Viewed by 3949

Abstract

Mitochondria are well known to participate in multiple aspects of tumor formation and progression. They indeed can alter the susceptibility of cells to engage regulated cell death, regulate pro-survival signal transduction pathways and confer metabolic plasticity that adapts to specific tumor cell demands. [...] Read more.

Mitochondria are well known to participate in multiple aspects of tumor formation and progression. They indeed can alter the susceptibility of cells to engage regulated cell death, regulate pro-survival signal transduction pathways and confer metabolic plasticity that adapts to specific tumor cell demands. Interestingly, a relatively poorly explored aspect of mitochondria in neoplastic disease is their contribution to the characteristic genomic instability that underlies the evolution of the disease. In this review, we summarize the known mechanisms by which mitochondrial alterations in cancer tolerate and support the accumulation of DNA mutations which leads to genomic instability. We describe recent studies elucidating mitochondrial responses to DNA damage as well as the direct contribution of mitochondria to favor the accumulation of DNA alterations. Full article

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2020

Jump to: 2023, 2021, 2019

28 pages, 2035 KiB

Open AccessReview

In Situ Detection of Complex DNA Damage Using Microscopy: A Rough Road Ahead

by Zacharenia Nikitaki, Eloise Pariset, Damir Sudar, Sylvain V. Costes and Alexandros G. Georgakilas

Cancers 2020, 12(11), 3288; https://doi.org/10.3390/cancers12113288 - 6 Nov 2020

Cited by 15 | Viewed by 4382

Abstract

Complexity of DNA damage is considered currently one if not the primary instigator of biological responses and determinant of short and long-term effects in organisms and their offspring. In this review, we focus on the detection of complex (clustered) DNA damage (CDD) induced [...] Read more.

Complexity of DNA damage is considered currently one if not the primary instigator of biological responses and determinant of short and long-term effects in organisms and their offspring. In this review, we focus on the detection of complex (clustered) DNA damage (CDD) induced for example by ionizing radiation (IR) and in some cases by high oxidative stress. We perform a short historical perspective in the field, emphasizing the microscopy-based techniques and methodologies for the detection of CDD at the cellular level. We extend this analysis on the pertaining methodology of surrogate protein markers of CDD (foci) colocalization and provide a unique synthesis of imaging parameters, software, and different types of microscopy used. Last but not least, we critically discuss the main advances and necessary future direction for the better detection of CDD, with important outcomes in biological and clinical setups. Full article

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11 pages, 2269 KiB

Open AccessArticle

Ionizing Irradiation Induces Vascular Damage in the Aorta of Wild-Type Mice

by Nobuyuki Hamada, Ki-ichiro Kawano, Farina Mohamad Yusoff, Kyoji Furukawa, Ayumu Nakashima, Makoto Maeda, Hiroshi Yasuda, Tatsuya Maruhashi and Yukihito Higashi

Cancers 2020, 12(10), 3030; https://doi.org/10.3390/cancers12103030 - 18 Oct 2020

Cited by 16 | Viewed by 3166

Abstract

There has been a recent upsurge of interest in the effects of ionizing radiation exposure on the circulatory system, because a mounting body of epidemiological evidence suggests that irradiation induces cardio- and cerebrovascular disease at a much lower dose and lower dose rate [...] Read more.

There has been a recent upsurge of interest in the effects of ionizing radiation exposure on the circulatory system, because a mounting body of epidemiological evidence suggests that irradiation induces cardio- and cerebrovascular disease at a much lower dose and lower dose rate than previously considered. The goal of our project is to determine whether dose protraction alters radiation effects on the circulatory system in a mouse model. To this end, the use of wild-type mice is pivotal albeit without manifestation of vascular diseases, because disease models (e.g., apolipoprotein E-deficient mice) are prone to hormetic responses following protracted exposures. As such, here, we first set out to analyze prelesional changes in the descending thoracic aorta of wild-type mice up to six months after a single acute exposure to 0 or 5 Gy of ¹³⁷Cs γ-rays. Scanning electron microscopy demonstrated that irradiation facilitated structural disorganizations and detachment of the aortic endothelium. The Miles assay with an albumin-binding dye Evans Blue revealed that irradiation enhanced vascular permeability. Immunofluorescence staining showed that irradiation led to partial loss of the aortic endothelium (evidenced by a lack of adhesion molecule CD31 and 4′,6-diamidino-2-phenylindole (DAPI) signals), a decrease in endothelial nitric oxide synthase and adherens junction protein (vascular endothelial (VE)-cadherin) in the aortic endothelium, along with an increase in inflammation (tumor necrosis factor (TNF)-α) and macrophage (F4/80) markers in the aorta. These findings suggest that irradiation produces vascular damage manifested as endothelial cell loss and increased vascular permeability, and that the decreased adherens junction and the increased inflammation lead to macrophage recruitment implicated in the early stage of atherosclerosis. Full article

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20 pages, 2594 KiB

Open AccessArticle

Monitoring DNA Damage and Repair in Peripheral Blood Mononuclear Cells of Lung Cancer Radiotherapy Patients

by Pavel N. Lobachevsky, Nicholas W. Bucknell, Joel Mason, Diane Russo, Xiaoyu Yin, Lisa Selbie, David L. Ball, Tomas Kron, Michael Hofman, Shankar Siva and Olga A. Martin

Cancers 2020, 12(9), 2517; https://doi.org/10.3390/cancers12092517 - 4 Sep 2020

Cited by 9 | Viewed by 3605

Abstract

Thoracic radiotherapy (RT) is required for the curative management of inoperable lung cancer, however, treatment delivery is limited by normal tissue toxicity. Prior studies suggest that using radiation-induced DNA damage response (DDR) in peripheral blood mononuclear cells (PBMC) has potential to predict RT-associated [...] Read more.

Thoracic radiotherapy (RT) is required for the curative management of inoperable lung cancer, however, treatment delivery is limited by normal tissue toxicity. Prior studies suggest that using radiation-induced DNA damage response (DDR) in peripheral blood mononuclear cells (PBMC) has potential to predict RT-associated toxicities. We collected PBMC from 38 patients enrolled on a prospective clinical trial who received definitive fractionated RT for non-small cell lung cancer. DDR was measured by automated counting of nuclear γ-H2AX foci in immunofluorescence images. Analysis of samples collected before, during and after RT demonstrated the induction of DNA damage in PBMC collected shortly after RT commenced, however, this damage repaired later. Radiation dose to the tumour and lung contributed to the in vivo induction of γ-H2AX foci. Aliquots of PBMC collected before treatment were also irradiated ex vivo, and γ-H2AX kinetics were analyzed. A trend for increasing of fraction of irreparable DNA damage in patients with higher toxicity grades was revealed. Slow DNA repair in three patients was associated with a combined dysphagia/cough toxicity and was confirmed by elevated in vivo RT-generated irreparable DNA damage. These results warrant inclusion of an assessment of DDR in PBMC in a panel of predictive biomarkers that would identify patients at a higher risk of toxicity. Full article

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19 pages, 3310 KiB

Open AccessArticle

Interphase Cytogenetic Analysis of G0 Lymphocytes Exposed to α-Particles, C-Ions, and Protons Reveals their Enhanced Effectiveness for Localized Chromosome Shattering—A Critical Risk for Chromothripsis

by Antonio Pantelias, Demetre Zafiropoulos, Roberto Cherubini, Lucia Sarchiapone, Viviana De Nadal, Gabriel E. Pantelias, Alexandros G. Georgakilas and Georgia I. Terzoudi

Cancers 2020, 12(9), 2336; https://doi.org/10.3390/cancers12092336 - 19 Aug 2020

Cited by 7 | Viewed by 4398

Abstract

For precision cancer radiotherapy, high linear energy transfer (LET) particle irradiation offers a substantial advantage over photon-based irradiation. In contrast to the sparse deposition of low-density energy by χ- or γ-rays, particle irradiation causes focal DNA damage through high-density energy deposition along the [...] Read more.

For precision cancer radiotherapy, high linear energy transfer (LET) particle irradiation offers a substantial advantage over photon-based irradiation. In contrast to the sparse deposition of low-density energy by χ- or γ-rays, particle irradiation causes focal DNA damage through high-density energy deposition along the particle tracks. This is characterized by the formation of multiple damage sites, comprising localized clustered patterns of DNA single- and double-strand breaks as well as base damage. These clustered DNA lesions are key determinants of the enhanced relative biological effectiveness (RBE) of energetic nuclei. However, the search for a fingerprint of particle exposure remains open, while the mechanisms underlying the induction of chromothripsis-like chromosomal rearrangements by high-LET radiation (resembling chromothripsis in tumors) await to be elucidated. In this work, we investigate the transformation of clustered DNA lesions into chromosome fragmentation, as indicated by the induction and post-irradiation repair of chromosomal damage under the dynamics of premature chromosome condensation in G0 human lymphocytes. Specifically, this study provides, for the first time, experimental evidence that particle irradiation induces localized shattering of targeted chromosome domains. Yields of chromosome fragments and shattered domains are compared with those generated by γ-rays; and the RBE values obtained are up to 28.6 for α-particles (92 keV/μm), 10.5 for C-ions (295 keV/μm), and 4.9 for protons (28.5 keV/μm). Furthermore, we test the hypothesis that particle radiation-induced persistent clustered DNA lesions and chromatin decompaction at damage sites evolve into localized chromosome shattering by subsequent chromatin condensation in a single catastrophic event—posing a critical risk for random rejoining, chromothripsis, and carcinogenesis. Consistent with this hypothesis, our results highlight the potential use of shattered chromosome domains as a fingerprint of high-LET exposure, while conforming to the new model we propose for the mechanistic origin of chromothripsis-like rearrangements. Full article

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20 pages, 3235 KiB

Open AccessArticle

MiR-302b as a Combinatorial Therapeutic Approach to Improve Cisplatin Chemotherapy Efficacy in Human Triple-Negative Breast Cancer

by Alessandra Cataldo, Sandra Romero-Cordoba, Ilaria Plantamura, Giulia Cosentino, Alfredo Hidalgo-Miranda, Elda Tagliabue and Marilena V. Iorio

Cancers 2020, 12(8), 2261; https://doi.org/10.3390/cancers12082261 - 12 Aug 2020

Cited by 15 | Viewed by 2935

Abstract

Introduction: Chemotherapy is still the standard of care for triple-negative breast cancers (TNBCs). Here, we investigated miR-302b as a therapeutic tool to enhance cisplatin sensitivity in vivo and unraveled the molecular mechanism. Materials and Methods: TNBC-xenografted mice were treated with miR-302b [...] Read more.

Introduction: Chemotherapy is still the standard of care for triple-negative breast cancers (TNBCs). Here, we investigated miR-302b as a therapeutic tool to enhance cisplatin sensitivity in vivo and unraveled the molecular mechanism. Materials and Methods: TNBC-xenografted mice were treated with miR-302b or control, alone or with cisplatin. Genome-wide transcriptome analysis and independent-validation of Integrin Subunit Alpha 6 (ITGA6) expression was assessed on mice tumor samples. Silencing of ITGA6 was performed to evaluate cisplatin response in vitro. Further, potential transcription factors of ITGA6 (E2F transcription facor 1 (E2F1), E2F transcription factor 2 (E2F2), and Yin Yang 1 (YY1)) were explored to define the miRNA molecular mechanism. The miR-302b expression was also assessed in TNBC patients treated with chemotherapy. Results: The miR–302b-cisplatin combination significantly impaired tumor growth versus the control through indirect ITGA6 downregulation. Indeed, ITGA6 was downmodulated in mice treated with miR-302b–cisplatin, and ITGA6 silencing increased drug sensitivity in TNBC cells. In silico analyses and preclinical assays pointed out the regulatory role of the E2F family and YY1 on ITGA6 expression under miR-302b–cisplatin treatment. Finally, miR-302b enrichment correlated with better overall survival in 118 TNBC patients. Conclusion: MiR-302b can be exploited as a new therapeutic tool to improve the response to chemotherapy, modulating the E2F family, YY1, and ITGA6 expression. Moreover, miR-302b could be defined as a new prognostic factor in TNBC patients. Full article

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29 pages, 1681 KiB

Open AccessReview

Interplay between Cellular Metabolism and the DNA Damage Response in Cancer

by Amandine Moretton and Joanna I. Loizou

Cancers 2020, 12(8), 2051; https://doi.org/10.3390/cancers12082051 - 25 Jul 2020

Cited by 46 | Viewed by 9227

Abstract

Metabolism is a fundamental cellular process that can become harmful for cells by leading to DNA damage, for instance by an increase in oxidative stress or through the generation of toxic byproducts. To deal with such insults, cells have evolved sophisticated DNA damage [...] Read more.

Metabolism is a fundamental cellular process that can become harmful for cells by leading to DNA damage, for instance by an increase in oxidative stress or through the generation of toxic byproducts. To deal with such insults, cells have evolved sophisticated DNA damage response (DDR) pathways that allow for the maintenance of genome integrity. Recent years have seen remarkable progress in our understanding of the diverse DDR mechanisms, and, through such work, it has emerged that cellular metabolic regulation not only generates DNA damage but also impacts on DNA repair. Cancer cells show an alteration of the DDR coupled with modifications in cellular metabolism, further emphasizing links between these two fundamental processes. Taken together, these compelling findings indicate that metabolic enzymes and metabolites represent a key group of factors within the DDR. Here, we will compile the current knowledge on the dynamic interplay between metabolic factors and the DDR, with a specific focus on cancer. We will also discuss how recently developed high-throughput technologies allow for the identification of novel crosstalk between the DDR and metabolism, which is of crucial importance to better design efficient cancer treatments. Full article

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37 pages, 2858 KiB

Open AccessReview

DNA Repair and Ovarian Carcinogenesis: Impact on Risk, Prognosis and Therapy Outcome

by Kristyna Tomasova, Andrea Cumova, Karolina Seborova, Josef Horak, Kamila Koucka, Ludmila Vodickova, Radka Vaclavikova and Pavel Vodicka

Cancers 2020, 12(7), 1713; https://doi.org/10.3390/cancers12071713 - 28 Jun 2020

Cited by 27 | Viewed by 5209

Abstract

There is ample evidence for the essential involvement of DNA repair and DNA damage response in the onset of solid malignancies, including ovarian cancer. Indeed, high-penetrance germline mutations in DNA repair genes are important players in familial cancers: BRCA1, BRCA2 mutations or [...] Read more.

There is ample evidence for the essential involvement of DNA repair and DNA damage response in the onset of solid malignancies, including ovarian cancer. Indeed, high-penetrance germline mutations in DNA repair genes are important players in familial cancers: BRCA1, BRCA2 mutations or mismatch repair, and polymerase deficiency in colorectal, breast, and ovarian cancers. Recently, some molecular hallmarks (e.g., TP53, KRAS, BRAF, RAD51C/D or PTEN mutations) of ovarian carcinomas were identified. The manuscript overviews the role of DNA repair machinery in ovarian cancer, its risk, prognosis, and therapy outcome. We have attempted to expose molecular hallmarks of ovarian cancer with a focus on DNA repair system and scrutinized genetic, epigenetic, functional, and protein alterations in individual DNA repair pathways (homologous recombination, non-homologous end-joining, DNA mismatch repair, base- and nucleotide-excision repair, and direct repair). We suggest that lack of knowledge particularly in non-homologous end joining repair pathway and the interplay between DNA repair pathways needs to be confronted. The most important genes of the DNA repair system are emphasized and their targeting in ovarian cancer will deserve further attention. The function of those genes, as well as the functional status of the entire DNA repair pathways, should be investigated in detail in the near future. Full article

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15 pages, 2461 KiB

Open AccessArticle

SPOP Deregulation Improves the Radiation Response of Prostate Cancer Models by Impairing DNA Damage Repair

by Rihan El Bezawy, Martina Tripari, Stefano Percio, Alessandro Cicchetti, Monica Tortoreto, Claudio Stucchi, Stella Tinelli, Valentina Zuco, Valentina Doldi, Paolo Gandellini, Riccardo Valdagni and Nadia Zaffaroni

Cancers 2020, 12(6), 1462; https://doi.org/10.3390/cancers12061462 - 4 Jun 2020

Cited by 8 | Viewed by 3836

Abstract

Speckle-type POZ (pox virus and zinc finger protein) protein (SPOP) is the most commonly mutated gene in prostate cancer (PCa). Recent evidence reports a role of SPOP in DNA damage response (DDR), indicating a possible impact of SPOP deregulation on PCa radiosensitivity. This [...] Read more.

Speckle-type POZ (pox virus and zinc finger protein) protein (SPOP) is the most commonly mutated gene in prostate cancer (PCa). Recent evidence reports a role of SPOP in DNA damage response (DDR), indicating a possible impact of SPOP deregulation on PCa radiosensitivity. This study aimed to define the role of SPOP deregulation (by gene mutation or knockdown) as a radiosensitizing factor in PCa preclinical models. To express WT or mutant (Y87N, K129E and F133V) SPOP, DU145 and PC-3 cells were transfected with pMCV6 vectors. Sensitivity profiles were assessed using clonogenic assay and immunofluorescent staining of γH2AX and RAD51 foci. SCID xenografts were treated with 5 Gy single dose irradiation using an image-guided small animal irradiator. siRNA and miRNA mimics were used to silence SPOP or express the SPOP negative regulator miR-145, respectively. SPOP deregulation, by either gene mutation or knockdown, consistently enhanced the radiation response of PCa models by impairing DDR, as indicated by transcriptome analysis and functionally confirmed by decreased RAD51 foci. SPOP silencing also resulted in a significant downregulation of RAD51 and CHK1 expression, consistent with the impairment of homologous recombination. Our results indicate that SPOP deregulation plays a radiosensitizing role in PCa by impairing DDR via downregulation of RAD51 and CHK1. Full article

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15 pages, 1835 KiB

Open AccessArticle

Depletion of Trichoplein (TpMs) Causes Chromosome Mis-Segregation, DNA Damage and Chromosome Instability in Cancer Cells

by Angela Lauriola, Andrea Martello, Sebastian Fantini, Gaetano Marverti, Tommaso Zanocco-Marani, Pierpaola Davalli, Daniele Guardavaccaro, Sabine Mai, Andrea Caporali and Domenico D’Arca

Cancers 2020, 12(4), 993; https://doi.org/10.3390/cancers12040993 - 17 Apr 2020

Cited by 9 | Viewed by 4058

Abstract

Mitotic perturbations frequently lead to chromosome mis-segregation that generates genome instability, thereby triggering tumor onset and/or progression. Error-free mitosis depends on fidelity-monitoring systems that ensure the temporal and spatial coordination of chromosome segregation. Recent investigations are focused on mitotic DNA damage response (DDR) [...] Read more.

Mitotic perturbations frequently lead to chromosome mis-segregation that generates genome instability, thereby triggering tumor onset and/or progression. Error-free mitosis depends on fidelity-monitoring systems that ensure the temporal and spatial coordination of chromosome segregation. Recent investigations are focused on mitotic DNA damage response (DDR) and chromosome mis-segregations with the aim of developing more efficient anti-cancer therapies. We previously demonstrated that trichoplein keratin filament binding protein (TpMs) exhibits hallmarks of a tumor suppressor gene in cancer-derived cells and human tumors. Here, we show that silencing of TpMs expression results in chromosome mis-segregation, DNA damage and chromosomal instability. TpMs interacts with Mad2, and TpMs depletion results in decreased levels of Mad2 and Cyclin B1 proteins. All the genetic alterations observed are consistent with both defective activation of the spindle assembly checkpoint and mitotic progression. Thus, low levels of TpMs found in certain human tumors may contribute to cellular transformation by promoting genomic instability. Full article

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17 pages, 1948 KiB

Open AccessReview

Role of DNA Damage Response in Suppressing Malignant Progression of Chronic Myeloid Leukemia and Polycythemia Vera: Impact of Different Oncogenes

by Jan Stetka, Jan Gursky, Julie Liñan Velasquez, Renata Mojzikova, Pavla Vyhlidalova, Lucia Vrablova, Jiri Bartek and Vladimir Divoky

Cancers 2020, 12(4), 903; https://doi.org/10.3390/cancers12040903 - 7 Apr 2020

Cited by 16 | Viewed by 5973

Abstract

Inflammatory and oncogenic signaling, both known to challenge genome stability, are key drivers of BCR-ABL-positive chronic myeloid leukemia (CML) and JAK2 V617F-positive chronic myeloproliferative neoplasms (MPNs). Despite similarities in chronic inflammation and oncogene signaling, major differences in disease course exist. Although BCR-ABL [...] Read more.

Inflammatory and oncogenic signaling, both known to challenge genome stability, are key drivers of BCR-ABL-positive chronic myeloid leukemia (CML) and JAK2 V617F-positive chronic myeloproliferative neoplasms (MPNs). Despite similarities in chronic inflammation and oncogene signaling, major differences in disease course exist. Although BCR-ABL has robust transformation potential, JAK2 V617F-positive polycythemia vera (PV) is characterized by a long and stable latent phase. These differences reflect increased genomic instability of BCR-ABL-positive CML, compared to genome-stable PV with rare cytogenetic abnormalities. Recent studies have implicated BCR-ABL in the development of a "mutator" phenotype fueled by high oxidative damage, deficiencies of DNA repair, and defective ATR-Chk1-dependent genome surveillance, providing a fertile ground for variants compromising the ATM-Chk2-p53 axis protecting chronic phase CML from blast crisis. Conversely, PV cells possess multiple JAK2 V617F-dependent protective mechanisms, which ameliorate replication stress, inflammation-mediated oxidative stress and stress-activated protein kinase signaling, all through up-regulation of RECQL5 helicase, reactive oxygen species buffering system, and DUSP1 actions. These attenuators of genome instability then protect myeloproliferative progenitors from DNA damage and create a barrier preventing cellular stress-associated myelofibrosis. Therefore, a better understanding of BCR-ABL and JAK2 V617F roles in the DNA damage response and disease pathophysiology can help to identify potential dependencies exploitable for therapeutic interventions. Full article

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17 pages, 5285 KiB

Open AccessArticle

MiRNAs Targeting Double Strand DNA Repair Pathways Lurk in Genomically Unstable Rare Fragile Sites and Determine Cancer Outcomes

by Stephan Marquardt, Christin Richter, Brigitte M. Pützer and Stella Logotheti

Cancers 2020, 12(4), 876; https://doi.org/10.3390/cancers12040876 - 3 Apr 2020

Cited by 2 | Viewed by 2998

Abstract

Double strand break (DSB) repair mechanisms guard genome integrity and their deterioration causes genomic instability. Common and rare fragile sites (CFS and RFS, respectively) are particularly vulnerable to instability, and there is an inverse correlation between fragile site (FS) expression and DSB repair [...] Read more.

Double strand break (DSB) repair mechanisms guard genome integrity and their deterioration causes genomic instability. Common and rare fragile sites (CFS and RFS, respectively) are particularly vulnerable to instability, and there is an inverse correlation between fragile site (FS) expression and DSB repair protein levels. Upon DSB repair dysfunction, genes residing at these sites are at greater risk of deregulation compared to genes located at non-FS. In this regard, it remains enigmatic why the incidence of miRNA genes at FS is higher compared to non-FS. Herein, using bioinformatics, we examined whether miRNA genes localized at FS inhibit components of DSB repair pathways and assessed their effects on cancer. We show that such miRNAs over-accumulate in RFS, and that FRAXA, which is expressed in Fragile X syndrome, is a conserved hotspot for miRNAs inhibiting DSB repair. Axes of FRAXA-residing miRNAs/DSB repair targets affect survival in a cancer type-specific manner. Moreover, copy number variations in the region encompassing these miRNA genes discriminate survival between male and female patients. Given that, thus far, only CFS have been considered relevant for carcinogenesis, our data are the first to associate RFS with cancer, through the impairment of DSB repair by the FRAXA-residing miRNAs. Full article

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15 pages, 2790 KiB

Open AccessArticle

Vinorelbine Augments Radiotherapy in Hepatocellular Carcinoma

by Kheng Wei Yeoh, Aldo Prawira, Muhammad Zafrie Bin Saad, Kok Ming Lee, Eric Ming Hon Lee, Gee Keng Low, Mohamed Hakim Bin Mohd Nasir, Jun Hao Phua, Wendy Wan Li Chow, Iris Jiu Hia Lim, Yusnita Binte Omar, Rebecca Zhi Wen Ho, Thi Bich Uyen Le, Thanh Chung Vu, Khee Chee Soo and Hung Huynh

Cancers 2020, 12(4), 872; https://doi.org/10.3390/cancers12040872 - 3 Apr 2020

Cited by 8 | Viewed by 3170

Abstract

There is a need to improve the effectiveness of radiotherapy (RT) in hepatocellular carcinoma (HCC). Therefore, the purpose of this study was to explore the efficacy and toxicity of the anti-microtubule agent Vinorelbine as a radiosensitizer in HCC. The radio sensitivity of 16 [...] Read more.

There is a need to improve the effectiveness of radiotherapy (RT) in hepatocellular carcinoma (HCC). Therefore, the purpose of this study was to explore the efficacy and toxicity of the anti-microtubule agent Vinorelbine as a radiosensitizer in HCC. The radio sensitivity of 16 HCC patient-derived xenograft (PDX) models was determined by quantifying the survival fraction following irradiation in vitro, and Vinorelbine radio sensitization was determined by clonogenic assay. Ectopic HCC xenografts were treated with a single dose of 8 Gy irradiation and twice-weekly 3 mg/kg Vinorelbine. Tumor growth and changes in the proteins involved in DNA repair, angiogenesis, tumor cell proliferation, and survival were assessed, and the 3/16 (18.75%), 7/16 (43.75%), and 6/16 (37.5%) HCC lines were classified as sensitive, moderately sensitive, and resistant, respectively. The combination of RT and Vinorelbine significantly inhibited tumor growth, DNA repair proteins, angiogenesis, and cell proliferation, and promoted more apoptosis compared with RT or Vinorelbine treatment alone. Vinorelbine improved HCC tumor response to standard irradiation with no increase in toxicity. HCC is prevalent in less developed parts of the world and is mostly unresectable on presentation. Vinorelbine and conventional radiotherapy are cost-effective, well-established modalities of cancer treatment that are readily available. Therefore, this strategy can potentially address an unmet clinical need, warranting further investigation in early-phase clinical trials. Full article

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23 pages, 2276 KiB

Open AccessReview

Ionizing Radiation and Complex DNA Damage: Quantifying the Radiobiological Damage Using Monte Carlo Simulations

by Konstantinos P. Chatzipapas, Panagiotis Papadimitroulas, Dimitris Emfietzoglou, Spyridon A. Kalospyros, Megumi Hada, Alexandros G. Georgakilas and George C. Kagadis

Cancers 2020, 12(4), 799; https://doi.org/10.3390/cancers12040799 - 26 Mar 2020

Cited by 65 | Viewed by 7880

Abstract

Ionizing radiation is a common tool in medical procedures. Monte Carlo (MC) techniques are widely used when dosimetry is the matter of investigation. The scientific community has invested, over the last 20 years, a lot of effort into improving the knowledge of radiation [...] Read more.

Ionizing radiation is a common tool in medical procedures. Monte Carlo (MC) techniques are widely used when dosimetry is the matter of investigation. The scientific community has invested, over the last 20 years, a lot of effort into improving the knowledge of radiation biology. The present article aims to summarize the understanding of the field of DNA damage response (DDR) to ionizing radiation by providing an overview on MC simulation studies that try to explain several aspects of radiation biology. The need for accurate techniques for the quantification of DNA damage is crucial, as it becomes a clinical need to evaluate the outcome of various applications including both low- and high-energy radiation medical procedures. Understanding DNA repair processes would improve radiation therapy procedures. Monte Carlo simulations are a promising tool in radiobiology studies, as there are clear prospects for more advanced tools that could be used in multidisciplinary studies, in the fields of physics, medicine, biology and chemistry. Still, lot of effort is needed to evolve MC simulation tools and apply them in multiscale studies starting from small DNA segments and reaching a population of cells. Full article

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12 pages, 1762 KiB

Open AccessArticle

Changes in DNA Damage Response Markers with Treatment in Advanced Ovarian Cancer

by Paul Kubelac, Catherine Genestie, Aurelie Auguste, Soizick Mesnage, Audrey Le Formal, Patricia Pautier, Sebastien Gouy, Philippe Morice, Enrica Bentivegna, Amandine Maulard, Julien Adam, Patriciu Achimas-Cadariu and Alexandra Leary

Cancers 2020, 12(3), 707; https://doi.org/10.3390/cancers12030707 - 17 Mar 2020

Cited by 15 | Viewed by 4236

Abstract

Ovarian cancer (OC) is sensitive to upfront chemotherapy, which is likely attributable to defects in DNA damage repair (DDR). Unfortunately, patients relapse and the evolution of DDR competency are poorly described. We examined the expression of proposed effectors in homologous recombination (HR: RAD51, [...] Read more.

Ovarian cancer (OC) is sensitive to upfront chemotherapy, which is likely attributable to defects in DNA damage repair (DDR). Unfortunately, patients relapse and the evolution of DDR competency are poorly described. We examined the expression of proposed effectors in homologous recombination (HR: RAD51, ATM, FANCD2), error-prone non-homologous end-joining (NHEJ: 53BP1), and base excision repair pathways (BER: PAR and PARP1) in a cohort of sequential OC samples obtained at diagnosis, after neoadjuvant chemotherapy (NACT), and/or at relapse from a total of 147 patients. Immunohistochemical (IHC) expression was quantified using the H-score (0–300), where H ≤ 10 defined negativity. Before NACT, a significant number of cases lacked the expression of some effectors: 60%, 60%, and 24% were PAR-, FANCD2-, or RAD51-negative, with a reassuringly similar proportion of negative biomarkers after NACT. In multivariate analysis, there was a poorer progression-free survival (PFS) and overall survival (OS) for cases with competent HR at diagnosis (PRE-NACT 53BP1−/RAD51+, hazard ratio (HR) 3.13, p = 0.009 and HR 2.78, p = 0.024) and after NACT (POST-NACT FANCD2+/RAD51+ HR 1.89, p = 0.05 and HR 2.38, p = 0.02; POST-NACT PARP-1+/RAD51+ HR 1.79, p = 0.038 and HR 2.04, p = 0.034), reflecting proficient DNA repair. Overall, HR-competent tumors appeared to have a dismal prognosis in comparison with tumors utilizing NHEJ, as assessed either at baseline or post-NACT. Accurate knowledge of the HR status during treatment is clinically important for the efficient timing of platinum-based and targeted therapies with poly(ADP-ribose) polymerase inhibitors (PARPi). Full article

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14 pages, 2314 KiB

Open AccessArticle

Genomic Characterization of Non-Invasive Differentiated-Type Gastric Cancer in the Japanese Population

by Koki Nakamura, Yuji Urabe, Kenichi Kagemoto, Ryo Yuge, Ryohei Hayashi, Atsushi Ono, C. Nelson Hayes, Shiro Oka, Masanori Ito, Takashi Nishisaka, Kazuaki Tanabe, Koji Arihiro, Hideki Ohdan, Shinji Tanaka and Kazuaki Chayama

Cancers 2020, 12(2), 510; https://doi.org/10.3390/cancers12020510 - 22 Feb 2020

Cited by 7 | Viewed by 3608

Abstract

Background and aims: Recent genomic characterization of gastric cancer (GC) by sequencing has revealed a large number of cancer-related genes. Research to characterize the genomic landscape of cancer has focused on established invasive cancer to develop biomarkers for therapeutic or diagnostic targets, and [...] Read more.

Background and aims: Recent genomic characterization of gastric cancer (GC) by sequencing has revealed a large number of cancer-related genes. Research to characterize the genomic landscape of cancer has focused on established invasive cancer to develop biomarkers for therapeutic or diagnostic targets, and nearly all GC reports have been about advanced GC. The aim of this study is to identify recurrently mutated genes in non-invasive GC and, in particular, the driver mutations that are associated with the development of GC. Methods and results: We performed whole-exome sequencing of 19 fresh frozen specimens of differentiated-type non-invasive GC and targeted sequencing for 168 genes of 30 formalin-fixed paraffin-embedded archival specimens of differentiated-type non-invasive GC. We found that TP53 and LRP1 are significantly associated with non-invasive GC. It has been reported that LPR1 is associated with CagA autophagy in gastric mucosa. Therefore, we downloaded RNA sequence data for gastric cancer from the The Cancer Genome Atlas (TCGA) Genomic Data Commons Data Portal and examined the differences in LRP1 gene expression levels. The expression level was significantly lower in cases without LRP1 mutation than in cases with LRP1 mutation. Based on these results, fluorescent immunostaining for CagA was performed for 49 of the above samples to evaluate CagA accumulation within the cancerous tissue. Accumulation of CagA was significantly greater when an LRP1 mutation was present than without a mutation. Conclusion: These data suggest that LRP1 mutation is an important change promoting the transformation of gastric mucosa to GC early in the carcinogenesis of cancer. Full article

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2019

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15 pages, 3729 KiB

Open AccessReview

The Role of E3, E4 Ubiquitin Ligase (UBE4B) in Human Pathologies

by Nikolaos Antoniou, Nefeli Lagopati, Dimitrios Ilias Balourdas, Michail Nikolaou, Alexandros Papalampros, Panagiotis V. S. Vasileiou, Vassilios Myrianthopoulos, Athanassios Kotsinas, Yosef Shiloh, Michalis Liontos and Vassilis G. Gorgoulis

Cancers 2020, 12(1), 62; https://doi.org/10.3390/cancers12010062 - 24 Dec 2019

Cited by 23 | Viewed by 5497

Abstract

The genome is exposed daily to many deleterious factors. Ubiquitination is a mechanism that regulates several crucial cellular functions, allowing cells to react upon various stimuli in order to preserve their homeostasis. Ubiquitin ligases act as specific regulators and actively participate among others [...] Read more.

The genome is exposed daily to many deleterious factors. Ubiquitination is a mechanism that regulates several crucial cellular functions, allowing cells to react upon various stimuli in order to preserve their homeostasis. Ubiquitin ligases act as specific regulators and actively participate among others in the DNA damage response (DDR) network. UBE4B is a newly identified member of E3 ubiquitin ligases that appears to be overexpressed in several human neoplasms. The aim of this review is to provide insights into the role of UBE4B ubiquitin ligase in DDR and its association with p53 expression, shedding light particularly on the molecular mechanisms of carcinogenesis. Full article

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16 pages, 3372 KiB

Open AccessArticle

Impact of ATM and DNA-PK Inhibition on Gene Expression and Individual Response of Human Lymphocytes to Mixed Beams of Alpha Particles and X-Rays

by Lei Cheng, Beata Brzozowska-Wardecka, Halina Lisowska, Andrzej Wojcik and Lovisa Lundholm

Cancers 2019, 11(12), 2013; https://doi.org/10.3390/cancers11122013 - 13 Dec 2019

Cited by 11 | Viewed by 2907

Abstract

Accumulating evidence suggests a synergistic effect in cells simultaneously exposed to different types of clustered and dispersed DNA damage. We aimed to analyse the effect of mixed beams of alpha particles and X-rays (1:1 dose of each) on DNA damage response genes in [...] Read more.

Accumulating evidence suggests a synergistic effect in cells simultaneously exposed to different types of clustered and dispersed DNA damage. We aimed to analyse the effect of mixed beams of alpha particles and X-rays (1:1 dose of each) on DNA damage response genes in human peripheral blood lymphocytes isolated from four donors. Two donors were compared upon inhibition of ATM or DNA-PK and at different sampling times. qPCR was used to measure mRNA levels of FDXR, GADD45A, BBC3, MDM2, CDKN1A, and XPC 24 h following exposure. Generally, alpha particles and mixed beams were stronger inducers of gene expression compared to X-rays, displaying saturated versus linear dose–response curves, respectively. Three out of four donors responded synergistically to mixed beams. When two donors were sampled again one year later, the former additive effect in one donor was now synergistic and no significant difference in intrinsic radiosensitivity was displayed, as determined by gamma-radiation-induced micronuclei. ATM, but not DNA-PK inhibition, reduced the radiation-induced gene expression, but differently for alpha radiation between the two donors. In conclusion, synergy was present for all donors, but the results suggest individual variability in the response to mixed beams, most likely due to lifestyle changes. Full article

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29 pages, 1078 KiB

Open AccessReview

Ionizing Radiation and Complex DNA Damage: From Prediction to Detection Challenges and Biological Significance

by Ifigeneia V. Mavragani, Zacharenia Nikitaki, Spyridon A. Kalospyros and Alexandros G. Georgakilas

Cancers 2019, 11(11), 1789; https://doi.org/10.3390/cancers11111789 - 14 Nov 2019

Cited by 122 | Viewed by 10226

Abstract

Biological responses to ionizing radiation (IR) have been studied for many years, generally showing the dependence of these responses on the quality of radiation, i.e., the radiation particle type and energy, types of DNA damage, dose and dose rate, type of cells, etc. [...] Read more.

Biological responses to ionizing radiation (IR) have been studied for many years, generally showing the dependence of these responses on the quality of radiation, i.e., the radiation particle type and energy, types of DNA damage, dose and dose rate, type of cells, etc. There is accumulating evidence on the pivotal role of complex (clustered) DNA damage towards the determination of the final biological or even clinical outcome after exposure to IR. In this review, we provide literature evidence about the significant role of damage clustering and advancements that have been made through the years in its detection and prediction using Monte Carlo (MC) simulations. We conclude that in the future, emphasis should be given to a better understanding of the mechanistic links between the induction of complex DNA damage, its processing, and systemic effects at the organism level, like genomic instability and immune responses. Full article

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15 pages, 2914 KiB

Open AccessArticle

Antitumor Reactive T-Cell Responses Are Enhanced In Vivo by DAMP Prothymosin Alpha and Its C-Terminal Decapeptide

by Anastasios I. Birmpilis, Chrysoula-Evangelia Karachaliou, Pinelopi Samara, Kyriaki Ioannou, Platon Selemenakis, Ioannis V. Kostopoulos, Nadia Kavrochorianou, Hubert Kalbacher, Evangelia Livaniou, Sylva Haralambous, Athanasios Kotsinas, Farzin Farzaneh, Ioannis P. Trougakos, Wolfgang Voelter, Meletios-Athanasios Dimopoulos, Aristotelis Bamias and Ourania Tsitsilonis

Cancers 2019, 11(11), 1764; https://doi.org/10.3390/cancers11111764 - 9 Nov 2019

Cited by 9 | Viewed by 3096

Abstract

Prothymosin α (proTα) and its C-terminal decapeptide proTα(100–109) were shown to pleiotropically enhance innate and adaptive immune responses. Their activities have been broadly studied in vitro, focusing primarily on the restoration of the deficient immunoreactivity of cancer patients’ leukocytes. Previously, we showed that [...] Read more.

Prothymosin α (proTα) and its C-terminal decapeptide proTα(100–109) were shown to pleiotropically enhance innate and adaptive immune responses. Their activities have been broadly studied in vitro, focusing primarily on the restoration of the deficient immunoreactivity of cancer patients’ leukocytes. Previously, we showed that proTα and proTα(100–109) act as danger-associated molecular patterns (DAMPs), ligate Toll-like receptor-4, signal through TRIF- and MyD88-dependent pathways, promote the maturation of dendritic cells and elicit T-helper type 1 (Th1) immune responses in vitro, leading to the optimal priming of tumor antigen-reactive T-cell functions. Herein, we assessed their activity in a preclinical melanoma model. Immunocompetent mice bearing B16.F1 tumors were treated with two cycles of proTα or proTα(100–109) together with a B16.F1-derived peptide vaccine. Coadministration of proTα or proTα(100–109) and the peptide vaccine suppressed melanoma-cell proliferation, as evidenced by reduced tumor-growth rates. Higher melanoma infiltration by CD3+ T cells was observed, whereas ex vivo analysis of mouse total spleen cells verified the in vivo induction of melanoma-reactive cytotoxic responses. Additionally, increased levels of proinflammatory and Th1-type cytokines were detected in mouse serum. We propose that, in the presence of tumor antigens, DAMPs proTα and proTα(100–109) induce Th1-biased immune responses in vivo. Their adjuvant ability to orchestrate antitumor immunoreactivities can eventually be exploited therapeutically in humans. Full article

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15 pages, 1223 KiB

Open AccessArticle

Antileukemic Efficacy in Vitro of Talazoparib and APE1 Inhibitor III Combined with Decitabine in Myeloid Malignancies

by Vanessa Kohl, Johanna Flach, Nicole Naumann, Susanne Brendel, Helga Kleiner, Christel Weiss, Wolfgang Seifarth, Daniel Nowak, Wolf-Karsten Hofmann, Alice Fabarius and Henning D. Popp

Cancers 2019, 11(10), 1493; https://doi.org/10.3390/cancers11101493 - 3 Oct 2019

Cited by 12 | Viewed by 3732

Abstract

Malignant hematopoietic cells of myelodysplastic syndromes (MDS)/chronic myelomonocytic leukemias (CMML) and acute myeloid leukemias (AML) may be vulnerable to inhibition of poly(ADP ribose) polymerase 1/2 (PARP1/2) and apurinic/apyrimidinic endonuclease 1 (APE1). PARP1/2 and APE1 are critical enzymes involved in single-strand break repair and [...] Read more.

Malignant hematopoietic cells of myelodysplastic syndromes (MDS)/chronic myelomonocytic leukemias (CMML) and acute myeloid leukemias (AML) may be vulnerable to inhibition of poly(ADP ribose) polymerase 1/2 (PARP1/2) and apurinic/apyrimidinic endonuclease 1 (APE1). PARP1/2 and APE1 are critical enzymes involved in single-strand break repair and base excision repair, respectively. Here, we investigated the cytotoxic efficacy of talazoparib and APE1 inhibitor III, inhibitors of PARP1/2 and APE1, in primary CD34+ MDS/CMML cell samples (n = 8; 4 MDS and 4 CMML) and in primary CD34+ or CD34− AML cell samples (n = 18) in comparison to healthy CD34+ donor cell samples (n = 8). Strikingly, talazoparib and APE1 inhibitor III demonstrated critical antileukemic efficacy in selected MDS/CMML and AML cell samples. Low doses of talazoparib and APE1 inhibitor III further increased the cytotoxic efficacy of decitabine in MDS/CMML and AML cells. Moreover, low doses of APE1 inhibitor III increased the cytotoxic efficacy of talazoparib in MDS/CMML and AML cells. In summary, talazoparib and APE1 inhibitor III demonstrated substantial antileukemic efficacy as single agents, in combination with decitabine, and combined with each other. Hence, our findings support further investigation of these agents in sophisticated clinical trials. Full article

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