Next Issue
Volume 10, April
Previous Issue
Volume 10, February
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
8.0
4.5
Journals
Cancers
Volume 10
Issue 3
share announcement

Cancers, Volume 10, Issue 3 (March 2018) – 27 articles

Cover Story (view full-size image): Endoplasmic reticulum (ER) is a crucial organelle that is responsible for several fundamental cellular activities. Disturbances to ER homeostasis leads to the accumulation of unfolded/aggregated proteins, which in turn leads to unfolded protein response (UPR). Controlling induced UPR via ER stress could be an attractive molecular target in cancer therapies. Tannic acid (TA, a naturally occurring polyphenol) is a commonly used compound as a food, drink, and pharmaceutical additive. Herein, we demonstrated the holistic mechanism of TA in annihilating prostate cancer cell growth, clonogenic, invasive, and migratory potential of prostate cancer cells. This study corroborates that TA promotes ER stress-mediated cancer cell death. View this paper.
  • Issues are regarded as officially published after their release is announced to the table of contents alert mailing list.
  • You may sign up for e-mail alerts to receive table of contents of newly released issues.
  • PDF is the official format for papers published in both, html and pdf forms. To view the papers in pdf format, click on the "PDF Full-text" link, and use the free Adobe Reader to open them.
Order results
Result details
Section
Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:
21 pages, 2028 KiB  
Review
Role of Pattern Recognition Receptors in KSHV Infection
by Timsy Uppal, Roni Sarkar, Ranjit Dhelaria and Subhash C. Verma
Cancers 2018, 10(3), 85; https://doi.org/10.3390/cancers10030085 - 20 Mar 2018
Cited by 15 | Viewed by 8264
Abstract
Kaposi’s sarcoma-associated herpesvirus or Human herpesvirus-8 (KSHV/HHV-8), an oncogenic human herpesvirus and the leading cause of cancer in HIV-infected individuals, is a major public health concern with recurring reports of epidemics on a global level. The early detection of KSHV virus and subsequent [...] Read more.
Kaposi’s sarcoma-associated herpesvirus or Human herpesvirus-8 (KSHV/HHV-8), an oncogenic human herpesvirus and the leading cause of cancer in HIV-infected individuals, is a major public health concern with recurring reports of epidemics on a global level. The early detection of KSHV virus and subsequent activation of the antiviral immune response by the host’s immune system are crucial to prevent KSHV infection. The host’s immune system is an evolutionary conserved system that provides the most important line of defense against invading microbial pathogens, including viruses. Viruses are initially detected by the cells of the host innate immune system, which evoke concerted antiviral responses via the secretion of interferons (IFNs) and inflammatory cytokines/chemokines for elimination of the invaders. Type I IFN and cytokine gene expression are regulated by multiple intracellular signaling pathways that are activated by germline-encoded host sensors, i.e., pattern recognition receptors (PRRs) that recognize a conserved set of ligands, known as ‘pathogen-associated molecular patterns (PAMPs)’. On the contrary, persistent and dysregulated signaling of PRRs promotes numerous tumor-causing inflammatory events in various human cancers. Being an integral component of the mammalian innate immune response and due to their constitutive activation in tumor cells, targeting PRRs appears to be an effective strategy for tumor prevention and/or treatment. Cellular PRRs are known to respond to KSHV infection, and KSHV has been shown to be armed with an array of strategies to selectively inhibit cellular PRR-based immune sensing to its benefit. In particular, KSHV has acquired specific immunomodulatory genes to effectively subvert PRR responses during the early stages of primary infection, lytic reactivation and latency, for a successful establishment of a life-long persistent infection. The current review aims to comprehensively summarize the latest advances in our knowledge of role of PRRs in KSHV infections. Full article
(This article belongs to the Special Issue Cancer Biomarkers)
►▼ Show Figures

Figure 1

16 pages, 5433 KiB  
Article
Peptide Mediated In Vivo Tumor Targeting of Nanoparticles through Optimization in Single and Multilayer In Vitro Cell Models
by Celina Yang, Kyle Bromma and Devika Chithrani
Cancers 2018, 10(3), 84; https://doi.org/10.3390/cancers10030084 - 20 Mar 2018
Cited by 33 | Viewed by 5040
Abstract
Optimizing the interface between nanoparticles (NPs) and the biological environment at various levels should be considered for improving delivery of NPs to the target tumor area. For NPs to be successfully delivered to cancer cells, NPs needs to be functionalized for circulation through [...] Read more.
Optimizing the interface between nanoparticles (NPs) and the biological environment at various levels should be considered for improving delivery of NPs to the target tumor area. For NPs to be successfully delivered to cancer cells, NPs needs to be functionalized for circulation through the blood vessels. In this study, accumulation of Polyethylene Glycol (PEG) functionalized gold nanoparticles (GNPs) was first tested using in vitro monolayer cells and multilayer cell models prior to in vivo models. A diameter of 10 nm sized GNP was selected for this study for sufficient penetration through tumor tissue. The surfaces of the GNPs were modified with PEG molecules, to improve circulation time by reducing non-specific uptake by the reticuloendothelial system (RES) in animal models, and with a peptide containing integrin binding domain, RGD (arginyl-glycyl-aspartic acid), to improve internalization at the cellular level. A 10–12% accumulation of the injected GNP dose within the tumor was observed in vivo and the GNPs remained within the tumor tissue up to 72 h. This study suggests an in vitro platform for optimizing the accumulation of NP complexes in cells and tissue structures before testing them in animal models. Higher accumulation within the tumor in vivo upon surface modification is a promising outcome for future applications where GNPs can be used for drug delivery and radiation therapy. Full article
►▼ Show Figures

Graphical abstract

29 pages, 1260 KiB  
Review
The Complex Interplay between Chronic Inflammation, the Microbiome, and Cancer: Understanding Disease Progression and What We Can Do to Prevent It
by Heather Armstrong, Michael Bording-Jorgensen, Stephanie Dijk and Eytan Wine
Cancers 2018, 10(3), 83; https://doi.org/10.3390/cancers10030083 - 20 Mar 2018
Cited by 82 | Viewed by 17168
Abstract
Cancer is a multifaceted condition, in which a senescent cell begins dividing in an irregular manner due to various factors such as DNA damage, growth factors and inflammation. Inflammation is not typically discussed as carcinogenic; however, a significant percentage of cancers arise from [...] Read more.
Cancer is a multifaceted condition, in which a senescent cell begins dividing in an irregular manner due to various factors such as DNA damage, growth factors and inflammation. Inflammation is not typically discussed as carcinogenic; however, a significant percentage of cancers arise from chronic microbial infections and damage brought on by chronic inflammation. A hallmark cancer-inducing microbe is Helicobacter pylori and its causation of peptic ulcers and potentially gastric cancer. This review discusses the recent developments in understanding microbes in health and disease and their potential role in the progression of cancer. To date, microbes can be linked to almost every cancer, including colon, pancreatic, gastric, and even prostate. We discuss the known mechanisms by which these microbes can induce cancer growth and development and how inflammatory cells may contribute to cancer progression. We also discuss new treatments that target the chronic inflammatory conditions and their associated cancers, and the impact microbes have on treatment success. Finally, we examine common dietary misconceptions in relation to microbes and cancer and how to avoid getting caught up in the misinterpretation and over inflation of the results. Full article
(This article belongs to the Special Issue Inflammation and Cancer)
►▼ Show Figures

Figure 1

21 pages, 645 KiB  
Review
The Roles of Protein Tyrosine Phosphatases in Hepatocellular Carcinoma
by Yide Huang, Yafei Zhang, Lilin Ge, Yao Lin and Hang Fai Kwok
Cancers 2018, 10(3), 82; https://doi.org/10.3390/cancers10030082 - 20 Mar 2018
Cited by 35 | Viewed by 8084
Abstract
The protein tyrosine phosphatase (PTP) family is involved in multiple cellular functions and plays an important role in various pathological and physiological processes. In many chronic diseases, for example cancer, PTP is a potential therapeutic target for cancer treatment. In the last two [...] Read more.
The protein tyrosine phosphatase (PTP) family is involved in multiple cellular functions and plays an important role in various pathological and physiological processes. In many chronic diseases, for example cancer, PTP is a potential therapeutic target for cancer treatment. In the last two decades, dozens of PTP inhibitors which specifically target individual PTP molecules were developed as therapeutic agents. Hepatocellular carcinoma (HCC) is one of the most common malignant tumors and is the second most lethal cancer worldwide due to a lack of effective therapies. Recent studies have unveiled both oncogenic and tumor suppressive functions of PTP in HCC. Here, we review the current knowledge on the involvement of PTP in HCC and further discuss the possibility of targeting PTP in HCC. Full article
(This article belongs to the Special Issue Tyrosine Kinase Signaling Pathways in Cancer)
►▼ Show Figures

Figure 1

15 pages, 2589 KiB  
Review
Targeting the Hippo Pathway and Cancer through the TEAD Family of Transcription Factors
by Jeffrey K. Holden and Christian N. Cunningham
Cancers 2018, 10(3), 81; https://doi.org/10.3390/cancers10030081 - 20 Mar 2018
Cited by 132 | Viewed by 15756
Abstract
The Hippo pathway is a critical transcriptional signaling pathway that regulates cell growth, proliferation and organ development. The transcriptional enhanced associate domain (TEAD) protein family consists of four paralogous transcription factors that function to modulate gene expression in response to the Hippo signaling [...] Read more.
The Hippo pathway is a critical transcriptional signaling pathway that regulates cell growth, proliferation and organ development. The transcriptional enhanced associate domain (TEAD) protein family consists of four paralogous transcription factors that function to modulate gene expression in response to the Hippo signaling pathway. Transcriptional activation of these proteins occurs upon binding to the co-activator YAP/TAZ whose entry into the nucleus is regulated by Lats1/2 kinase. In recent years, it has become apparent that the dysregulation and/or overexpression of Hippo pathway effectors is implicated in a wide range of cancers, including prostate, gastric and liver cancer. A large body of work has been dedicated to understanding the therapeutic potential of modulating the phosphorylation and localization of YAP/TAZ. However, YAP/TAZ are considered to be natively unfolded and may be intractable as drug targets. Therefore, TEAD proteins present themselves as an excellent therapeutic target for intervention of the Hippo pathway. This review summarizes the functional role of TEAD proteins in cancer and assesses the therapeutic potential of antagonizing TEAD function in vivo. Full article
(This article belongs to the Special Issue Hippo Pathway in Cancer, towards Realization of the Hippo-Targeted Therapy)
►▼ Show Figures

Figure 1

22 pages, 919 KiB  
Review
Aptamer Therapeutics in Cancer: Current and Future
by Yoshihiro Morita, Macall Leslie, Hiroyasu Kameyama, David E. Volk and Takemi Tanaka
Cancers 2018, 10(3), 80; https://doi.org/10.3390/cancers10030080 - 19 Mar 2018
Cited by 167 | Viewed by 11676
Abstract
Aptamer-related technologies represent a revolutionary advancement in the capacity to rapidly develop new classes of targeting ligands. Structurally distinct RNA and DNA oligonucleotides, aptamers mimic small, protein-binding molecules and exhibit high binding affinity and selectivity. Although their molecular weight is relatively small—approximately one-tenth [...] Read more.
Aptamer-related technologies represent a revolutionary advancement in the capacity to rapidly develop new classes of targeting ligands. Structurally distinct RNA and DNA oligonucleotides, aptamers mimic small, protein-binding molecules and exhibit high binding affinity and selectivity. Although their molecular weight is relatively small—approximately one-tenth that of monoclonal antibodies—their complex tertiary folded structures create sufficient recognition surface area for tight interaction with target molecules. Additionally, unlike antibodies, aptamers can be readily chemically synthesized and modified. In addition, aptamers’ long storage period and low immunogenicity are favorable properties for clinical utility. Due to their flexibility of chemical modification, aptamers are conjugated to other chemical entities including chemotherapeutic agents, siRNA, nanoparticles, and solid phase surfaces for therapeutic and diagnostic applications. However, as relatively small sized oligonucleotides, aptamers present several challenges for successful clinical translation. Their short plasma half-lives due to nuclease degradation and rapid renal excretion necessitate further structural modification of aptamers for clinical application. Since the US Food and Drug Administration (FDA) approval of the first aptamer drug, Macugen® (pegaptanib), which treats wet-age-related macular degeneration, several aptamer therapeutics for oncology have followed and shown promise in pre-clinical models as well as clinical trials. This review discusses the advantages and challenges of aptamers and introduces therapeutic aptamers under investigation and in clinical trials for cancer treatments. Full article
(This article belongs to the Special Issue Aptamers: Promising Tools for Cancer Diagnosis and Therapy)
►▼ Show Figures

Figure 1

1 pages, 152 KiB  
Erratum
Erratum: Roche, J. The Epithelial-to-Mesenchymal Transition in Cancer. Cancers, 2018, 10, 52
by Joëlle Roche
Cancers 2018, 10(3), 79; https://doi.org/10.3390/cancers10030079 - 19 Mar 2018
Cited by 22 | Viewed by 3277
Abstract
The author wishes to make the following correction to the paper[...] Full article
(This article belongs to the Special Issue The Epithelial-to-Mesenchymal Transition (EMT) in Cancer)
33 pages, 1685 KiB  
Review
New Insights into Protein Kinase B/Akt Signaling: Role of Localized Akt Activation and Compartment-Specific Target Proteins for the Cellular Radiation Response
by Klaudia Szymonowicz, Sebastian Oeck, Nathalie M. Malewicz and Verena Jendrossek
Cancers 2018, 10(3), 78; https://doi.org/10.3390/cancers10030078 - 18 Mar 2018
Cited by 89 | Viewed by 13519
Abstract
Genetic alterations driving aberrant activation of the survival kinase Protein Kinase B (Akt) are observed with high frequency during malignant transformation and cancer progression. Oncogenic gene mutations coding for the upstream regulators or Akt, e.g., growth factor receptors, RAS and phosphatidylinositol-3-kinase (PI3K), or [...] Read more.
Genetic alterations driving aberrant activation of the survival kinase Protein Kinase B (Akt) are observed with high frequency during malignant transformation and cancer progression. Oncogenic gene mutations coding for the upstream regulators or Akt, e.g., growth factor receptors, RAS and phosphatidylinositol-3-kinase (PI3K), or for one of the three Akt isoforms as well as loss of the tumor suppressor Phosphatase and Tensin Homolog on Chromosome Ten (PTEN) lead to constitutive activation of Akt. By activating Akt, these genetic alterations not only promote growth, proliferation and malignant behavior of cancer cells by phosphorylation of various downstream signaling molecules and signaling nodes but can also contribute to chemo- and radioresistance in many types of tumors. Here we review current knowledge on the mechanisms dictating Akt’s activation and target selection including the involvement of miRNAs and with focus on compartmentalization of the signaling network. Moreover, we discuss recent advances in the cross-talk with DNA damage response highlighting nuclear Akt target proteins with potential involvement in the regulation of DNA double strand break repair. Full article
(This article belongs to the Special Issue Advances in the biological responses to radiation-induced DNA damage: A selection of papers from the Joint 43rd European Radiation Research Society (ERRS) and 20th German Society for Biological Radiation Research (GBS) Annual Meetings)
►▼ Show Figures

Figure 1

27 pages, 1673 KiB  
Review
Should We Keep Walking along the Trail for Pancreatic Cancer Treatment? Revisiting TNF-Related Apoptosis-Inducing Ligand for Anticancer Therapy
by Anna-Laura Kretz, Silvia Von Karstedt, Andreas Hillenbrand, Doris Henne-Bruns, Uwe Knippschild, Anna Trauzold and Johannes Lemke
Cancers 2018, 10(3), 77; https://doi.org/10.3390/cancers10030077 - 18 Mar 2018
Cited by 35 | Viewed by 9888
Abstract
Despite recent advances in oncology, diagnosis, and therapy, treatment of pancreatic ductal adenocarcinoma (PDAC) is still exceedingly challenging. PDAC remains the fourth leading cause of cancer-related deaths worldwide. Poor prognosis is due to the aggressive growth behavior with early invasion and distant metastasis, [...] Read more.
Despite recent advances in oncology, diagnosis, and therapy, treatment of pancreatic ductal adenocarcinoma (PDAC) is still exceedingly challenging. PDAC remains the fourth leading cause of cancer-related deaths worldwide. Poor prognosis is due to the aggressive growth behavior with early invasion and distant metastasis, chemoresistance, and a current lack of adequate screening methods for early detection. Consequently, novel therapeutic approaches are urgently needed. Many hopes for cancer treatment have been placed in the death ligand tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) since it was reported to induce apoptosis selectively in tumor cells in vitro and in vivo. TRAIL triggers apoptosis through binding of the trans-membrane death receptors TRAIL receptor 1 (TRAIL-R1) also death receptor 4 (DR4) and TRAIL receptor 2 (TRAIL-R2) also death receptor 5 (DR5) thereby inducing the formation of the death-inducing signaling complex (DISC) and activation of the apoptotic cascade. Unlike chemotherapeutics, TRAIL was shown to be able to induce apoptosis in a p53-independent manner, making TRAIL a promising anticancer approach for p53-mutated tumors. These cancer-selective traits of TRAIL led to the development of TRAIL-R agonists, categorized into either recombinant variants of TRAIL or agonistic antibodies against TRAIL-R1 or TRAIL-R2. However, clinical trials making use of these agonists in various tumor entities including pancreatic cancer were disappointing so far. This is thought to be caused by TRAIL resistance of numerous primary tumor cells, an insufficient agonistic activity of the drug candidates tested, and a lack of suitable biomarkers for patient stratification. Nevertheless, recently gained knowledge on the biology of the TRAIL-TRAIL-R system might now provide the chance to overcome intrinsic or acquired resistance against TRAIL and TRAIL-R agonists. In this review, we summarize the status quo of clinical studies involving TRAIL-R agonists for the treatment of pancreatic cancer and critically discuss the suitability of utilizing the TRAIL-TRAIL-R system for successful treatment. Full article
(This article belongs to the Special Issue Latest Development in Pancreatic Cancer)
►▼ Show Figures

Figure 1

14 pages, 1579 KiB  
Article
Epstein–Barr Virus Gene BARF1 Expression is Regulated by the Epithelial Differentiation Factor ΔNp63α in Undifferentiated Nasopharyngeal Carcinoma
by Eveline Hoebe, Coral Wille, Stacy Hagemeier, Shannon Kenney, Astrid Greijer and Jaap Middeldorp
Cancers 2018, 10(3), 76; https://doi.org/10.3390/cancers10030076 - 17 Mar 2018
Cited by 13 | Viewed by 5116
Abstract
Epstein–Barr Virus (EBV) BamHI-A rightward frame 1 (BARF1) protein is considered a viral oncogene in epithelial cells and has immune-modulating properties. During viral lytic replication BARF1 is expressed as an early gene, regulated by the immediate early EBV protein R. However, in viral [...] Read more.
Epstein–Barr Virus (EBV) BamHI-A rightward frame 1 (BARF1) protein is considered a viral oncogene in epithelial cells and has immune-modulating properties. During viral lytic replication BARF1 is expressed as an early gene, regulated by the immediate early EBV protein R. However, in viral latency BARF1 is exclusively expressed in epithelial tumors such as nasopharyngeal (NPC) and gastric carcinoma (GC) but not in lymphomas, indicating that activation of the BARF1 promoter is cell type specific. Undifferentiated NPC is characterized by high expression of ΔNp63 isoforms of the epithelial differentiation marker p63, a member of the p53 family of transcription factors. Transcription factor binding site analysis indicated potential p53 family binding sites within the BARF1 promoter region. This study investigated ability of various p53 family members to transactivate the BARF1 promoter. Using BARF1 promoter luciferase reporter constructs we demonstrate that only p63 isoform ΔNp63α is capable of transactivating the BARF1 promoter, but not the TAp63 isoforms, p53 or p73. Direct promoter binding of ΔNp63α was confirmed by Chromatin Immune Precipitation (ChIP) analysis. Deletion mutants of the BARF1 promoter revealed multiple ΔNp63 response elements to be responsible for BARF1 promoter transactivation. However, ΔNp63α alone was not sufficient to induce BARF1 in tumor cells harboring full EBV genomes, indicating that additional cofactors might be required for full BARF1 regulation. In conclusion, in EBV positive NPC and GC, BARF1 expression might be induced by the epithelial differentiation marker ΔNp63α, explaining BARF1 expression in the absence of lytic reactivation. Full article
(This article belongs to the Special Issue Epstein–Barr Virus Associated Cancers)
►▼ Show Figures

Figure 1

12 pages, 3952 KiB  
Review
Stereotactic Radiotherapy and Particle Therapy for Pancreatic Cancer
by Sweet Ping Ng and Joseph M. Herman
Cancers 2018, 10(3), 75; https://doi.org/10.3390/cancers10030075 - 16 Mar 2018
Cited by 19 | Viewed by 7152
Abstract
Pancreatic cancer is a devastating disease with poor survival outcomes. Recent studies have shown that the addition of radiotherapy to chemotherapy in the setting of locally advanced pancreatic cancer did not improve overall survival outcome. These studies commonly utilize conventional radiotherapy treatment fractionation [...] Read more.
Pancreatic cancer is a devastating disease with poor survival outcomes. Recent studies have shown that the addition of radiotherapy to chemotherapy in the setting of locally advanced pancreatic cancer did not improve overall survival outcome. These studies commonly utilize conventional radiotherapy treatment fractionation and technique (typically 3-D conformal radiotherapy or intensity modulated radiotherapy). Although no clear benefit in overall survival was demonstrated in those studies, those who received radiotherapy did have a clear benefit in terms of local control. Therefore, there is increasing interest in exploring different techniques and/or modality of radiotherapy and dose/fractionation. Stereotactic radiotherapy, which employs a hypofractionated regimen, has the potential advantage of delivering a high dose of radiation to the tumor in a short period of time (typically over 5 days) with minimal dose to the surrounding normal structures. Particle therapy such as proton and carbon ion therapy are being explored as potential radiation modality that could cause greater biological damage to the tumor compared to photon treatment, with rapid dose falloff resulting in minimal to no dose to adjacent structures. This review will discuss the current literature and emerging roles of stereotactic radiotherapy and particle therapy in pancreatic cancer. Full article
(This article belongs to the Special Issue Latest Development in Pancreatic Cancer)
►▼ Show Figures

Figure 1

2 pages, 332 KiB  
Correction
Correction: Alessia Stornetta et al. Alcohol-Derived Acetaldehyde Exposure in the Oral Cavity. Cancers 2018, 10, 20
by Alessia Stornetta, Valeria Guidolin and Silvia Balbo
Cancers 2018, 10(3), 74; https://doi.org/10.3390/cancers10030074 - 16 Mar 2018
Cited by 6 | Viewed by 2891
Abstract
The authors would like to make a correction to their published paper[...] Full article
25 pages, 834 KiB  
Review
Coming of Age for Autotaxin and Lysophosphatidate Signaling: Clinical Applications for Preventing, Detecting and Targeting Tumor-Promoting Inflammation
by Matthew G.K. Benesch, Iain T.K. MacIntyre, Todd P.W. McMullen and David N. Brindley
Cancers 2018, 10(3), 73; https://doi.org/10.3390/cancers10030073 - 15 Mar 2018
Cited by 59 | Viewed by 7044
Abstract
A quarter-century after the discovery of autotaxin in cell culture, the autotaxin-lysophosphatidate (LPA)-lipid phosphate phosphatase axis is now a promising clinical target for treating chronic inflammatory conditions, mitigating fibrosis progression, and improving the efficacy of existing cancer chemotherapies and radiotherapy. Nearly half of [...] Read more.
A quarter-century after the discovery of autotaxin in cell culture, the autotaxin-lysophosphatidate (LPA)-lipid phosphate phosphatase axis is now a promising clinical target for treating chronic inflammatory conditions, mitigating fibrosis progression, and improving the efficacy of existing cancer chemotherapies and radiotherapy. Nearly half of the literature on this axis has been published during the last five years. In cancer biology, LPA signaling is increasingly being recognized as a central mediator of the progression of chronic inflammation in the establishment of a tumor microenvironment which promotes cancer growth, immune evasion, metastasis, and treatment resistance. In this review, we will summarize recent advances made in understanding LPA signaling with respect to chronic inflammation and cancer. We will also provide perspectives on the applications of inhibitors of LPA signaling in preventing cancer initiation, as adjuncts extending the efficacy of current cancer treatments by blocking inflammation caused by either the cancer or the cancer therapy itself, and by disruption of the tumor microenvironment. Overall, LPA, a simple molecule that mediates a plethora of biological effects, can be targeted at its levels of production by autotaxin, LPA receptors or through LPA degradation by lipid phosphate phosphatases. Drugs for these applications will soon be entering clinical practice. Full article
(This article belongs to the Special Issue Inflammation and Cancer)
►▼ Show Figures

Figure 1

15 pages, 8021 KiB  
Review
Update on Immunohistochemistry for the Diagnosis of Lung Cancer
by Kentaro Inamura
Cancers 2018, 10(3), 72; https://doi.org/10.3390/cancers10030072 - 14 Mar 2018
Cited by 98 | Viewed by 16718
Abstract
Immunohistochemistry is a widely available technique that is less challenging and can provide clinically meaningful results quickly and cost-efficiently in comparison with other techniques. In addition, immunohistochemistry allows for the evaluation of cellular localization of proteins in the context of tumor structure. In [...] Read more.
Immunohistochemistry is a widely available technique that is less challenging and can provide clinically meaningful results quickly and cost-efficiently in comparison with other techniques. In addition, immunohistochemistry allows for the evaluation of cellular localization of proteins in the context of tumor structure. In an era of precision medicine, pathologists are required to classify lung cancer into specific subtypes and assess biomarkers relevant to molecular-targeted therapies. This review summarizes the hot topics of immunohistochemistry in lung cancer, including (i) adenocarcinoma vs squamous cell carcinoma; (ii) neuroendocrine markers; (iii) ALK, ROS1, and EGFR; (iv) PD-L1 (CD274); (v) lung carcinoma vs malignant mesothelioma; and (vi) NUT carcinoma. Major pitfalls in evaluating immunohistochemical results are also described. Full article
(This article belongs to the Special Issue Immunohistochemistry and Cancer Diagnosis)
►▼ Show Figures

Figure 1

10 pages, 966 KiB  
Article
Proton Beam Therapy without Fiducial Markers Using Four-Dimensional CT Planning for Large Hepatocellular Carcinomas
by Satoshi Shibata, Shigeyuki Takamatsu, Kazutaka Yamamoto, Miu Mizuhata, Sayuri Bou, Yoshitaka Sato, Mariko Kawamura, Satoko Asahi, Yuji Tameshige, Yoshikazu Maeda, Makoto Sasaki, Tomoyasu Kumano, Satoshi Kobayashi, Hiroyasu Tamamura and Toshifumi Gabata
Cancers 2018, 10(3), 71; https://doi.org/10.3390/cancers10030071 - 14 Mar 2018
Cited by 8 | Viewed by 4328
Abstract
We evaluated the effectiveness and toxicity of proton beam therapy (PBT) for hepatocellular carcinomas (HCC) >5 cm without fiducial markers using four-dimensional CT (4D-CT) planning. The subjects were 29 patients treated at our hospital between March 2011 and March 2015. The median total [...] Read more.
We evaluated the effectiveness and toxicity of proton beam therapy (PBT) for hepatocellular carcinomas (HCC) >5 cm without fiducial markers using four-dimensional CT (4D-CT) planning. The subjects were 29 patients treated at our hospital between March 2011 and March 2015. The median total dose was 76 Cobalt Gray Equivalents (CGE) in 20 fractions (range; 66–80.5 CGE in 10–32 fractions). Therapy was delivered with end-expiratory phase gating. An internal target volume (ITV) margin was added through the analysis of respiratory movement with 4D-CT. Patient age ranged from 38 to 87 years (median, 71 years). Twenty-four patients were Child–Pugh class A and five patients were class B. Tumor size ranged from 5.0 to 13.9 cm (median, 6.9 cm). The follow-up period ranged from 2 to 72 months (median; 27 months). All patients completed PBT according to the treatment protocol without grade 4 (CTCAE v4.03 (draft v5.0)) or higher adverse effects. The two-year local tumor control (LTC), progression-free survival (PFS), and overall survival (OS) rates were 95%, 22%, and 61%, respectively. The LTC was not inferior to that of previous reports using fiducial markers. Respiratory-gated PBT with 4D-CT planning without fiducial markers is a less invasive and equally effective treatment for large HCCs as PBT with fiducial markers. Full article
(This article belongs to the Special Issue Proton and Carbon Ion Therapy)
►▼ Show Figures

Figure 1

20 pages, 6702 KiB  
Review
Any Place for Immunohistochemistry within the Predictive Biomarkers of Treatment in Lung Cancer Patients?
by Véronique Hofman, Sandra Lassalle, Coraline Bence, Elodie Long-Mira, Sacha Nahon-Estève, Simon Heeke, Virginie Lespinet-Fabre, Catherine Butori, Marius Ilié and Paul Hofman
Cancers 2018, 10(3), 70; https://doi.org/10.3390/cancers10030070 - 13 Mar 2018
Cited by 22 | Viewed by 5639
Abstract
The identification of certain genomic alterations (EGFR, ALK, ROS1, BRAF) or immunological markers (PD-L1) in tissues or cells has led to targeted treatment for patients presenting with late stage or metastatic lung cancer. These biomarkers can be detected [...] Read more.
The identification of certain genomic alterations (EGFR, ALK, ROS1, BRAF) or immunological markers (PD-L1) in tissues or cells has led to targeted treatment for patients presenting with late stage or metastatic lung cancer. These biomarkers can be detected by immunohistochemistry (IHC) and/or by molecular biology (MB) techniques. These approaches are often complementary but depending on, the quantity and quality of the biological material, the urgency to get the results, the access to technological platforms, the financial resources and the expertise of the team, the choice of the approach can be questioned. The possibility of detecting simultaneously several molecular targets, and of analyzing the degree of tumor mutation burden and of the micro-satellite instability, as well as the recent requirement to quantify the expression of PD-L1 in tumor cells, has led to case by case development of algorithms and international recommendations, which depend on the quality and quantity of biological samples. This review will highlight the different predictive biomarkers detected by IHC for treatment of lung cancer as well as the present advantages and limitations of this approach. A number of perspectives will be considered. Full article
(This article belongs to the Special Issue Immunohistochemistry and Cancer Diagnosis)
►▼ Show Figures

Figure 1

19 pages, 1974 KiB  
Article
Nano-Pulse Stimulation Ablates Orthotopic Rat Hepatocellular Carcinoma and Induces Innate and Adaptive Memory Immune Mechanisms that Prevent Recurrence
by Brittany P. Lassiter, Siqi Guo and Stephen J. Beebe
Cancers 2018, 10(3), 69; https://doi.org/10.3390/cancers10030069 - 13 Mar 2018
Cited by 25 | Viewed by 5877
Abstract
Nano-pulse stimulation (NPS), previously called nsPEFs, induced a vaccine-like effect after ablation of orthotopic N1-S1 hepatocellular carcinoma (HCC), protecting rats from subsequent challenges with N1-S1 cells. To determine immunity, immune cell phenotypes were analyzed in naïve, treated and protected rats. NPS provides a [...] Read more.
Nano-pulse stimulation (NPS), previously called nsPEFs, induced a vaccine-like effect after ablation of orthotopic N1-S1 hepatocellular carcinoma (HCC), protecting rats from subsequent challenges with N1-S1 cells. To determine immunity, immune cell phenotypes were analyzed in naïve, treated and protected rats. NPS provides a positive, post-ablation immuno-therapeutic outcome by alleviating immunosuppressive T regulatory cells (Treg) in the tumor microenvironment (TME), allowing dendritic cell influx and inducing dynamic changes in natural killer cells (NKs), NKT-cells and T-lymphocytes in blood, spleen and liver. NPS induced specific increases in NKs and NKT-cells expressing CD8 and activation receptors CD314-NKG2D and CD161 (NK1.1) in the TME after treatment, as well as some variable changes in CD4+ and CD8+ effector (Tem) and central memory (Tem) lymphocytes in blood and spleen. After orthotopic challenge, CD8+ T-cells were cytotoxic, inducing apoptosis in N1-S1 cells; additionally, in contrast to post-treatment immune responses, CD4+ and CD8+ memory precursor effector cells (MPECs) and short-lived effector cells (SLECs) were present, while still including CD8+ CD161 NK cells, but not involving CD8+ CD314-NKG2D+ NKs. This immunity was N1-S1-specific and was sustained for at least 8 months. NPS vaccinates rats in vivo against HCC by activating innate and adaptive immune memory mechanisms that prevent HCC recurrence. Full article
►▼ Show Figures

Figure 1

17 pages, 3071 KiB  
Article
Tannic Acid Induces Endoplasmic Reticulum Stress-Mediated Apoptosis in Prostate Cancer
by Prashanth K.B. Nagesh, Elham Hatami, Pallabita Chowdhury, Vivek K. Kashyap, Sheema Khan, Bilal B. Hafeez, Subhash C. Chauhan, Meena Jaggi and Murali M. Yallapu
Cancers 2018, 10(3), 68; https://doi.org/10.3390/cancers10030068 - 7 Mar 2018
Cited by 51 | Viewed by 8297
Abstract
Endoplasmic reticulum (ER) stress is an intriguing target with significant clinical importance in chemotherapy. Interference with ER functions can lead to the accumulation of unfolded proteins, as detected by transmembrane sensors that instigate the unfolded protein response (UPR). Therefore, controlling induced UPR via [...] Read more.
Endoplasmic reticulum (ER) stress is an intriguing target with significant clinical importance in chemotherapy. Interference with ER functions can lead to the accumulation of unfolded proteins, as detected by transmembrane sensors that instigate the unfolded protein response (UPR). Therefore, controlling induced UPR via ER stress with natural compounds could be a novel therapeutic strategy for the management of prostate cancer. Tannic acid (a naturally occurring polyphenol) was used to examine the ER stress mediated UPR pathway in prostate cancer cells. Tannic acid treatment inhibited the growth, clonogenic, invasive, and migratory potential of prostate cancer cells. Tannic acid demonstrated activation of ER stress response (Protein kinase R-like endoplasmic reticulum kinase (PERK) and inositol requiring enzyme 1 (IRE1)) and altered its regulatory proteins (ATF4, Bip, and PDI) expression. Tannic acid treatment affirmed upregulation of apoptosis-associated markers (Bak, Bim, cleaved caspase 3, and cleaved PARP), while downregulation of pro-survival proteins (Bcl-2 and Bcl-xL). Tannic acid exhibited elevated G1 population, due to increase in p18INK4C and p21WAF1/CIP1 expression, while cyclin D1 expression was inhibited. Reduction of MMP2 and MMP9, and reinstated E-cadherin signifies the anti-metastatic potential of this compound. Altogether, these results demonstrate that tannic acid can promote apoptosis via the ER stress mediated UPR pathway, indicating a potential candidate for cancer treatment. Full article
(This article belongs to the Special Issue Molecular Stress Response Dysregulation in Cancer: Therapeutic Targets and Opportunities)
►▼ Show Figures

Graphical abstract

12 pages, 452 KiB  
Perspective
Protein Biomarkers for Early Detection of Pancreatic Ductal Adenocarcinoma: Progress and Challenges
by Alex Root, Peter Allen, Paul Tempst and Kenneth Yu
Cancers 2018, 10(3), 67; https://doi.org/10.3390/cancers10030067 - 7 Mar 2018
Cited by 21 | Viewed by 7456
Abstract
Approximately 75% of patients with pancreatic ductal adenocarcinoma are diagnosed with advanced cancer, which cannot be safely resected. The most commonly used biomarker CA19-9 has inadequate sensitivity and specificity for early detection, which we define as Stage I/II cancers. Therefore, progress in next-generation [...] Read more.
Approximately 75% of patients with pancreatic ductal adenocarcinoma are diagnosed with advanced cancer, which cannot be safely resected. The most commonly used biomarker CA19-9 has inadequate sensitivity and specificity for early detection, which we define as Stage I/II cancers. Therefore, progress in next-generation biomarkers is greatly needed. Recent reports have validated a number of biomarkers, including combination assays of proteins and DNA mutations; however, the history of translating promising biomarkers to clinical utility suggests that several major hurdles require careful consideration by the medical community. The first set of challenges involves nominating and verifying biomarkers. Candidate biomarkers need to discriminate disease from benign controls with high sensitivity and specificity for an intended use, which we describe as a two-tiered strategy of identifying and screening high-risk patients. Community-wide efforts to share samples, data, and analysis methods have been beneficial and progress meeting this challenge has been achieved. The second set of challenges is assay optimization and validating biomarkers. After initial candidate validation, assays need to be refined into accurate, cost-effective, highly reproducible, and multiplexed targeted panels and then validated in large cohorts. To move the most promising candidates forward, ideally, biomarker panels, head-to-head comparisons, meta-analysis, and assessment in independent data sets might mitigate risk of failure. Much more investment is needed to overcome these challenges. The third challenge is achieving clinical translation. To moonshot an early detection test to the clinic requires a large clinical trial and organizational, regulatory, and entrepreneurial know-how. Additional factors, such as imaging technologies, will likely need to improve concomitant with molecular biomarker development. The magnitude of the clinical translational challenge is uncertain, but interdisciplinary cooperation within the PDAC community is poised to confront it. Full article
(This article belongs to the Special Issue Cancer Biomarkers)
►▼ Show Figures

Figure 1

22 pages, 1615 KiB  
Review
Evolution of Carbon Ion Radiotherapy at the National Institute of Radiological Sciences in Japan
by Osama Mohamad, Hirokazu Makishima and Tadashi Kamada
Cancers 2018, 10(3), 66; https://doi.org/10.3390/cancers10030066 - 6 Mar 2018
Cited by 67 | Viewed by 9091
Abstract
Charged particles can achieve better dose distribution and higher biological effectiveness compared to photon radiotherapy. Carbon ions are considered an optimal candidate for cancer treatment using particles. The National Institute of Radiological Sciences (NIRS) in Chiba, Japan was the first radiotherapy hospital dedicated [...] Read more.
Charged particles can achieve better dose distribution and higher biological effectiveness compared to photon radiotherapy. Carbon ions are considered an optimal candidate for cancer treatment using particles. The National Institute of Radiological Sciences (NIRS) in Chiba, Japan was the first radiotherapy hospital dedicated for carbon ion treatments in the world. Since its establishment in 1994, the NIRS has pioneered this therapy with more than 69 clinical trials so far, and hundreds of ancillary projects in physics and radiobiology. In this review, we will discuss the evolution of carbon ion radiotherapy at the NIRS and some of the current and future projects in the field. Full article
(This article belongs to the Special Issue Proton and Carbon Ion Therapy)
►▼ Show Figures

Figure 1

15 pages, 1660 KiB  
Article
Survival Analysis in Patients with Pancreatic Ductal Adenocarcinoma Undergoing Chemoradiotherapy Followed by Surgery According to the International Consensus on the 2017 Definition of Borderline Resectable Cancer
by Aoi Hayasaki, Shuji Isaji, Masashi Kishiwada, Takehiro Fujii, Yusuke Iizawa, Hiroyuki Kato, Akihiro Tanemura, Yasuhiro Murata, Yoshinori Azumi, Naohisa Kuriyama, Shugo Mizuno, Masanobu Usui and Hiroyuki Sakurai
Cancers 2018, 10(3), 65; https://doi.org/10.3390/cancers10030065 - 5 Mar 2018
Cited by 40 | Viewed by 4678
Abstract
Background: The aim of this study was to validate a new definition of borderline resectable pancreatic ductal adenocarcinoma (PDAC) provided by the 2017 international consensus on the basis of three dimensions of anatomical (A), biological (B), and conditional (C) factors, using the [...] Read more.
Background: The aim of this study was to validate a new definition of borderline resectable pancreatic ductal adenocarcinoma (PDAC) provided by the 2017 international consensus on the basis of three dimensions of anatomical (A), biological (B), and conditional (C) factors, using the data of the patients who had been registered for our institutional protocol of chemoradiotherapy followed by surgery (CRTS) for localized patients with PDAC. Methods: Among 307 consecutive patients pathologically diagnosed with localized PDAC who were enrolled in our CRTS protocol from February 2005 to December 2016, we selected 285 patients who could be re-evaluated after CRT. These 285 patients were classified according to international consensus A definitions as follows: R (resectable; n = 62), BR-PV (borderline resectable, superior mesenteric vein (SMV)/portal vein (PV) involvement alone; n = 27), BR-A (borderline resectable, arterial involvement; n = 50), LA (locally advanced; n = 146). Disease-specific survival (DSS) was analyzed according to A, B (serum CA 19-9 levels and lymph node metastasis diagnosed by computed tomography findings before CRT), and C factors (performance status (PS)) factors. Results: The rates of resection and R0 resection were similar between R (83.9 and 98.0%) and BR-PV (85.2 and 95.5%), but much lower in BR-A (70.0 and 84.8%) and LA (46.6 and 62.5%). DSS evaluated by median survival time (months) showed a similar trend to surgical outcomes: 33.7 in R, 27.3 in BR-PV, 18.9 in BR-A and 19.3 in LA, respectively. DSS in R patients with CA 19-9 levels > 500 U/mL was significantly poorer than in patients with CA 19-9 levels ≤ 500 U/mL, but there were no differences in DSS among BR-PV, BR-A, and LA patients according to CA 19-9 levels. Regarding lymph node metastasis, there was no significant difference in DSS according to each resectability group. DSS in R patients with PS ≥ 2 was significantly worse than in patients with PS 0-1. Conclusions: The international consensus on the definition of BR-PDAC based on three dimensions of A, B, and C is useful and practicable because prognosis of PDAC patients is influenced by anatomical factors as well as biological and conditional factors, which in turn may help to decide treatment strategy. Full article
►▼ Show Figures

Figure 1

12 pages, 1765 KiB  
Review
The Role of Oncogenic Tyrosine Kinase NPM-ALK in Genomic Instability
by Cosimo Lobello, Vasilis Bikos, Andrea Janikova and Sarka Pospisilova
Cancers 2018, 10(3), 64; https://doi.org/10.3390/cancers10030064 - 5 Mar 2018
Cited by 10 | Viewed by 6146
Abstract
Genomic stability is crucial for cell life and transmitting genetic material is one of the primary tasks of the cell. The cell needs to be able to recognize any possible error and quickly repair it, and thus, cells have developed several mechanisms to [...] Read more.
Genomic stability is crucial for cell life and transmitting genetic material is one of the primary tasks of the cell. The cell needs to be able to recognize any possible error and quickly repair it, and thus, cells have developed several mechanisms to detect DNA damage and promote repair during evolution. The DNA damage response (DDR) and DNA repair pathways ensure the control of possible errors that could impair the duplication of genetic information and introduce variants in the DNA. Endogenous and exogenous factors compromise genomic stability and cause dysregulation in the DDR and DNA repair pathways. Cancer cells often impair these mechanisms to overcome cellular barriers (cellular senescence and/or apoptosis), leading to malignancy. NPM (nucleophosmin)-ALK (anaplastic lymphoma kinase) is an oncogenic tyrosine kinase that is involved in the development of anaplastic large cell lymphoma (ALCL). NPM-ALK is known to be involved in the activation of proliferative and anti-apoptotic signaling pathways. New evidence reveals that NPM-ALK translocation also impairs the ability of cells to maintain the genomic stability through both DDR and DNA repair pathways. This review aims to highlight the role of the oncogenic tyrosine kinase NPM-ALK in the cell, and pointing to new possible therapeutic strategies. Full article
(This article belongs to the Special Issue Advances in Our Understanding of ALK-Related Cancers: A Selection of Papers from the Joint Annual Meeting of the European Research Initiative for ALK-Related Malignancies (ERIA) and the European Union Marie Curie European Training Network ALKATRAS)
►▼ Show Figures

Figure 1

7 pages, 858 KiB  
Editorial
Kinases and Cancer
by Jonas Cicenas, Egle Zalyte, Amos Bairoch and Pascale Gaudet
Cancers 2018, 10(3), 63; https://doi.org/10.3390/cancers10030063 - 1 Mar 2018
Cited by 97 | Viewed by 8520
Abstract
Protein kinases are a large family of enzymes catalyzing protein phosphorylation. The human genome contains 518 protein kinase genes, 478 of which belong to the classical protein kinase family and 40 are atypical protein kinases [...]
Full article
(This article belongs to the Collection Kinases and Cancer)
►▼ Show Figures

Figure 1

30 pages, 1702 KiB  
Review
Tumor Resistance against ALK Targeted Therapy-Where It Comes From and Where It Goes
by Geeta Geeta Sharma, Ines Mota, Luca Mologni, Enrico Patrucco, Carlo Gambacorti-Passerini and Roberto Chiarle
Cancers 2018, 10(3), 62; https://doi.org/10.3390/cancers10030062 - 28 Feb 2018
Cited by 82 | Viewed by 9725
Abstract
Anaplastic lymphoma kinase (ALK) is a validated molecular target in several ALK-rearranged malignancies, particularly in non-small-cell lung cancer (NSCLC), which has generated considerable interest and effort in developing ALK tyrosine kinase inhibitors (TKI). Crizotinib was the first ALK inhibitor to receive FDA approval [...] Read more.
Anaplastic lymphoma kinase (ALK) is a validated molecular target in several ALK-rearranged malignancies, particularly in non-small-cell lung cancer (NSCLC), which has generated considerable interest and effort in developing ALK tyrosine kinase inhibitors (TKI). Crizotinib was the first ALK inhibitor to receive FDA approval for ALK-positive NSCLC patients treatment. However, the clinical benefit observed in targeting ALK in NSCLC is almost universally limited by the emergence of drug resistance with a median of occurrence of approximately 10 months after the initiation of therapy. Thus, to overcome crizotinib resistance, second/third-generation ALK inhibitors have been developed and received, or are close to receiving, FDA approval. However, even when treated with these new inhibitors tumors became resistant, both in vitro and in clinical settings. The elucidation of the diverse mechanisms through which resistance to ALK TKI emerges, has informed the design of novel therapeutic strategies to improve patients disease outcome. This review summarizes the currently available knowledge regarding ALK physiologic function/structure and neoplastic transforming role, as well as an update on ALK inhibitors and resistance mechanisms along with possible therapeutic strategies that may overcome the development of resistance. Full article
(This article belongs to the Special Issue Advances in Our Understanding of ALK-Related Cancers: A Selection of Papers from the Joint Annual Meeting of the European Research Initiative for ALK-Related Malignancies (ERIA) and the European Union Marie Curie European Training Network ALKATRAS)
►▼ Show Figures

Figure 1

25 pages, 821 KiB  
Review
Teaming Up for Trouble: Cancer Cells, Transforming Growth Factor-β1 Signaling and the Epigenetic Corruption of Stromal Naïve Fibroblasts
by Sergio Lamprecht, Ina Sigal-Batikoff, Shraga Shany, Naim Abu-Freha, Eduard Ling, George J. Delinasios, Keren Moyal-Atias, John G. Delinasios and Alexander Fich
Cancers 2018, 10(3), 61; https://doi.org/10.3390/cancers10030061 - 27 Feb 2018
Cited by 35 | Viewed by 5013
Abstract
It is well recognized that cancer cells subvert the phenotype of stromal naïve fibroblasts and instruct the neighboring cells to sustain their growth agenda. The mechanisms underpinning the switch of fibroblasts to cancer-associated fibroblasts (CAFs) are the focus of intense investigation. One of [...] Read more.
It is well recognized that cancer cells subvert the phenotype of stromal naïve fibroblasts and instruct the neighboring cells to sustain their growth agenda. The mechanisms underpinning the switch of fibroblasts to cancer-associated fibroblasts (CAFs) are the focus of intense investigation. One of the most significant hallmarks of the biological identity of CAFs is that their tumor-promoting phenotype is stably maintained during in vitro and ex vivo propagation without the continual interaction with the adjacent cancer cells. In this review, we discuss robust evidence showing that the master cytokine Transforming Growth Factor-β1 (TGFβ-1) is a prime mover in reshaping, via epigenetic switches, the phenotype of stromal fibroblasts to a durable state. We also examine, in detail, the pervasive involvement of TGFβ-1 signaling from both cancer cells and CAFs in fostering cancer development, taking colorectal cancer (CRC) as a paradigm of human neoplasia. Finally, we review the stroma-centric anticancer therapeutic approach focused on CAFs—the most abundant cell population of the tumor microenvironment (TME)—as target cells. Full article
►▼ Show Figures

Figure 1

14 pages, 2414 KiB  
Article
Clinically Usable Interleukin 12 Plasmid without an Antibiotic Resistance Gene: Functionality and Toxicity Study in Murine Melanoma Model
by Urska Kamensek, Natasa Tesic, Gregor Sersa and Maja Cemazar
Cancers 2018, 10(3), 60; https://doi.org/10.3390/cancers10030060 - 27 Feb 2018
Cited by 16 | Viewed by 4620
Abstract
Plasmids, which are currently used in interleukin 12 (IL-12) gene electrotransfer (GET) clinical trials in the USA, contain antibiotic resistance genes and are thus, according to the safety recommendation of the European Medicines Agency (EMA), not suitable for clinical trials in the EU. [...] Read more.
Plasmids, which are currently used in interleukin 12 (IL-12) gene electrotransfer (GET) clinical trials in the USA, contain antibiotic resistance genes and are thus, according to the safety recommendation of the European Medicines Agency (EMA), not suitable for clinical trials in the EU. In the current study, our aim was to prepare an IL-12 plasmid without an antibiotic resistance gene and test its functionality and toxicity after GET in a preclinical B16F10 mouse melanoma model. The antibiotic resistance-free plasmid encoding the human IL-12 fusion gene linked to the p21 promoter, i.e., p21-hIL-12-ORT, was constructed using operator-repressor titration (ORT) technology. Next, the expression profile of the plasmid after GET was determined in B16F10 cells and tumors. Additionally, blood chemistry, hematological and histological changes, and antitumor response were evaluated after GET of the plasmid in melanoma tumors. The results demonstrated a good expression and safety profile of the p21-hIL-12-ORT GET and indications of efficacy. We hope that the obtained results will help to accelerate the transfer of this promising treatment from preclinical studies to clinical application in the EU. Full article
(This article belongs to the Special Issue Electric Field Based Therapies for Cancer: A Selection of Papers from the 2nd World Congress on Electroporation)
►▼ Show Figures

Figure 1

25 pages, 1087 KiB  
Review
Post-Translational Modifications of H2A Histone Variants and Their Role in Cancer
by David Corujo and Marcus Buschbeck
Cancers 2018, 10(3), 59; https://doi.org/10.3390/cancers10030059 - 27 Feb 2018
Cited by 69 | Viewed by 10999
Abstract
Histone variants are chromatin components that replace replication-coupled histones in a fraction of nucleosomes and confer particular characteristics to chromatin. H2A variants represent the most numerous and diverse group among histone protein families. In the nucleosomal structure, H2A-H2B dimers can be removed and [...] Read more.
Histone variants are chromatin components that replace replication-coupled histones in a fraction of nucleosomes and confer particular characteristics to chromatin. H2A variants represent the most numerous and diverse group among histone protein families. In the nucleosomal structure, H2A-H2B dimers can be removed and exchanged more easily than the stable H3-H4 core. The unstructured N-terminal histone tails of all histones, but also the C-terminal tails of H2A histones protrude out of the compact structure of the nucleosome core. These accessible tails are the preferential target sites for a large number of post-translational modifications (PTMs). While some PTMs are shared between replication-coupled H2A and H2A variants, many modifications are limited to a specific histone variant. The present review focuses on the H2A variants H2A.Z, H2A.X, and macroH2A, and summarizes their functions in chromatin and how these are linked to cancer development and progression. H2A.Z primarily acts as an oncogene and macroH2A and H2A.X as tumour suppressors. We further focus on the regulation by PTMs, which helps to understand a degree of context dependency. Full article
(This article belongs to the Collection Histone Modification in Cancer)
►▼ Show Figures

Figure 1

Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:
 
Displaying articles 1-27
Previous Issue
Next Issue
Back to TopTop