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Cancers, Volume 10, Issue 10 (October 2018) – 52 articles

Cover Story (view full-size image): Tumor cells take advantage of cell stress response pathways to enable their survival under adverse conditions. In breast cancer cells, constitutive activation of unfolded protein response (UPR) promotes an adaptive, therapy-resistant phenotype. This UPR-dependence exposes a weakness in breast cancer cells that can be exploited for therapeutic purposes. The UPR is mediated by signalling through three transmembrane ER stress sensors, IRE1, PERK and ATF6. Several novel drugs that target these pathways, particularly the IRE1 pathway, show promise in preclinical studies, supporting the case for their clinical development. View this paper
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19 pages, 1219 KiB  
Article
Prognostic Values of EPDR1 Hypermethylation and Its Inhibitory Function on Tumor Invasion in Colorectal Cancer
by Chun-Ho Chu, Shih-Ching Chang, Hsiu-Hua Wang, Shung-Haur Yang, Kuo-Chu Lai and Te-Chang Lee
Cancers 2018, 10(10), 393; https://doi.org/10.3390/cancers10100393 - 22 Oct 2018
Cited by 21 | Viewed by 3764
Abstract
Aberrant DNA methylation is a potential mechanism underlying the development of colorectal cancer (CRC). Thus, identification of prognostic DNA methylation markers and understanding the related molecular functions may offer a new perspective on CRC pathogenesis. To that end, we explored DNA methylation profile [...] Read more.
Aberrant DNA methylation is a potential mechanism underlying the development of colorectal cancer (CRC). Thus, identification of prognostic DNA methylation markers and understanding the related molecular functions may offer a new perspective on CRC pathogenesis. To that end, we explored DNA methylation profile changes in CRC subtypes based on the microsatellite instability (MSI) status through genome-wide DNA methylation profiling analysis. Of 34 altered genes, three hypermethylated (epidermal growth factor, EGF; carbohydrate sulfotransferase 10, CHST10; ependymin related 1, EPDR1) and two hypomethylated (bone marrow stromal antigen 2, BST2; Rac family small GTPase 3, RAC3) candidates were further validated in CRC patients. Based on quantitative methylation-specific polymerase chain reaction (Q-MSP), EGF, CHST10 and EPDR1 showed higher hypermethylated levels in CRC tissues than those in adjacent normal tissues, whereas BST2 showed hypomethylation in CRC tissues relative to adjacent normal tissues. Additionally, among 75 CRC patients, hypermethylation of CHST10 and EPDR1 was significantly correlated with the MSI status and a better prognosis. Moreover, EPDR1 hypermethylation was significantly correlated with node negativity and a lower tumor stage as well as with mutations in B-Raf proto-oncogene serine/threonine kinase (BRAF) and human transforming growth factor beta receptor 2 (TGFβR2). Conversely, a negative correlation between the mRNA expression and methylation levels of EPDR1 in CRC tissues and cell lines was observed, revealing that DNA methylation has a crucial function in modulating EPDR1 expression in CRC cells. EPDR1 knockdown by a transient small interfering RNA significantly suppressed invasion by CRC cells, suggesting that decreased EPDR1 levels may attenuate CRC cell invasion. These results suggest that DNA methylation-mediated EPDR1 epigenetic silencing may play an important role in preventing CRC progression. Full article
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15 pages, 652 KiB  
Article
Predicting 90-Day Mortality in Locoregionally Advanced Head and Neck Squamous Cell Carcinoma after Curative Surgery
by Lei Qin, Tsung-Ming Chen, Yi-Wei Kao, Kuan-Chou Lin, Kevin Sheng-Po Yuan, Alexander T. H. Wu, Ben-Chang Shia and Szu-Yuan Wu
Cancers 2018, 10(10), 392; https://doi.org/10.3390/cancers10100392 - 22 Oct 2018
Cited by 17 | Viewed by 3434
Abstract
Purpose: To propose a risk classification scheme for locoregionally advanced (Stages III and IV) head and neck squamous cell carcinoma (LA-HNSCC) by using the Wu comorbidity score (WCS) to quantify the risk of curative surgeries, including tumor resection and radical neck dissection. Methods: [...] Read more.
Purpose: To propose a risk classification scheme for locoregionally advanced (Stages III and IV) head and neck squamous cell carcinoma (LA-HNSCC) by using the Wu comorbidity score (WCS) to quantify the risk of curative surgeries, including tumor resection and radical neck dissection. Methods: This study included 55,080 patients with LA-HNSCC receiving curative surgery between 2006 and 2015 who were identified from the Taiwan Cancer Registry database; the patients were classified into two groups, mortality (n = 1287, mortality rate = 2.34%) and survival (n = 53,793, survival rate = 97.66%), according to the event of mortality within 90 days of surgery. Significant risk factors for mortality were identified using a stepwise multivariate Cox proportional hazards model. The WCS was calculated using the relative risk of each risk factor. The accuracy of the WCS was assessed using mortality rates in different risk strata. Results: Fifteen comorbidities significantly increased mortality risk after curative surgery. The patients were divided into low-risk (WCS, 0–6; 90-day mortality rate, 0–1.57%), intermediate-risk (7–11; 2.71–9.99%), high-risk (12–16; 17.30–20.00%), and very-high-risk (17–18 and >18; 46.15–50.00%) strata. The 90-day survival rates were 98.97, 95.85, 81.20, and 53.13% in the low-, intermediate-, high-, and very-high-risk patients, respectively (log-rank p < 0.0001). The five-year overall survival rates after surgery were 70.86, 48.62, 22.99, and 18.75% in the low-, intermediate-, high-, and very-high-risk patients, respectively (log-rank p < 0.0001). Conclusion: The WCS is an accurate tool for assessing curative-surgery-related 90-day mortality risk and overall survival in patients with LA-HNSCC. Full article
(This article belongs to the Special Issue Application of Bioinformatics in Cancers)
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19 pages, 4401 KiB  
Article
Choline Kinase Alpha Inhibition by EB-3D Triggers Cellular Senescence, Reduces Tumor Growth and Metastatic Dissemination in Breast Cancer
by Elena Mariotto, Giampietro Viola, Roberto Ronca, Luca Persano, Sanja Aveic, Zaver M. Bhujwalla, Noriko Mori, Benedetta Accordi, Valentina Serafin, Luisa Carlota López-Cara and Roberta Bortolozzi
Cancers 2018, 10(10), 391; https://doi.org/10.3390/cancers10100391 - 22 Oct 2018
Cited by 21 | Viewed by 5136
Abstract
Choline kinase (ChoK) is the first enzyme of the Kennedy pathway leading to the biosynthesis of phosphatidylcholine (PtdCho), the most abundant phospholipid in eukaryotic cell membranes. EB-3D is a novel choline kinase α1 (ChoKα1) inhibitor with potent antiproliferative activity against a panel of [...] Read more.
Choline kinase (ChoK) is the first enzyme of the Kennedy pathway leading to the biosynthesis of phosphatidylcholine (PtdCho), the most abundant phospholipid in eukaryotic cell membranes. EB-3D is a novel choline kinase α1 (ChoKα1) inhibitor with potent antiproliferative activity against a panel of several cancer cell lines. ChoKα1 is particularly overexpressed and hyperactivated in aggressive breast cancer. By NMR analysis, we demonstrated that EB-3D is able to reduce the synthesis of phosphocholine, and using flow cytometry, immunoblotting, and q-RT-PCR as well as proliferation and invasion assays, we proved that EB-3D strongly impairs breast cancer cell proliferation, migration, and invasion. EB-3D induces senescence in breast cancer cell lines through the activation of the metabolic sensor AMPK and the subsequent dephosphorylation of mTORC1 downstream targets, such as p70S6K, S6 ribosomal protein, and 4E-BP1. Moreover, EB-3D strongly synergizes with drugs commonly used for breast cancer treatment. The antitumorigenic potential of EB-3D was evaluated in vivo in the syngeneic orthotopic E0771 mouse model of breast cancer, where it induces a significant reduction of the tumor mass at low doses. In addition, EB-3D showed an antimetastatic effect in experimental and spontaneous metastasis models. Altogether, our results indicate that EB-3D could be a promising new anticancer agent to improve aggressive breast cancer treatment protocols. Full article
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11 pages, 702 KiB  
Article
Druggable Nucleolin Identifies Breast Tumours Associated with Poor Prognosis That Exhibit Different Biological Processes
by Flora Nguyen Van Long, Audrey Lardy-Cleaud, Susan Bray, Sylvie Chabaud, Thierry Dubois, Alexandra Diot, Lee B. Jordan, Alastair M. Thompson, Jean-Christophe Bourdon, David Perol, Philippe Bouvet, Jean-Jacques Diaz and Virginie Marcel
Cancers 2018, 10(10), 390; https://doi.org/10.3390/cancers10100390 - 22 Oct 2018
Cited by 12 | Viewed by 3145
Abstract
Background: Nucleolin (NCL) is a multifunctional protein with oncogenic properties. Anti-NCL drugs show strong cytotoxic effects, including in triple-negative breast cancer (TNBC) models, and are currently being evaluated in phase II clinical trials. However, few studies have investigated the clinical value of NCL [...] Read more.
Background: Nucleolin (NCL) is a multifunctional protein with oncogenic properties. Anti-NCL drugs show strong cytotoxic effects, including in triple-negative breast cancer (TNBC) models, and are currently being evaluated in phase II clinical trials. However, few studies have investigated the clinical value of NCL and whether NCL stratified cancer patients. Here, we have investigated for the first time the association of NCL with clinical characteristics in breast cancers independently of the different subtypes. Methods: Using two independent series (n = 216; n = 661), we evaluated the prognostic value of NCL in non-metastatic breast cancers using univariate and/or multivariate Cox-regression analyses. Results: We reported that NCL mRNA expression levels are markers of poor survivals independently of tumour size and lymph node invasion status (n = 216). In addition, an association of NCL expression levels with poor survival was observed in TNBC (n = 40, overall survival (OS) p = 0.0287, disease-free survival (DFS) p = 0.0194). Transcriptomic analyses issued from The Cancer Genome Atlas (TCGA) database (n = 661) revealed that breast tumours expressing either low or high NCL mRNA expression levels exhibit different gene expression profiles. These data suggest that tumours expressing high NCL mRNA levels are different from those expressing low NCL mRNA levels. Conclusions: NCL is an independent marker of prognosis in breast cancers. We anticipated that anti-NCL is a promising therapeutic strategy that could rapidly be evaluated in high NCL-expressing tumours to improve breast cancer management. Full article
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13 pages, 2147 KiB  
Article
Perivascular Tumor-Infiltrating Leukocyte Scoring for Prognosis of Resected Hepatocellular Carcinoma Patients
by Markus Bo Schoenberg, Jingcheng Hao, Julian Nikolaus Bucher, Rainer Christoph Miksch, Hubertus Johann Wolfgang Anger, Barbara Mayer, Julia Mayerle, Jens Neumann, Markus Otto Guba, Jens Werner and Alexandr V. Bazhin
Cancers 2018, 10(10), 389; https://doi.org/10.3390/cancers10100389 - 18 Oct 2018
Cited by 26 | Viewed by 4495
Abstract
Liver resection is a curative treatment for hepatocellular carcinoma (HCC). Tumor-infiltrating leukocytes (TILs) are important players in predicting HCC recurrence. However, the invasive margin could not be confirmed as relevant for HCC. The migration of immune cells into HCC may originate from intratumoral [...] Read more.
Liver resection is a curative treatment for hepatocellular carcinoma (HCC). Tumor-infiltrating leukocytes (TILs) are important players in predicting HCC recurrence. However, the invasive margin could not be confirmed as relevant for HCC. The migration of immune cells into HCC may originate from intratumoral vessels. No previous study has examined perivascular (PV) infiltration. Tumors from 60 patients were examined. Immunohistochemistry was performed against CD3, CD8, CD20, and CD66b. TILs were counted in the PV regions using an algorithm for quantification of the tumor immune stroma (QTiS). The results were correlated with overall (OS) and disease-free survival (DFS), clinical parameters, and laboratory values. PV infiltration of TILs was predominant in resected HCC. Higher PV infiltration of CD3+ (p = 0.016) and CD8+ (p = 0.028) independently predicted better OS and DFS, respectively. CD20+ showed a trend towards better DFS (p = 0.076). Scoring of CD3+, CD8+, and CD20+ independently predicted OS and DFS (p < 0.01). The amount of perivascular-infiltrating CD3+ cells is an independent predictor of better OS, and CD8+ cells independently predict prolonged DFS. Our novel perivascular infiltration scoring (PVIS) can independently predict both DFS and OS in resected HCC patients. Full article
(This article belongs to the Special Issue Cancer Biomarkers)
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12 pages, 594 KiB  
Article
Accelerated Hypofractionated Active Raster-Scanned Carbon Ion Radiotherapy (CIRT) for Laryngeal Malignancies: Feasibility and Safety
by Sati Akbaba, Kristin Lang, Thomas Held, Olcay Cem Bulut, Matthias Mattke, Matthias Uhl, Alexandra Jensen, Peter Plinkert, Stefan Rieken, Klaus Herfarth, Juergen Debus and Sebastian Adeberg
Cancers 2018, 10(10), 388; https://doi.org/10.3390/cancers10100388 - 18 Oct 2018
Cited by 8 | Viewed by 3063
Abstract
(1) Background: The authors present the first results of active raster-scanned carbon ion radiotherapy (CIRT) for radioresistant laryngeal malignancies regarding efficacy and toxicity. (2) Methods: 15 patients with laryngeal adenoid cystic carcinoma (ACC; n = 8; 53.3%) or chondrosarcoma (CS; n = 7; [...] Read more.
(1) Background: The authors present the first results of active raster-scanned carbon ion radiotherapy (CIRT) for radioresistant laryngeal malignancies regarding efficacy and toxicity. (2) Methods: 15 patients with laryngeal adenoid cystic carcinoma (ACC; n = 8; 53.3%) or chondrosarcoma (CS; n = 7; 46.7%) who underwent radiotherapy with carbon ions (C12) at the Heidelberg Ion Beam Therapy Center (HIT) between 2013 and 2018 were identified retrospectively and analyzed for local control (LC), overall survival (OS), and distant progression-free survival using the Kaplan–Meier method. CIRT was applied either alone (n = 7, 46.7%) or in combination with intensity modulated radiotherapy (IMRT) (n = 8, 53.3%). The toxicity was assessed according to the Common Toxicity Terminology Criteria for Adverse Events (CTCAE) v4.03. (3). Results: the median follow-up was 24 months (range 5–61 months). Overall, the therapy was tolerated very well. No grade >3 acute and chronic toxicity could be identified. The most reported acute grade 3 side effects were acute dysphagia (n = 2; 13%) and acute odynophagia (n = 3; 20%), making supportive nutrition via gastric tube (n = 2; 13.3%) and via high caloric drinks (n = 1; 6.7%) necessary due to swallowing problems (n = 4; 27%). Overall, chronic grade 3 toxicity in the form of chronic hoarseness occurred in 7% of the patients (n = 1; 7%). At the last follow-up, all the patients were alive. No local or locoregional recurrence could be identified. Only one patient with laryngeal ACC developed lung metastases three years after the first diagnosis. (4) Conclusions: the accelerated hypofractionated active raster-scanned carbon ion radiotherapy for radioresistant laryngeal malignancies is feasible in practice with excellent local control rates and moderate acute and late toxicity. Further follow-ups are necessary to evaluate the long-term clinical outcome. Full article
(This article belongs to the Special Issue New Developments in Radiotherapy)
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16 pages, 1979 KiB  
Article
Impact of HACA on Immunomodulation and Treatment Toxicity Following ch14.18/CHO Long-Term Infusion with Interleukin-2: Results from a SIOPEN Phase 2 Trial
by Nikolai Siebert, Sascha Troschke-Meurer, Madlen Marx, Maxi Zumpe, Karoline Ehlert, Juliet Gray, Alberto Garaventa, Carla Manzitti, Shifra Ash, Thomas Klingebiel, James Beck, Victoria Castel, Dominique Valteau-Couanet, Hans Loibner, Ruth Ladenstein and Holger N. Lode
Cancers 2018, 10(10), 387; https://doi.org/10.3390/cancers10100387 - 17 Oct 2018
Cited by 13 | Viewed by 4256
Abstract
GD2-directed immunotherapies improve survival of high-risk neuroblastoma (NB) patients (pts). Treatment with chimeric anti-GD2 antibodies (Ab), such as ch14.18, can induce development of human anti-chimeric Ab (HACA). Here, we report HACA effects on ch14.18/CHO pharmacokinetics, pharmacodynamics and pain intensity in [...] Read more.
GD2-directed immunotherapies improve survival of high-risk neuroblastoma (NB) patients (pts). Treatment with chimeric anti-GD2 antibodies (Ab), such as ch14.18, can induce development of human anti-chimeric Ab (HACA). Here, we report HACA effects on ch14.18/CHO pharmacokinetics, pharmacodynamics and pain intensity in pts treated by long-term infusion (LTI) of ch14.18/CHO combined with IL-2. 124 pts received up to 5 cycles of ch14.18/CHO 10 days (d) infusion (10 mg/m2/d; d8–18) combined with s.c. IL-2 (6 × 106 IU/m2/d; d1–5, d8–12). HACA, treatment toxicity, ch14.18/CHO levels, Ab-dependent cellular- (ADCC) and complement-dependent cytotoxicity (CDC) were assessed using respective validated assays. HACA-negative pts showed a steadily decreased pain in cycle 1 (74% pts without morphine by d5 of LTI) with further decrease in subsequent cycles. Ch14.18/CHO peak concentrations of 11.26 ± 0.50 µg/mL found in cycle 1 were further elevated in subsequent cycles and resulted in robust GD2-specific CDC and ADCC. Development of HACA (21% of pts) resulted in strong reduction of ch14.18/CHO levels, abrogated CDC and ADCC. Surprisingly, no difference in pain toxicity between HACA-positive and -negative pts was found. In conclusion, ch14.18/CHO LTI combined with IL-2 results in strong activation of Ab effector functions. Importantly, HACA response abrogated CDC but did not affect pain intensity indicating CDC-independent pain induction. Full article
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16 pages, 2754 KiB  
Article
Nafamostat Mesilate Enhances the Radiosensitivity and Reduces the Radiation-Induced Invasive Ability of Colorectal Cancer Cells
by Hiroshi Sugano, Yoshihiro Shirai, Takashi Horiuchi, Nobuhiro Saito, Yohta Shimada, Ken Eto, Tadashi Uwagawa, Toya Ohashi and Katsuhiko Yanaga
Cancers 2018, 10(10), 386; https://doi.org/10.3390/cancers10100386 - 17 Oct 2018
Cited by 11 | Viewed by 4663 | Correction
Abstract
Neoadjuvant chemoradiotherapy followed by radical surgery is the standard treatment for patients with locally advanced low rectal cancer. However, several studies have reported that ionizing radiation (IR) activates nuclear factor kappa B (NF-κB) that causes radioresistance and induces matrix metalloproteinase (MMP)-2/-9, which promote [...] Read more.
Neoadjuvant chemoradiotherapy followed by radical surgery is the standard treatment for patients with locally advanced low rectal cancer. However, several studies have reported that ionizing radiation (IR) activates nuclear factor kappa B (NF-κB) that causes radioresistance and induces matrix metalloproteinase (MMP)-2/-9, which promote tumor migration and invasion. Nafamostat mesilate (FUT175), a synthetic serine protease inhibitor, enhances the chemosensitivity to cytotoxic agents in digestive system cancer cells by inhibiting NF-κB activation. Therefore, we evaluated the combined effect of IR and FUT175 on cell proliferation, migration and invasion of colorectal cancer (CRC) cells. IR-induced upregulation of intranuclear NF-κB, FUT175 counteracted this effect. Moreover, the combination treatment suppressed cell viability and induced apoptosis. Similar effects were also observed in xenograft tumors. In addition, FUT175 prevented the migration and invasion of cancer cells caused by IR by downregulating the enzymatic activity of MMP-2/-9. In conclusion, FUT175 enhances the anti-tumor effect of radiotherapy through downregulation of NF-κB and reduces IR-induced tumor invasiveness by directly inhibiting MMP-2/-9 in CRC cells. Therefore, the use of FUT175 during radiotherapy might improve the efficacy of radiotherapy in patients with CRC. Full article
(This article belongs to the Collection Drug Resistance and Novel Therapies in Cancers)
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20 pages, 8837 KiB  
Article
SPARC Inhibits Metabolic Plasticity in Ovarian Cancer
by Christine Naczki, Bincy John, Chirayu Patel, Ashlyn Lafferty, Alia Ghoneum, Hesham Afify, Michael White, Amanda Davis, Guangxu Jin, Steven Kridel and Neveen Said
Cancers 2018, 10(10), 385; https://doi.org/10.3390/cancers10100385 - 16 Oct 2018
Cited by 20 | Viewed by 4628
Abstract
The tropism of ovarian cancer (OvCa) to the peritoneal cavity is implicated in widespread dissemination, suboptimal surgery, and poor prognosis. This tropism is influenced by stromal factors that are not only critical for the oncogenic and metastatic cascades, but also in the modulation [...] Read more.
The tropism of ovarian cancer (OvCa) to the peritoneal cavity is implicated in widespread dissemination, suboptimal surgery, and poor prognosis. This tropism is influenced by stromal factors that are not only critical for the oncogenic and metastatic cascades, but also in the modulation of cancer cell metabolic plasticity to fulfill their high energy demands. In this respect, we investigated the role of Secreted Protein Acidic and Rich in Cysteine (SPARC) in metabolic plasticity of OvCa. We used a syngeneic model of OvCa in Sparc-deficient and proficient mice to gain comprehensive insight into the paracrine effect of stromal-SPARC in metabolic programming of OvCa in the peritoneal milieu. Metabolomic and transcriptomic profiling of micro-dissected syngeneic peritoneal tumors revealed that the absence of stromal-Sparc led to significant upregulation of the enzymes involved in glycolysis, TCA cycle, and mitochondrial electron transport chain (ETC), and their metabolic intermediates. Absence of stromal-Sparc increased reactive oxygen species and perturbed redox homeostasis. Recombinant SPARC exerted a dose-dependent inhibitory effect on glycolysis, mitochondrial respiration, ATP production and ROS generation. Comparative analysis with human tumors revealed that SPARC-regulated ETC-signature inversely correlated with SPARC transcripts. Targeting mitochondrial ETC by phenformin treatment of tumor-bearing Sparc-deficient and proficient mice mitigated the effect of SPARC-deficiency and significantly reduced tumor burden, ROS, and oxidative tissue damage in syngeneic tumors. In summary, our findings provide novel insights into the role of SPARC in regulating metabolic plasticity and bioenergetics in OvCa, and shines light on its potential therapeutic efficacy. Full article
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10 pages, 505 KiB  
Article
Risk Factors for Severe Diarrhea with an Afatinib Treatment of Non-Small Cell Lung Cancer: A Pooled Analysis of Clinical Trials
by Ashley M. Hopkins, Anh-Minh Nguyen, Christos S. Karapetis, Andrew Rowland and Michael J. Sorich
Cancers 2018, 10(10), 384; https://doi.org/10.3390/cancers10100384 - 15 Oct 2018
Cited by 11 | Viewed by 3675
Abstract
Afatinib is an effective therapy for metastatic non-small cell lung cancer (NSCLC) but it is associated with a relatively high incidence of severe diarrhea. The association between pre-treatment candidate predictors (age, sex, race, performance status, renal function, hemoglobin, and measures of body mass) [...] Read more.
Afatinib is an effective therapy for metastatic non-small cell lung cancer (NSCLC) but it is associated with a relatively high incidence of severe diarrhea. The association between pre-treatment candidate predictors (age, sex, race, performance status, renal function, hemoglobin, and measures of body mass) and severe (grade ≥ 3) diarrhea was evaluated using logistic regression with pooled individual participant data from seven clinical studies. A risk score was developed based on the count of major risk factors. Overall, 184 of 1151 participants (16%) experienced severe diarrhea with use of afatinib. Body weight, body mass index, and body surface area all exhibited a prominent non-linear association where risk increased markedly at the lower range (p < 0.005). Low weight (<45 kg), female sex, and older age (≥60 years) were identified as major independent risk factors (p < 0.01). Each risk factor was associated with a two-fold increase in the odds of severe diarrhea, and this was consistent between individuals commenced on 40 mg or 50 mg afatinib. A simple risk score based on the count of these risk factors identifies individuals at lowest and highest risk (C-statistic of 0.65). Risk of severe diarrhea for individuals commenced on 40 mg afatinib ranged from 6% for individuals with no risk factors to 33% for individuals with all three risk factors. Full article
(This article belongs to the Special Issue Epidermal Growth Factor Receptor Signaling in Cancer)
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3 pages, 153 KiB  
Editorial
Hippo Pathway in Cancer, towards the Realization of Hippo-Targeted Therapy
by Yutaka Hata
Cancers 2018, 10(10), 383; https://doi.org/10.3390/cancers10100383 - 12 Oct 2018
Cited by 1 | Viewed by 2414
Abstract
n/a Full article
(This article belongs to the Special Issue Hippo Pathway in Cancer, towards Realization of the Hippo-Targeted Therapy)
15 pages, 2364 KiB  
Article
Targeting MicroRNA-143 Leads to Inhibition of Glioblastoma Tumor Progression
by Eunice L. Lozada-Delgado, Nilmary Grafals-Ruiz, Miguel A. Miranda-Román, Yasmarie Santana-Rivera, Fatma Valiyeva, Mónica Rivera-Díaz, María J. Marcos-Martínez and Pablo E. Vivas-Mejía
Cancers 2018, 10(10), 382; https://doi.org/10.3390/cancers10100382 - 12 Oct 2018
Cited by 24 | Viewed by 4693
Abstract
Glioblastoma (GBM) is the most common and aggressive of all brain tumors, with a median survival of only 14 months after initial diagnosis. Novel therapeutic approaches are an unmet need for GBM treatment. MicroRNAs (miRNAs) are a class of small non-coding RNAs that [...] Read more.
Glioblastoma (GBM) is the most common and aggressive of all brain tumors, with a median survival of only 14 months after initial diagnosis. Novel therapeutic approaches are an unmet need for GBM treatment. MicroRNAs (miRNAs) are a class of small non-coding RNAs that regulate gene expression at the post-transcriptional level. Several dysregulated miRNAs have been identified in all cancer types including GBM. In this study, we aimed to uncover the role of miR-143 in GBM cell lines, patient samples, and mouse models. Quantitative real-time RT-PCR of RNA extracted from formalin-fixed paraffin-embedded (FFPE) samples showed that the relative expression of miR-143 was higher in GBM patients compared to control individuals. Transient transfection of GBM cells with a miR-143 oligonucleotide inhibitor (miR-143-inh) resulted in reduced cell proliferation, increased apoptosis, and cell cycle arrest. SLC30A8, a glucose metabolism-related protein, was identified as a direct target of miR-143 in GBM cells. Moreover, multiple injections of GBM tumor-bearing mice with a miR-143-inh-liposomal formulation significantly reduced tumor growth compared to control mice. The reduced in vitro cell growth and in vivo tumor growth following miRNA-143 inhibition suggests that miR-143 is a potential therapeutic target for GBM therapy. Full article
(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)
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13 pages, 631 KiB  
Review
Involving the microRNA Targetome in Esophageal-Cancer Development and Behavior
by Francisca Dias, Mariana Morais, Ana Luísa Teixeira and Rui Medeiros
Cancers 2018, 10(10), 381; https://doi.org/10.3390/cancers10100381 - 12 Oct 2018
Cited by 9 | Viewed by 3155
Abstract
Esophageal cancer (EC) is the eighth most common and sixth leading cause of cancer-related mortality in the world. Despite breakthroughs in EC diagnosis and treatment, patients with complete pathologic response after being submitted to chemoradiotherapy are still submitted to surgery, despite its high [...] Read more.
Esophageal cancer (EC) is the eighth most common and sixth leading cause of cancer-related mortality in the world. Despite breakthroughs in EC diagnosis and treatment, patients with complete pathologic response after being submitted to chemoradiotherapy are still submitted to surgery, despite its high morbidity. Single-nucleotide polymorphisms (SNPs) in miRNA, miRNA-binding sites, and in its biogenesis pathway genes can alter miRNA expression patterns, thereby influencing cancer risk and prognosis. In this review, we systematized the information available regarding the impact of these miR-SNPs in EC development and prognosis. We found 34 miR-SNPs that were associated with EC risk. Despite the promising applicability of these miR-SNPs as disease biomarkers, they still lack validation in non-Asian populations. Moreover, there should be more pathway-based approaches to evaluate the cumulative effect of multiple unfavorable genotypes and, consequently, identify miR-SNPs signatures capable of predicting EC therapy response and prognosis. Full article
(This article belongs to the Special Issue MicroRNA-Associated Cancer Metastasis)
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21 pages, 996 KiB  
Review
Cancer-Associated Thrombosis: An Overview of Mechanisms, Risk Factors, and Treatment
by Norbaini Binti Abdol Razak, Gabrielle Jones, Mayank Bhandari, Michael C. Berndt and Pat Metharom
Cancers 2018, 10(10), 380; https://doi.org/10.3390/cancers10100380 - 11 Oct 2018
Cited by 351 | Viewed by 22901
Abstract
Cancer-associated thrombosis is a major cause of mortality in cancer patients, the most common type being venous thromboembolism (VTE). Several risk factors for developing VTE also coexist with cancer patients, such as chemotherapy and immobilisation, contributing to the increased risk cancer patients have [...] Read more.
Cancer-associated thrombosis is a major cause of mortality in cancer patients, the most common type being venous thromboembolism (VTE). Several risk factors for developing VTE also coexist with cancer patients, such as chemotherapy and immobilisation, contributing to the increased risk cancer patients have of developing VTE compared with non-cancer patients. Cancer cells are capable of activating the coagulation cascade and other prothrombotic properties of host cells, and many anticancer treatments themselves are being described as additional mechanisms for promoting VTE. This review will give an overview of the main thrombotic complications in cancer patients and outline the risk factors for cancer patients developing cancer-associated thrombosis, focusing on VTE as it is the most common complication observed in cancer patients. The multiple mechanisms involved in cancer-associated thrombosis, including the role of anticancer drugs, and a brief outline of the current treatment for cancer-associated thrombosis will also be discussed. Full article
(This article belongs to the Special Issue The Role of Thrombosis and Haemostasis in Cancer)
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20 pages, 1039 KiB  
Article
Identification of the Transcription Factor Relationships Associated with Androgen Deprivation Therapy Response and Metastatic Progression in Prostate Cancer
by Nitya V. Sharma, Kathryn L. Pellegrini, Veronique Ouellet, Felipe O. Giuste, Selvi Ramalingam, Kenneth Watanabe, Eloise Adam-Granger, Lucresse Fossouo, Sungyong You, Michael R. Freeman, Paula Vertino, Karen Conneely, Adeboye O. Osunkoya, Dominique Trudel, Anne-Marie Mes-Masson, John A. Petros, Fred Saad and Carlos S. Moreno
Cancers 2018, 10(10), 379; https://doi.org/10.3390/cancers10100379 - 11 Oct 2018
Cited by 19 | Viewed by 4952
Abstract
Background: Patients with locally advanced or recurrent prostate cancer typically undergo androgen deprivation therapy (ADT), but the benefits are often short-lived and the responses variable. ADT failure results in castration-resistant prostate cancer (CRPC), which inevitably leads to metastasis. We hypothesized that differences in [...] Read more.
Background: Patients with locally advanced or recurrent prostate cancer typically undergo androgen deprivation therapy (ADT), but the benefits are often short-lived and the responses variable. ADT failure results in castration-resistant prostate cancer (CRPC), which inevitably leads to metastasis. We hypothesized that differences in tumor transcriptional programs may reflect differential responses to ADT and subsequent metastasis. Results: We performed whole transcriptome analysis of 20 patient-matched Pre-ADT biopsies and 20 Post-ADT prostatectomy specimens, and identified two subgroups of patients (high impact and low impact groups) that exhibited distinct transcriptional changes in response to ADT. We found that all patients lost the AR-dependent subtype (PCS2) transcriptional signatures. The high impact group maintained the more aggressive subtype (PCS1) signal, while the low impact group more resembled an AR-suppressed (PCS3) subtype. Computational analyses identified transcription factor coordinated groups (TFCGs) enriched in the high impact group network. Leveraging a large public dataset of over 800 metastatic and primary samples, we identified 33 TFCGs in common between the high impact group and metastatic lesions, including SOX4/FOXA2/GATA4, and a TFCG containing JUN, JUNB, JUND, FOS, FOSB, and FOSL1. The majority of metastatic TFCGs were subsets of larger TFCGs in the high impact group network, suggesting a refinement of critical TFCGs in prostate cancer progression. Conclusions: We have identified TFCGs associated with pronounced initial transcriptional response to ADT, aggressive signatures, and metastasis. Our findings suggest multiple new hypotheses that could lead to novel combination therapies to prevent the development of CRPC following ADT. Full article
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14 pages, 1678 KiB  
Article
Tumor Location Influences Oncologic Outcomes of Hepatocellular Carcinoma Patients Undergoing Radiofrequency Ablation
by Jinbin Chen, Kangqiang Peng, Dandan Hu, Jingxian Shen, Zhongguo Zhou, Li Xu, Jiancong Chen, Yangxun Pan, Juncheng Wang, Yaojun Zhang and Minshan Chen
Cancers 2018, 10(10), 378; https://doi.org/10.3390/cancers10100378 - 10 Oct 2018
Cited by 33 | Viewed by 3959
Abstract
Radiofrequency ablation (RFA) is recommended as a first-line therapy for small hepatocellular carcinoma (HCC). Tumor location is a potential factor influencing the procedure of RFA. To compare oncologic outcomes of RFA for different tumor locations, this retrospective study enrolled 194 patients with small [...] Read more.
Radiofrequency ablation (RFA) is recommended as a first-line therapy for small hepatocellular carcinoma (HCC). Tumor location is a potential factor influencing the procedure of RFA. To compare oncologic outcomes of RFA for different tumor locations, this retrospective study enrolled 194 patients with small HCC who had undertaken RFA. The HCC nodules were classified as peri-hepatic-vein (pHV) or non-pHV, peri-portal-vein (pPV) or non-pPV, and subcapsular or non-subcapsular HCC. The regional recurrence-free survival (rRFS), overall survival (OS), recurrence-free survival (recurrence in any location, RFS) and distant recurrence-free survival (dRFS) were compared. Operation failures were recorded in five pPV HCC patients, which was more frequent than in non-pPV HCC patients (p = 0.041). The 1-, 3-, and 5-year rRFS was 68.7%, 53.7%, and 53.7% for pHV patients and 85.1%, 76.1%, and 71.9% for non-pHV patients, respectively (p = 0.012). After propensity score matching, the 1-, 3-, and 5-year rRFS was still worse than that of non-pHV patients (p = 0.013). The OS, RFS, and dRFS were not significantly different between groups. Conclusions: A pHV location was a risk factor for the regional recurrence after RFA in small HCC patients. The tumor location may not influence OS, RFS, and dRFS. Additionally, a pPV location was a potential high-risk factor for incomplete ablation. Full article
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16 pages, 2657 KiB  
Article
Classification of Cells in CTC-Enriched Samples by Advanced Image Analysis
by Sanne De Wit, Leonie L. Zeune, T. Jeroen N. Hiltermann, Harry J. M. Groen, Guus Van Dalum and Leon W. M. M. Terstappen
Cancers 2018, 10(10), 377; https://doi.org/10.3390/cancers10100377 - 10 Oct 2018
Cited by 32 | Viewed by 5089
Abstract
In the CellSearch® system, blood is immunomagnetically enriched for epithelial cell adhesion molecule (EpCAM) expression and cells are stained with the nucleic acid dye 4′6-diamidino-2-phenylindole (DAPI), Cytokeratin-PE (CK), and CD45-APC. Only DAPI+/CK+ objects are presented to the operator to identify circulating tumor [...] Read more.
In the CellSearch® system, blood is immunomagnetically enriched for epithelial cell adhesion molecule (EpCAM) expression and cells are stained with the nucleic acid dye 4′6-diamidino-2-phenylindole (DAPI), Cytokeratin-PE (CK), and CD45-APC. Only DAPI+/CK+ objects are presented to the operator to identify circulating tumor cells (CTC) and the identity of all other cells and potential undetected CTC remains unrevealed. Here, we used the open source imaging program Automatic CTC Classification, Enumeration and PhenoTyping (ACCEPT) to analyze all DAPI+ nuclei in EpCAM-enriched blood samples obtained from 192 metastatic non-small cell lung cancer (NSCLC) patients and 162 controls. Significantly larger numbers of nuclei were detected in 300 patient samples with an average and standard deviation of 73,570 ± 74,948, as compared to 359 control samples with an average and standard deviation of 4191 ± 4463 (p < 0.001). In patients, only 18% ± 21% and in controls 23% ± 15% of the nuclei were identified as leukocytes or CTC. Adding CD16-PerCP for granulocyte staining, the use of an LED as the light source for CD45-APC excitation and plasma membrane staining obtained with wheat germ agglutinin significantly improved the classification of EpCAM-enriched cells, resulting in the identification of 94% ± 5% of the cells. However, especially in patients, the origin of the unidentified cells remains unknown. Further studies are needed to determine if undetected EpCAM+/DAPI+/CK-/CD45- CTC is present among these cells. Full article
(This article belongs to the Special Issue Circulating Tumor Cells (CTCs))
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15 pages, 666 KiB  
Review
Molecular Markers of Anticancer Drug Resistance in Head and Neck Squamous Cell Carcinoma: A Literature Review
by Sandra López-Verdín, Jesús Lavalle-Carrasco, Ramón G. Carreón-Burciaga, Nicolás Serafín-Higuera, Nelly Molina-Frechero, Rogelio González-González and Ronell Bologna-Molina
Cancers 2018, 10(10), 376; https://doi.org/10.3390/cancers10100376 - 10 Oct 2018
Cited by 34 | Viewed by 5164
Abstract
This manuscript provides an update to the literature on molecules with roles in tumor resistance therapy in head and neck squamous cell carcinoma (HNSCC). Although significant improvements have been made in the treatment for head and neck squamous cell carcinoma, physicians face yet [...] Read more.
This manuscript provides an update to the literature on molecules with roles in tumor resistance therapy in head and neck squamous cell carcinoma (HNSCC). Although significant improvements have been made in the treatment for head and neck squamous cell carcinoma, physicians face yet another challenge—that of preserving oral functions, which involves the use of multidisciplinary therapies, such as multiple chemotherapies (CT) and radiotherapy (RT). Designing personalized therapeutic options requires the study of genes involved in drug resistance. This review provides an overview of the molecules that have been linked to resistance to chemotherapy in HNSCC, including the family of ATP-binding cassette transporters (ABCs), nucleotide excision repair/base excision repair (NER/BER) enzymatic complexes (which act on nonspecific DNA lesions generated by gamma and ultraviolet radiation by cross-linking and forming intra/interchain chemical adducts), cisplatin (a chemotherapeutic agent that causes DNA damage and induces apoptosis, which is a paradox because its effectiveness is based on the integrity of the genes involved in apoptotic signaling pathways), and cetuximab, including a discussion of the genes involved in the cell cycle and the proliferation of possible markers that confer resistance to cetuximab. Full article
(This article belongs to the Special Issue Cancer Chemoresistance)
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16 pages, 2664 KiB  
Article
Energy Stress-Mediated Cytotoxicity in Tuberous Sclerosis Complex 2-Deficient Cells with Nelfinavir and Mefloquine Treatment
by Henry D. McCann, Charlotte E. Johnson, Rachel J. Errington, D. Mark Davies, Elaine A. Dunlop and Andrew R. Tee
Cancers 2018, 10(10), 375; https://doi.org/10.3390/cancers10100375 - 10 Oct 2018
Cited by 5 | Viewed by 6276
Abstract
To find new anti-cancer drug therapies, we wanted to exploit homeostatic vulnerabilities within Tuberous Sclerosis Complex 2 (TSC2)-deficient cells with mechanistic target of rapamycin complex 1 (mTORC1) hyperactivity. We show that nelfinavir and mefloquine synergize to selectively evoke a cytotoxic response in TSC2-deficient [...] Read more.
To find new anti-cancer drug therapies, we wanted to exploit homeostatic vulnerabilities within Tuberous Sclerosis Complex 2 (TSC2)-deficient cells with mechanistic target of rapamycin complex 1 (mTORC1) hyperactivity. We show that nelfinavir and mefloquine synergize to selectively evoke a cytotoxic response in TSC2-deficient cell lines with mTORC1 hyperactivity. We optimize the concentrations of nelfinavir and mefloquine to a clinically viable range that kill cells that lack TSC2, while wild-type cells tolerate treatment. This new clinically viable drug combination causes a significant level of cell death in TSC2-deficient tumor spheroids. Furthermore, no cell recovery was apparent after drug withdrawal, revealing potent cytotoxicity. Transcriptional profiling by RNA sequencing of drug treated TSC2-deficient cells compared to wild-type cells suggested the cytotoxic mechanism of action, involving initial ER stress and an imbalance in energy homeostatic pathways. Further characterization revealed that supplementation with methyl pyruvate alleviated energy stress and reduced the cytotoxic effect, implicating energy deprivation as the trigger of cell death. This work underpins a critical vulnerability with cancer cells with aberrant signaling through the TSC2-mTORC1 pathway that lack flexibility in homeostatic pathways, which could be exploited with combined nelfinavir and mefloquine treatment. Full article
(This article belongs to the Collection Drug Resistance and Novel Therapies in Cancers)
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14 pages, 2374 KiB  
Article
Low PD-L1 Expression Strongly Correlates with Local Recurrence in Epstein-Barr Virus-Positive Nasopharyngeal Carcinoma after Radiation-Based Therapy
by Yu-Jen Liu, Ngan-Ming Tsang, Chuen Hsueh, Chi-Ju Yeh, Shir-Hwa Ueng, Tong-Hong Wang and Wen-Yu Chuang
Cancers 2018, 10(10), 374; https://doi.org/10.3390/cancers10100374 - 09 Oct 2018
Cited by 17 | Viewed by 3508
Abstract
The prognostic value of programmed death-ligand 1 (PD-L1) expression in nasopharyngeal carcinoma (NPC) is controversial, with previous studies showing conflicting results. Most NPCs in endemic areas are Epstein-Barr virus (EBV)-positive. Our aim was to evaluate the clinical significance of PD-L1 expression in EBV-positive [...] Read more.
The prognostic value of programmed death-ligand 1 (PD-L1) expression in nasopharyngeal carcinoma (NPC) is controversial, with previous studies showing conflicting results. Most NPCs in endemic areas are Epstein-Barr virus (EBV)-positive. Our aim was to evaluate the clinical significance of PD-L1 expression in EBV-positive NPC. We retrospectively analyzed PD-L1 expression on tumor cells (TCs) and immune cells (ICs) by immunohistochemistry in 208 EBV-positive NPC patients who underwent radiotherapy (203 with concurrent chemotherapy). The percentages of TCs and ICs expressing PD-L1 were evaluated respectively. There was a strong correlation between local recurrence and low PD-L1 expression on ICs (p = 0.0012), TCs (p = 0.013) or both (p = 0.000044), whereas all clinical parameters had no influence on local recurrence. Using multivariate analysis, low PD-L1 expression on ICs was an independent adverse prognostic factor (p = 0.0080; HR = 1.88; 95% CI = 1.18–3.00) for disease-free survival. High PD-L1 expression on both ICs and TCs was an independent favorable prognostic factor (p = 0.022; HR = 0.46; 95% CI = 0.24–0.89) for overall survival. We show for the first time that low PD-L1 expression on ICs and TCs strongly correlates with local recurrence in EBV-positive NPC patients after radiation-based therapy. A simple immunohistochemical study for PD-L1 can identify patients prone to local recurrence, and such patients might benefit from more aggressive treatment in future clinical trials. Full article
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22 pages, 7908 KiB  
Article
Cytoplasmic p21 Mediates 5-Fluorouracil Resistance by Inhibiting Pro-Apoptotic Chk2
by Arnatchai Maiuthed, Chuanpit Ninsontia, Katharina Erlenbach-Wuensch, Benardina Ndreshkjana, Julienne K. Muenzner, Aylin Caliskan, Husayn Ahmed P., Chatchai Chaotham, Arndt Hartmann, Adriana Vial Roehe, Vijayalakshmi Mahadevan, Pithi Chanvorachote and Regine Schneider-Stock
Cancers 2018, 10(10), 373; https://doi.org/10.3390/cancers10100373 - 09 Oct 2018
Cited by 23 | Viewed by 6021
Abstract
The oncogenic cytoplasmic p21 contributes to cancer aggressiveness and chemotherapeutic failure. However, the molecular mechanisms remain obscure. Here, we show for the first time that cytoplasmic p21 mediates 5-Fluorouracil (5FU) resistance by shuttling p-Chk2 out of the nucleus to protect the tumor cells [...] Read more.
The oncogenic cytoplasmic p21 contributes to cancer aggressiveness and chemotherapeutic failure. However, the molecular mechanisms remain obscure. Here, we show for the first time that cytoplasmic p21 mediates 5-Fluorouracil (5FU) resistance by shuttling p-Chk2 out of the nucleus to protect the tumor cells from its pro-apoptotic functions. We observed that cytoplasmic p21 levels were up-regulated in 5FU-resistant colorectal cancer cells in vitro and the in vivo Chorioallantoic membrane (CAM) model. Kinase array analysis revealed that p-Chk2 is a key target of cytoplasmic p21. Importantly, cytoplasmic form of p21 mediated by p21T145D transfection diminished p-Chk2-mediated activation of E2F1 and apoptosis induction. Co-immunoprecipitation, immunofluorescence, and proximity ligation assay showed that p21 forms a complex with p-Chk2 under 5FU exposure. Using in silico computer modeling, we suggest that the p21/p-Chk2 interaction hindered the nuclear localization signal of p-Chk2, and therefore, the complex is exported out of the nucleus. These findings unravel a novel mechanism regarding an oncogenic role of p21 in regulation of resistance to 5FU-based chemotherapy. We suggest a possible value of cytoplasmic p21 as a prognosis marker and a therapeutic target in colorectal cancer patients. Full article
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15 pages, 1118 KiB  
Article
Audencel Immunotherapy Based on Dendritic Cells Has No Effect on Overall and Progression-Free Survival in Newly Diagnosed Glioblastoma: A Phase II Randomized Trial
by Johanna Buchroithner, Friedrich Erhart, Josef Pichler, Georg Widhalm, Matthias Preusser, Günther Stockhammer, Martha Nowosielski, Sarah Iglseder, Christian F. Freyschlag, Stefan Oberndorfer, Karin Bordihn, Gord Von Campe, Markus Hoffermann, Reinhard Ruckser, Karl Rössler, Sabine Spiegl-Kreinecker, Michael B. Fischer, Thomas Czech, Carmen Visus, Günther Krumpl, Thomas Felzmann and Christine Marosiadd Show full author list remove Hide full author list
Cancers 2018, 10(10), 372; https://doi.org/10.3390/cancers10100372 - 05 Oct 2018
Cited by 67 | Viewed by 5920
Abstract
Dendritic cells (DCs) are antigen-presenting cells that are capable of priming anti-tumor immune responses, thus serving as attractive tools to generate tumor vaccines. In this multicentric randomized open-label phase II study, we investigated the efficacy of vaccination with tumor lysate-charged autologous DCs (Audencel) [...] Read more.
Dendritic cells (DCs) are antigen-presenting cells that are capable of priming anti-tumor immune responses, thus serving as attractive tools to generate tumor vaccines. In this multicentric randomized open-label phase II study, we investigated the efficacy of vaccination with tumor lysate-charged autologous DCs (Audencel) in newly diagnosed glioblastoma multiforme (GBM). Patients aged 18 to 70 years with histologically proven primary GBM and resection of at least 70% were randomized 1:1 to standard of care (SOC) or SOC plus vaccination (weekly intranodal application in weeks seven to 10, followed by monthly intervals). The primary endpoint was progression-free survival at 12 months. Secondary endpoints were overall survival, safety, and toxicity. Seventy-six adult patients were analyzed in this study. Vaccinations were given for seven (3–20) months on average. No severe toxicity was attributable to vaccination. Seven patients showed flu-like symptoms, and six patients developed local skin reactions. Progression-free survival at 12 months did not differ significantly between the control and vaccine groups (28.4% versus 24.5%, p = 0.9975). Median overall survival was similar with 18.3 months (vaccine: 564 days, 95% CI: 436–671 versus control: 568 days, 95% CI: 349–680; p = 0.89, harzard ratio (HR) 0.99). Hence, in this trial, the clinical outcomes of patients with primary GBM could not be improved by the addition of Audencel to SOC. Full article
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15 pages, 3539 KiB  
Article
Unliganded Progesterone Receptor Governs Estrogen Receptor Gene Expression by Regulating DNA Methylation in Breast Cancer Cells
by Gaetano Verde, Lara I. De Llobet, Roni H.G. Wright, Javier Quilez, Sandra Peiró, François Le Dily and Miguel Beato
Cancers 2018, 10(10), 371; https://doi.org/10.3390/cancers10100371 - 05 Oct 2018
Cited by 16 | Viewed by 4636
Abstract
Breast cancer prognosis and response to endocrine therapy strongly depends on the expression of the estrogen and progesterone receptors (ER and PR, respectively). Although much is known about ERα gene (ESR1) regulation after hormonal stimulation, how it is regulated in hormone-free [...] Read more.
Breast cancer prognosis and response to endocrine therapy strongly depends on the expression of the estrogen and progesterone receptors (ER and PR, respectively). Although much is known about ERα gene (ESR1) regulation after hormonal stimulation, how it is regulated in hormone-free condition is not fully understood. We used ER-/PR-positive breast cancer cells to investigate the role of PR in ESR1 regulation in the absence of hormones. We show that PR binds to the low-methylated ESR1 promoter and maintains both gene expression and DNA methylation of the ESR1 locus in hormone-deprived breast cancer cells. Depletion of PR reduces ESR1 expression, with a concomitant increase in gene promoter methylation. The high amount of methylation in the ESR1 promoter of PR-depleted cells persists after the stable re-expression of PR and inhibits PR binding to this genomic region. As a consequence, the rescue of PR expression in PR-depleted cells is insufficient to restore ESR1 expression. Consistently, DNA methylation impedes PR binding to consensus progesterone responsive elements. These findings contribute to understanding the complex crosstalk between PR and ER and suggest that the analysis of ESR1 promoter methylation in breast cancer cells can help to design more appropriate targeted therapies for breast cancer patients. Full article
(This article belongs to the Special Issue Epigenetic Influence on Cancer Metastasis and/or Treatment Resistance)
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15 pages, 3861 KiB  
Article
Microenvironmental pH and Exosome Levels Interplay in Human Cancer Cell Lines of Different Histotypes
by Mariantonia Logozzi, Davide Mizzoni, Daniela F. Angelini, Rossella Di Raimo, Mario Falchi, Luca Battistini and Stefano Fais
Cancers 2018, 10(10), 370; https://doi.org/10.3390/cancers10100370 - 05 Oct 2018
Cited by 136 | Viewed by 7195
Abstract
Exosomes are extracellular nanovesicles primarily involved in the pathogenesis of many diseases including cancer. This study was set out from recent evidence that extracellular acidity may increase the exosome release by cancer cells. However, this preliminary evidence did not provide solid information on [...] Read more.
Exosomes are extracellular nanovesicles primarily involved in the pathogenesis of many diseases including cancer. This study was set out from recent evidence that extracellular acidity may increase the exosome release by cancer cells. However, this preliminary evidence did not provide solid information on whether the pH-dependent exosome over-release represents a common feature of all cancers. To the purpose of demonstrating that cancer acidity is a major determinant in inducing an increased exosome release by human cancer cells, we evaluated human tumor cell lines deriving from either colon, breast, prostate cancers, melanoma, or osteosarcoma. All cell lines were cultured in either the current 7.4 pH or the typical pH of cancer that is 6.5. The levels of released extracellular vesicles were measured by protein counts, nanoparticle tracking analysis (NTA), and nanoscale flow cytometry. The results showed that pH 6.5 induced a remarkable increase in exosome release, and buffering the medium significantly reduced the exosome release in all cancers. With these results, we provide, for the first time, evidence that tumor acidity and exosome levels represent common cancer phenotypes. Full article
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18 pages, 917 KiB  
Article
Physical Activity and Gastric Cancer Risk in Patients with and without Helicobacter pylori Infection in A Korean Population: A Hospital-Based Case-Control Study
by Madhawa Neranjan Gunathilake, Jeonghee Lee, Aelee Jang, Il Ju Choi, Young-Il Kim and Jeongseon Kim
Cancers 2018, 10(10), 369; https://doi.org/10.3390/cancers10100369 - 02 Oct 2018
Cited by 11 | Viewed by 4300
Abstract
Although physical activity (PA) is beneficial for prolonging lifespan, evidence for the protective role of PA against the development of gastric cancer (GC) is not yet well established. This study assessed the association between PA and GC risk in patients with and without [...] Read more.
Although physical activity (PA) is beneficial for prolonging lifespan, evidence for the protective role of PA against the development of gastric cancer (GC) is not yet well established. This study assessed the association between PA and GC risk in patients with and without Helicobacter pylori (H. pylori) infection in a Korean population. In total, 415 GC patients and 830 controls were enrolled at the National Cancer Center, Korea. The International Physical Activity Questionnaire-Short Form was used to collect PA data. The odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression models. In the H. pylori-positive group, subjects who engaged in regular exercise showed a significantly reduced risk of GC in the entire population (OR = 0.52, 95% CI = 0.38–0.70) and in females (OR = 0.60, 95% CI = 0.21–0.64). Subjects who engaged in a high level of total PA showed a significantly reduced risk of GC relative to subjects in the lowest tertile in the fully adjusted model (OR = 0.46, 95% CI = 0.32–0.65, p-trend < 0.001). There was an inverse association between PA and GC risk in the entire population, and in the H. pylori-positive subgroup. Our data indicate the need for the promotion of all domains of PA, especially for Korean populations. Full article
(This article belongs to the Special Issue Helicobacter pylori Associated Cancer)
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17 pages, 3129 KiB  
Article
Gap Junction Intercellular Communication Positively Regulates Cisplatin Toxicity by Inducing DNA Damage through Bystander Signaling
by Sanjeevani Arora, Joshua R. Heyza, Elaine C. Chalfin, Randall J. Ruch and Steve M. Patrick
Cancers 2018, 10(10), 368; https://doi.org/10.3390/cancers10100368 - 02 Oct 2018
Cited by 28 | Viewed by 4108
Abstract
The radiation-induced bystander effect (RIBE) can increase cellular toxicity in a gap junction dependent manner in unirradiated bystander cells. Recent reports have suggested that cisplatin toxicity can also be mediated by functional gap junction intercellular communication (GJIC). In this study using lung and [...] Read more.
The radiation-induced bystander effect (RIBE) can increase cellular toxicity in a gap junction dependent manner in unirradiated bystander cells. Recent reports have suggested that cisplatin toxicity can also be mediated by functional gap junction intercellular communication (GJIC). In this study using lung and ovarian cancer cell lines, we showed that cisplatin cytotoxicity is mediated by cellular density. This effect is ablated when GJA1 or Connexin 43 (Cx43) is targeted, a gap junction gene and protein, respectively, leading to cisplatin resistance but only at high or gap junction forming density. We also observed that the cisplatin-mediated bystander effect was elicited as DNA Double Strand Breaks (DSBs) with positive H2AX Ser139 phosphorylation (γH2AX) formation, an indicator of DNA DSBs. These DSBs are not observed when gap junction formation is prevented. We next showed that cisplatin is not the “death” signal traversing the gap junctions by utilizing the cisplatin-GG intrastrand adduct specific antibody. Finally, we also showed that cells deficient in the structure-specific DNA endonuclease ERCC1-ERCC4 (ERCC1-XPF), an important mediator of cisplatin resistance, further sensitized when treated with cisplatin in the presence of gap junction forming density. Taken together, these results demonstrate the positive effect of GJIC on increasing cisplatin cytotoxicity. Full article
(This article belongs to the Special Issue Gap Junctions and Connexins in Cancer Formation, Progression, and Therapy)
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16 pages, 1722 KiB  
Article
Molecular Scoring of Hepatocellular Carcinoma for Predicting Metastatic Recurrence and Requirements of Systemic Chemotherapy
by Naoshi Nishida, Takafumi Nishimura, Toshimi Kaido, Kosuke Minaga, Kentaro Yamao, Ken Kamata, Mamoru Takenaka, Hiroshi Ida, Satoru Hagiwara, Yasunori Minami, Toshiharu Sakurai, Tomohiro Watanabe and Masatoshi Kudo
Cancers 2018, 10(10), 367; https://doi.org/10.3390/cancers10100367 - 29 Sep 2018
Cited by 25 | Viewed by 3560
Abstract
Hepatocellular carcinoma (HCC) causes one of the most frequent cancer-related deaths; an HCC subset shows rapid progression that affects survival. We clarify molecular features of aggressive HCC, and establish a molecular scoring system that predicts metastasis after curative treatment. In total, 125 HCCs [...] Read more.
Hepatocellular carcinoma (HCC) causes one of the most frequent cancer-related deaths; an HCC subset shows rapid progression that affects survival. We clarify molecular features of aggressive HCC, and establish a molecular scoring system that predicts metastasis after curative treatment. In total, 125 HCCs were examined for TP53, CTNNB1, and TERT promoter mutation, methylation of 8 tumor suppressor genes, and 3 repetitive DNA sequences to estimate promoter hypermethylation and global hypomethylation. A fractional allelic loss (FAL) was calculated to represent chromosomal instability through microsatellite analysis. Molecular subclasses were determined using corresponding and hierarchical clustering analyses. Next, twenty-five HCC patients who underwent liver transplantation were analyzed for associations between molecular characteristics and metastatic recurrence; survival analyses were validated using a publicly available dataset of 376 HCC cases from the Cancer Genome Atlas (TCGA). An HCC subtype characterized by TP53 mutation, high FAL, and global hypomethylation was associated with aggressive tumor characteristics, like vascular invasion; CTNNB1 mutation was a feature of the less-progressive phenotype. A number of molecular risk factors, including TP53 mutation, high FAL, significant global hypomethylation, and absence of CTNNB1 mutation, were noted to predict shorter recurrence-free survival in patients who underwent liver transplantation (p = 0.0090 by log-rank test). These findings were validated in a cohort of resected HCC cases from TCGA (p = 0.0076). We concluded that molecular risks determined by common genetic and epigenetic alterations could predict metastatic recurrence after curative treatments, and could be a marker for considering systemic therapy for HCC patients. Full article
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13 pages, 1055 KiB  
Review
Bipolar Tumor-Associated Macrophages in Ovarian Cancer as Targets for Therapy
by Vijayalaxmi Gupta, Fiona Yull and Dineo Khabele
Cancers 2018, 10(10), 366; https://doi.org/10.3390/cancers10100366 - 29 Sep 2018
Cited by 70 | Viewed by 6630
Abstract
Ovarian cancer, a rare but fatal disease, has been a challenging area in the field of gynecological cancer. Ovarian cancer is characterized by peritoneal metastasis, which is facilitated by a cross-talk between tumor cells and other cells in the tumor microenvironment (TME). In [...] Read more.
Ovarian cancer, a rare but fatal disease, has been a challenging area in the field of gynecological cancer. Ovarian cancer is characterized by peritoneal metastasis, which is facilitated by a cross-talk between tumor cells and other cells in the tumor microenvironment (TME). In epithelial ovarian cancer, tumor-associated macrophages (TAMs) constitute over 50% of cells in the peritoneal TME and malignant ascites, and are potential targets for therapy. Here, we review the bipolar nature of TAMs and the evolving strategies to target TAMs in ovarian cancer. Full article
(This article belongs to the Special Issue The Tumor Microenvironment of High Grade Serous Ovarian Cancer)
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15 pages, 20719 KiB  
Article
Oncobox Bioinformatical Platform for Selecting Potentially Effective Combinations of Target Cancer Drugs Using High-Throughput Gene Expression Data
by Maxim Sorokin, Roman Kholodenko, Maria Suntsova, Galina Malakhova, Andrew Garazha, Irina Kholodenko, Elena Poddubskaya, Dmitriy Lantsov, Ivan Stilidi, Petr Arhiri, Andreyan Osipov and Anton Buzdin
Cancers 2018, 10(10), 365; https://doi.org/10.3390/cancers10100365 - 29 Sep 2018
Cited by 24 | Viewed by 5430
Abstract
Sequential courses of anticancer target therapy lead to selection of drug-resistant cells, which results in continuous decrease of clinical response. Here we present a new approach for predicting effective combinations of target drugs, which act in a synergistic manner. Synergistic combinations of drugs [...] Read more.
Sequential courses of anticancer target therapy lead to selection of drug-resistant cells, which results in continuous decrease of clinical response. Here we present a new approach for predicting effective combinations of target drugs, which act in a synergistic manner. Synergistic combinations of drugs may prevent or postpone acquired resistance, thus increasing treatment efficiency. We cultured human ovarian carcinoma SKOV-3 and neuroblastoma NGP-127 cancer cell lines in the presence of Tyrosine Kinase Inhibitors (Pazopanib, Sorafenib, and Sunitinib) and Rapalogues (Temsirolimus and Everolimus) for four months and obtained cell lines demonstrating increased drug resistance. We investigated gene expression profiles of intact and resistant cells by microarrays and analyzed alterations in 378 cancer-related signaling pathways using the bioinformatical platform Oncobox. This revealed numerous pathways linked with development of drug resistant phenotypes. Our approach is based on targeting proteins involved in as many as possible signaling pathways upregulated in resistant cells. We tested 13 combinations of drugs and/or selective inhibitors predicted by Oncobox and 10 random combinations. Synergy scores for Oncobox predictions were significantly higher than for randomly selected drug combinations. Thus, the proposed approach significantly outperforms random selection of drugs and can be adopted to enhance discovery of new synergistic combinations of anticancer target drugs. Full article
(This article belongs to the Special Issue Drug Resistance in Cancers)
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11 pages, 1991 KiB  
Review
Sensitization of Cancer Cells to Radiation and Topoisomerase I Inhibitor Camptothecin Using Inhibitors of PARP and Other Signaling Molecules
by Yusuke Matsuno, Mai Hyodo, Haruka Fujimori, Atsuhiro Shimizu and Ken-ichi Yoshioka
Cancers 2018, 10(10), 364; https://doi.org/10.3390/cancers10100364 - 28 Sep 2018
Cited by 21 | Viewed by 4873
Abstract
Radiation and certain anticancer drugs damage DNA, resulting in apoptosis induction in cancer cells. Currently, the major limitations on the efficacy of such therapies are development of resistance and adverse side effects. Sensitization is an important strategy for increasing therapeutic efficacy while minimizing [...] Read more.
Radiation and certain anticancer drugs damage DNA, resulting in apoptosis induction in cancer cells. Currently, the major limitations on the efficacy of such therapies are development of resistance and adverse side effects. Sensitization is an important strategy for increasing therapeutic efficacy while minimizing adverse effects. In this manuscript, we review possible sensitization strategies for radiation and anticancer drugs that cause DNA damage, focusing especially on modulation of damage repair pathways and the associated reactions. Full article
(This article belongs to the Special Issue Sensitization Strategies in Cancer Treatment)
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