Cancers

30 pages, 9548 KiB

Open AccessArticle

Radiosensitization and a Less Aggressive Phenotype of Human Malignant Glioma Cells Expressing Isocitrate Dehydrogenase 1 (IDH1) Mutant Protein: Dissecting the Mechanisms

by Jacqueline Kessler, Tim Hohmann, Antje Güttler, Marina Petrenko, Christian Ostheimer, Urszula Hohmann, Matthias Bache, Faramarz Dehghani and Dirk Vordermark

Cancers 2019, 11(6), 889; https://doi.org/10.3390/cancers11060889 - 25 Jun 2019

Cited by 18 | Viewed by 4278

Abstract

The presence of an isocitrate dehydrogenase 1 (IDH1) mutation is associated with a less aggressive phenotype, increased sensitivity to radiation, and increased overall survival in patients with diffuse glioma. Based on in vitro experimentations in malignant glioma cell lines, the consequences on cellular [...] Read more.

The presence of an isocitrate dehydrogenase 1 (IDH1) mutation is associated with a less aggressive phenotype, increased sensitivity to radiation, and increased overall survival in patients with diffuse glioma. Based on in vitro experimentations in malignant glioma cell lines, the consequences on cellular processes of IDH1^R132H expression were analyzed. The results revealed that IDH1^R132H expression enhanced the radiation induced accumulation of residual γH2AX foci and decreased the amount of glutathione (GSH) independent of the oxygen status. In addition, expression of the mutant IDH1 caused a significant increase of cell stiffness and induced an altered organization of the cytoskeleton, which has been shown to reinforce cell stiffness. Furthermore, IDH1^R132H expression decreased the expression of vimentin, an important component of the cytoskeleton and regulator of the cell stiffness. The results emphasize the important role of mutant IDH1 in treatment of patients with diffuse gliomas especially in response to radiation. Hence, detection of the genetic status of IDH1 before therapy massively expands the utility of immunohistochemistry to accurately distinguish patients with a less aggressive and radiosensitive IDH1-mutant diffuse glioma suitable for radiotherapy from those with a more aggressive IDH1-wildtype diffuse glioma who might benefit from an individually intensified therapy comprising radiotherapy and alternative medical treatments. Full article

(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)

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16 pages, 1348 KiB

Open AccessReview

Exo-miRNAs as a New Tool for Liquid Biopsy in Lung Cancer

by Orazio Fortunato, Patrizia Gasparini, Mattia Boeri and Gabriella Sozzi

Cancers 2019, 11(6), 888; https://doi.org/10.3390/cancers11060888 - 25 Jun 2019

Cited by 57 | Viewed by 6723

Abstract

Lung cancer is the predominant cause of cancer-related deaths. The high mortality rates are mainly due to the lack of diagnosis before the cancer is at a late stage. Liquid biopsy is a promising technique that could allow early diagnosis of lung cancer [...] Read more.

Lung cancer is the predominant cause of cancer-related deaths. The high mortality rates are mainly due to the lack of diagnosis before the cancer is at a late stage. Liquid biopsy is a promising technique that could allow early diagnosis of lung cancer and better treatment selection for patients. Cell-free microRNAs have been detected in biological fluids, such as serum and plasma, and are considered interesting biomarkers for lung cancer screening and detection. Exosomes are nanovesicles of 30–150 nm and can be released by different cell types within the tumor microenvironment. Their exosomal composition reflects that of their parental cells and could be potentially useful as a biomarker for lung cancer diagnosis. This review summarizes the state-of-the-art of circulating microRNAs (miRNAs) in lung cancer, focusing on their potential use in clinical practice. Moreover, we describe the importance of exosomal miRNA cargo in lung cancer detection and their potential role during lung carcinogenesis. Finally, we discuss our experience with the analysis of circulating exosomal miRNAs in the bioMILD screening trial. Full article

(This article belongs to the Special Issue Liquid Biopsy for Cancer)

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19 pages, 2360 KiB

Open AccessArticle

Utility of Circulating Cell-Free RNA Analysis for the Characterization of Global Transcriptome Profiles of Multiple Myeloma Patients

by Maoshan Chen, Sridurga Mithraprabhu, Malarmathy Ramachandran, Kawa Choi, Tiffany Khong and Andrew Spencer

Cancers 2019, 11(6), 887; https://doi.org/10.3390/cancers11060887 - 25 Jun 2019

Cited by 22 | Viewed by 4439

Abstract

In this study, we evaluated the utility of extracellular RNA (exRNA) derived from the plasma of multiple myeloma (MM) patients for whole transcriptome characterization. exRNA from 10 healthy controls (HC), five newly diagnosed (NDMM), and 12 relapsed and refractory (RRMM) MM patients were [...] Read more.

In this study, we evaluated the utility of extracellular RNA (exRNA) derived from the plasma of multiple myeloma (MM) patients for whole transcriptome characterization. exRNA from 10 healthy controls (HC), five newly diagnosed (NDMM), and 12 relapsed and refractory (RRMM) MM patients were analyzed and compared. We showed that ~45% of the exRNA genes were protein-coding genes and ~85% of the identified genes were covered >70%. Compared to HC, we identified 632 differentially expressed genes (DEGs) in MM patients, of which 26 were common to NDMM and RRMM. We further identified 54 and 191 genes specific to NDMM and RRMM, respectively, and these included potential biomarkers such as LINC00863, MIR6754, CHRNE, ITPKA, and RGS18 in NDMM, and LINC00462, PPBP, RPL5, IER3, and MIR425 in RRMM, that were subsequently validated using droplet digital PCR. Moreover, single nucleotide polymorphisms and small indels were identified in the exRNA, including mucin family genes that demonstrated different rates of mutations between NDMM and RRMM. This is the first whole transcriptome study of exRNA in hematological malignancy and has provided the basis for the utilization of exRNA to enhance our understanding of the MM biology and to identify potential biomarkers relevant to the diagnosis and prognosis of MM patients. Full article

(This article belongs to the Special Issue Liquid Biopsy for Cancer)

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17 pages, 4605 KiB

Open AccessArticle

Systematic Analysis of Gene Expression in Lung Adenocarcinoma and Squamous Cell Carcinoma with a Case Study of FAM83A and FAM83B

by Ling Cai, Danni Luo, Bo Yao, Donghan M. Yang, ShinYi Lin, Luc Girard, Ralph J. DeBerardinis, John D. Minna, Yang Xie and Guanghua Xiao

Cancers 2019, 11(6), 886; https://doi.org/10.3390/cancers11060886 - 25 Jun 2019

Cited by 11 | Viewed by 4469

Abstract

Introduction: In our previous study, we constructed a Lung Cancer Explorer (LCE) database housing lung cancer-specific expression data and clinical data from over 6700 patients in 56 studies. Methods: Using this dataset of the largest collection of lung cancer gene expression along with [...] Read more.

Introduction: In our previous study, we constructed a Lung Cancer Explorer (LCE) database housing lung cancer-specific expression data and clinical data from over 6700 patients in 56 studies. Methods: Using this dataset of the largest collection of lung cancer gene expression along with our meta-analysis method, we systematically interrogated the association between gene expression and overall survival as well as the expression difference between tumor and normal (adjacent non-malignant tissue) samples in lung adenocarcinoma (ADC) and lung squamous cell carcinoma (SQCC). A case study for FAM83A and FAM83B was performed as a demonstration for hypothesis testing with our database. Results: We showed that the reproducibility of results across studies varied by histological subtype and analysis type. Genes and pathways unique or common to the two histological subtypes were identified and the results were integrated into LCE to facilitate user exploration. In our case study, we verified the findings from a previous study on FAM83A and FAM83B in non-small cell lung cancer. Conclusions: This study used gene expression data from a large cohort of patients to explore the molecular differences between lung ADC and SQCC. Full article

(This article belongs to the Special Issue Molecular Profiling of Lung Cancer)

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18 pages, 2280 KiB

Open AccessArticle

MiRNAs Are Involved in Tall Cell Morphology in Papillary Thyroid Carcinoma

by Laura A. Boos, Anja Schmitt, Holger Moch, Paul Komminoth, Cedric Simillion, Ilaria Marinoni, Yuri E. Nikiforov, Marina N. Nikiforova, Aurel Perren and Matthias S. Dettmer

Cancers 2019, 11(6), 885; https://doi.org/10.3390/cancers11060885 - 25 Jun 2019

Cited by 10 | Viewed by 3495

Abstract

Five percent of papillary thyroid carcinomas (PTC) show an adverse clinical outcome (ACO). The tall cell variant of papillary thyroid carcinomas (TCV) is a good predictor of an ACO, however, the identification of tall-cells is subjective. Micro RNAs are short non-coding ribonucleic acids [...] Read more.

Five percent of papillary thyroid carcinomas (PTC) show an adverse clinical outcome (ACO). The tall cell variant of papillary thyroid carcinomas (TCV) is a good predictor of an ACO, however, the identification of tall-cells is subjective. Micro RNAs are short non-coding ribonucleic acids (miRNA). Their expression in PTC could be a powerful, more objective predictor of prognosis. Methods: Forty-four PTC underwent miRNA profiling, twenty-four of them were TCV. The miRNA dataset was validated by analysis of expression of known target proteins (vascular endothelial growth factor (VEGF) and phosphatase and tensin homolog (PTEN)) in 125 patients including 48 TCV and 57 with an ACO. Results: One hundred and forty-nine miRNAs were significantly associated with an ACO, seventy-one of them with TC-morphology. Twenty-two miRNAs were identified as targets for VEGF and thirty-two as targets for PTEN. In univariate and multivariable analysis, reduced expression of PTEN and an increased expression of VEGF were associated with shorter relapse free survival. A classifier, including TC-morphology, pT-stage, VEGF, and PTEN, predicted relapse with an 80% accuracy. Conclusions: Some miRNAs predict outcome in PTC and are involved in TC-morphology in PTC. These miRNAs may serve as more objective indicators of an ACO than tall cell morphology. PTEN and VEGF protein expression are prognostically relevant and are at least partially regulated by miRNAs. Full article

(This article belongs to the Special Issue Thyroid Cancer)

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17 pages, 8426 KiB

Open AccessArticle

Loss of PTEN in Fallopian Tube Epithelium Results in Multicellular Tumor Spheroid Formation and Metastasis to the Ovary

by Matthew Dean, Vivian Jin, Tova M. Bergsten, Julia R. Austin, Daniel D. Lantvit, Angela Russo and Joanna E. Burdette

Cancers 2019, 11(6), 884; https://doi.org/10.3390/cancers11060884 - 25 Jun 2019

Cited by 22 | Viewed by 4565

Abstract

High-grade serous ovarian cancer (HGSOC) can originate in the fallopian tube and then spread to the ovary. Our objective was to evaluate the role of multicellular tumor spheroids (MTS) in ovarian metastasis. By testing a panel of murine oviductal epithelial (MOE) cells with [...] Read more.

High-grade serous ovarian cancer (HGSOC) can originate in the fallopian tube and then spread to the ovary. Our objective was to evaluate the role of multicellular tumor spheroids (MTS) in ovarian metastasis. By testing a panel of murine oviductal epithelial (MOE) cells with genetic alterations mimicking those seen in HGSOC, we found that loss of PTEN allowed MTS formation under ultra-low adhesion conditions. Confirming these results in vivo, MTS-like structures were observed in the oviducts of PAX8^Cre/+ PTEN^flox/flox mice. MOE PTEN^shRNA cells could incorporate up to 25% wild type cells into MTS, while higher percentages of wild type cells resulted in a loss of MTS formation. MTS formation allowed MOE PTEN^shRNA cells to survive better under ultra-low adhesion conditions than control cells. MTS also attached to the ovarian stroma, as would be exposed during ovulation. Interestingly, MTS more robustly cleared monolayers of murine ovarian surface epithelia than murine ovarian fibroblasts. When xenografted into the ovarian bursa, OVCAR8 MTS were able to form tumors in the ovary at a similar rate as an equal number of OVCAR8 cells grown on traditional cell culture plastic. In conclusion, loss of a single gene (PTEN) allows the fallopian tube epithelia to form MTS, which survive better under ultra-low adhesion conditions, attach to the extracellular matrix exposed during ovulation, and colonize the ovary. These results suggest that MTS may contribute to seeding of the ovary in HGSOC patients. Full article

(This article belongs to the Special Issue Ovarian Cancer Metastasis)

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19 pages, 5080 KiB

Open AccessArticle

Chemotherapeutic Drugs Inhibiting Topoisomerase 1 Activity Impede Cytokine-Induced and NF-κB p65-Regulated Gene Expression

by Tabea Riedlinger, Marek Bartkuhn, Tobias Zimmermann, Sandra B. Hake, Andrea Nist, Thorsten Stiewe, Michael Kracht and M. Lienhard Schmitz

Cancers 2019, 11(6), 883; https://doi.org/10.3390/cancers11060883 - 25 Jun 2019

Cited by 9 | Viewed by 4055

Abstract

Inhibitors of DNA topoisomerase I (TOP1), an enzyme relieving torsional stress of DNA by generating transient single-strand breaks, are clinically used to treat ovarian, small cell lung and cervical cancer. As torsional stress is generated during transcription by progression of RNA polymerase II [...] Read more.

Inhibitors of DNA topoisomerase I (TOP1), an enzyme relieving torsional stress of DNA by generating transient single-strand breaks, are clinically used to treat ovarian, small cell lung and cervical cancer. As torsional stress is generated during transcription by progression of RNA polymerase II through the transcribed gene, we tested the effects of camptothecin and of the approved TOP1 inhibitors Topotecan and SN-38 on TNFα-induced gene expression. RNA-seq experiments showed that inhibition of TOP1 but not of TOP2 activity suppressed the vast majority of TNFα-triggered genes. The TOP1 effects were fully reversible and preferentially affected long genes. TNFα stimulation led to inducible recruitment of TOP1 to the gene body of IL8, where its inhibition by camptothecin reduced transcription elongation and also led to altered histone H3 acetylation. Together, these data show that TOP1 inhibitors potently suppress expression of proinflammatory cytokines, a feature that may contribute to the increased infection risk occurring in tumor patients treated with these agents. On the other hand, TOP1 inhibitors could also be considered as a therapeutic option in order to interfere with exaggerated cytokine expression seen in several inflammatory diseases. Full article

(This article belongs to the Special Issue NF-kappaB signalling pathway)

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17 pages, 2984 KiB

Open AccessArticle

Molecular Comparison of Imatinib-Naïve and Resistant Gastrointestinal Stromal Tumors: Differentially Expressed microRNAs and mRNAs

by Azadeh Amirnasr, Caroline M.M. Gits, Patricia F. van Kuijk, Marcel Smid, Anne L.M. Vriends, Piotr Rutkowski, Raf Sciot, Patrick Schöffski, Maria Debiec-Rychter, Stefan Sleijfer and Erik A. C. Wiemer

Cancers 2019, 11(6), 882; https://doi.org/10.3390/cancers11060882 - 24 Jun 2019

Cited by 9 | Viewed by 3520

Abstract

Despite the success of imatinib in advanced gastrointestinal stromal tumor (GIST) patients, 50% of the patients experience resistance within two years of treatment underscoring the need to get better insight into the mechanisms conferring imatinib resistance. Here the microRNA and mRNA expression profiles [...] Read more.

Despite the success of imatinib in advanced gastrointestinal stromal tumor (GIST) patients, 50% of the patients experience resistance within two years of treatment underscoring the need to get better insight into the mechanisms conferring imatinib resistance. Here the microRNA and mRNA expression profiles in primary (imatinib-naïve) and imatinib-resistant GIST were examined. Fifty-three GIST samples harboring primary KIT mutations (exon 9; n = 11/exon 11; n = 41/exon 17; n = 1) and comprising imatinib-naïve (IM-n) (n = 33) and imatinib-resistant (IM-r) (n = 20) tumors, were analyzed. The microRNA expression profiles were determined and from a subset (IM-n, n = 14; IM-r, n = 15) the mRNA expression profile was established. Ingenuity pathway analyses were used to unravel biochemical pathways and gene networks in IM-r GIST. Thirty-five differentially expressed miRNAs between IM-n and IM-r GIST samples were identified. Additionally, miRNAs distinguished IM-r samples with and without secondary KIT mutations. Furthermore 352 aberrantly expressed genes were found in IM-r samples. Pathway and network analyses revealed an association of differentially expressed genes with cell cycle progression and cellular proliferation, thereby implicating genes and pathways involved in imatinib resistance in GIST. Differentially expressed miRNAs and mRNAs between IM-n and IM-r GIST were identified. Bioinformatic analyses provided insight into the genes and biochemical pathways involved in imatinib-resistance and highlighted key genes that may be putative treatment targets. Full article

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18 pages, 2357 KiB

Open AccessArticle

(Pro)renin Receptor Expression Increases throughout the Colorectal Adenoma—Adenocarcinoma Sequence and It Is Associated with Worse Colorectal Cancer Prognosis

by Maider Beitia, Jon Danel Solano-Iturri, Peio Errarte, Julio Calvete-Candenas, Alberto Loizate, Mari Carmen Etxezarraga, Begoña Sanz and Gorka Larrinaga

Cancers 2019, 11(6), 881; https://doi.org/10.3390/cancers11060881 - 24 Jun 2019

Cited by 12 | Viewed by 3525

Abstract

(Pro)renin receptor (PRR) is a protein that takes part in several signaling pathways such as Renin Angiotensin System and Wnt signalling. Its biological role has recently been related to cancer progression and in this study, we investigated its relevance in colorectal cancer (CRC). [...] Read more.

(Pro)renin receptor (PRR) is a protein that takes part in several signaling pathways such as Renin Angiotensin System and Wnt signalling. Its biological role has recently been related to cancer progression and in this study, we investigated its relevance in colorectal cancer (CRC). To that end, we analysed the immunohistochemical expression of PRR in adenomatous polyps and CRCs from the same patients (n = 42), and in primary tumours and nodal and liver metastases from advanced CRC patients (n = 294). In addition, the soluble fraction of PRR was measured by ELISA in plasma samples from 161 CRC patients. The results showed that PRR expression was gradually augmented along the uninvolved mucosa–adenoma–adenocarcinoma sequence. Besides, the stronger expression of PRR in primary tumours was markedly associated with local tumour extent and the onset of metastases. Moreover, PRR expression in both primary and distant metastases was associated with worse 5- and 10-year survival of CRC patients. Plasmatic PRR levels did not change with respect to controls and were not associated with CRC aggressiveness. These results suggest a key role of PRR in the development and progression of CRC and a potential use of this protein as a new prognostic biomarker and/or therapeutic target for this disease. Full article

(This article belongs to the Special Issue Colorectal Cancers)

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13 pages, 2134 KiB

Open AccessArticle

Role of Bruton’s Tyrosine Kinase in Stage III Colorectal Cancer

by Debora Basile, Lorenzo Gerratana, Angela Buonadonna, Silvio Ken Garattini, Tiziana Perin, Emanuela Grassilli, Gianmaria Miolo, Maria Grazia Cerrito, Claudio Belluco, Giulio Bertola, Antonino De Paoli, Renato Cannizzaro, Marialuisa Lavitrano, Fabio Puglisi and Vincenzo Canzonieri

Cancers 2019, 11(6), 880; https://doi.org/10.3390/cancers11060880 - 24 Jun 2019

Cited by 10 | Viewed by 3141

Abstract

Background: Bruton’s tyrosine kinase (BTK) is involved in the immune response and its deficiency impairs B cell maturation. We evaluated the expression of a novel BTK isoform, p65BTK, in colorectal cancer (CRC), to identify its impact on survival. Materials and Methods: This retrospective [...] Read more.

Background: Bruton’s tyrosine kinase (BTK) is involved in the immune response and its deficiency impairs B cell maturation. We evaluated the expression of a novel BTK isoform, p65BTK, in colorectal cancer (CRC), to identify its impact on survival. Materials and Methods: This retrospective study evaluated 87 consecutive stage III CRC patients treated at the National Cancer Institute of Aviano (1999–2017). Multiple specimens were collected and analyzed for staining intensity and percentage of tumor cells positive for p65BTK. Prognostic impact was tested by univariate Cox regression analysis. Results: After a median follow-up of 82.59 months, median disease-free survival (DFS) and overall survival (OS) were 11.67 months and 31.33 months, respectively. Interestingly, 10% of patients did not express p65BTK. For the immunohistochemistry IHC intensity 1, the best cutoff point was 1% of p65BTK positivity; for IHC intensity 2, it was 50%; and for IHC intensity 3, it was 80%. Through univariate analysis, patients with highly expressed p65BTK (IHC intensity 3 and ≥80%) were shown to have the worst prognosis in terms of DFS (HR: 6.23; p = 0.005; 95% C.I. 1.75–22.79) and OS (HR: 2.54; p = 0.025; 95% C.I. 1.12–5.76). Conclusions: p65BTK is frequently expressed in CRC and, if highly expressed, is an unfavourable prognostic factor. However, further confirmation is needed and its potential targeting needs to be studied. Full article

(This article belongs to the Collection Cancer Biomarkers)

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13 pages, 2135 KiB

Open AccessArticle

Prognostic Role of Albumin, Bilirubin, and ALBI Scores: Analysis of 1000 Patients with Hepatocellular Carcinoma Undergoing Radioembolization

by Mark Antkowiak, Ahmed Gabr, Arighno Das, Rehan Ali, Laura Kulik, Daniel Ganger, Christopher Moore, Michael Abecassis, Nitin Katariya, Samdeep Mouli, Devalingam Mahalingam, Robert J. Lewandowski, Riad Salem and Ahsun Riaz

Cancers 2019, 11(6), 879; https://doi.org/10.3390/cancers11060879 - 24 Jun 2019

Cited by 41 | Viewed by 4526

Abstract

Introduction: We compared the efficacy of the ALBI (albumin–bilirubin) score to the established Child–Pugh (CP) grade in hepatocellular carcinoma (HCC) patients treated with yttrium-90 radioembolization (Y90). We further assessed the individual contributions of albumin and bilirubin to survival prediction. Methods: 1000 consecutive HCC [...] Read more.

Introduction: We compared the efficacy of the ALBI (albumin–bilirubin) score to the established Child–Pugh (CP) grade in hepatocellular carcinoma (HCC) patients treated with yttrium-90 radioembolization (Y90). We further assessed the individual contributions of albumin and bilirubin to survival prediction. Methods: 1000 consecutive HCC patients treated with Y90 were included. Overall survival (OS) was assessed using Kaplan Meier analysis. Sub-stratification analyses were performed using CP and ALBI and in subgroups determined by United Network for Organ Sharing (UNOS) or Barcelona Clinic Liver Cancer (BCLC) staging. The independent impact (hazard ratio (HR)) of ALBI, CP, albumin, and bilirubin on survival was assessed using Cox proportional hazards analysis. Results: Median OS for ALBI 1, 2, and 3 grades was 46.7, 19.1, and 8.8 months, respectively. The HR for death for ALBI 2 vs. ALBI 1 was 3.39 (1.75–6.57); ALBI 3 vs. ALBI 1 was 7.58 (3.89–14.79); and the c-index was 0.623. Median OS for CP A, B, and C was 21.7, 11.3, and 6.0 months, respectively. The HR for death for CP B vs. CP A was 2.04 (1.71–2.43); CP C vs. CP A was 3.27 (2.08–5.14); and the c-index was 0.616. Stratified OS showed unique prognostic groups identified by ALBI within CP-B and CP-C. Median OS for albumin grades 1, 2, and 3 was 46.0, 17.1, and 9.1 months, respectively. Median OS for bilirubin grades 1, 2, and 3 was 15.6, 21.0, and 5.8 months, respectively. The HR for death for albumin 2 vs. 1 was 2.48 (1.81–3.41); albumin 3 vs. 1 was 4.74 (3.44–6.54); and the c-index was 0.640. The HR for death for bilirubin 2 vs. 1 was 1.09 (0.82–1.44); bilirubin 3 vs. 1 was 2.37 (1.66–3.40); and the c-index was 0.533. Conclusions: ALBI outperforms CP in survival prognosis in Y90 treated patients. On sub-analyses, serum albumin (not bilirubin) appears to be the main driver of survival prediction. Our study supports the prognostic ability of ALBI and may suggest a role of albumin alone as a biomarker for patients with HCC. Full article

(This article belongs to the Special Issue Hepatocellular Cancer Treatment)

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16 pages, 8901 KiB

Open AccessArticle

Targeting of Histone Demethylases KDM5A and KDM6B Inhibits the Proliferation of Temozolomide-Resistant Glioblastoma Cells

by Massimo Romani, Antonio Daga, Alessandra Forlani, Maria Pia Pistillo and Barbara Banelli

Cancers 2019, 11(6), 878; https://doi.org/10.3390/cancers11060878 - 24 Jun 2019

Cited by 38 | Viewed by 4837

Abstract

Lysine histone demethylases (KDMs) are considered potential therapeutic targets in several tumors, including glioblastoma (GB). In particular, KDM5A is involved in the acquisition of temozolomide (TMZ) resistance in adult GB cells and UDX/KDM6B regulates H3K27 methylation, which is involved in the pediatric diffuse [...] Read more.

Lysine histone demethylases (KDMs) are considered potential therapeutic targets in several tumors, including glioblastoma (GB). In particular, KDM5A is involved in the acquisition of temozolomide (TMZ) resistance in adult GB cells and UDX/KDM6B regulates H3K27 methylation, which is involved in the pediatric diffuse intrinsic pontine glioma (DIPG). Synthetic inhibitors of KDM5A (JIB 04 and CPI-455) efficiently block the proliferation of native and TMZ-resistant cells and the KDM6B inhibitor GSK J4 improves survival in a model of DIPG. The aim of our work was to determine if GSK J4 could be effective against GB cells that have acquired TMZ resistance and if it could synergize with TMZ or JIB 04 to increase the clinical utility of these molecules. Standard functional and pharmacological analytical procedures were utilized to determine the efficacy of the molecules under study when used alone or in combination against native GB cells and in a model of drug resistance. The results of this study indicated that although GSK J4 is active against native and TMZ-resistant cells, it does so at a lower efficacy than JIB 04. Drug combination studies revealed that GSK J4, differently from JIB 04, does not synergize with TMZ. Interestingly, GSK J4 and JIB 04 strongly synergize and are a potent combination against TMZ-resistant cells. Further studies in animal models will be necessary to determine if this combination of molecules might foster the development of novel therapeutic approaches for glioblastoma. Full article

(This article belongs to the Special Issue Histone Modification in Cancer)

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15 pages, 1218 KiB

Open AccessEditor’s ChoiceReview

DNAM-1 and the TIGIT/PVRIG/TACTILE Axis: Novel Immune Checkpoints for Natural Killer Cell-Based Cancer Immunotherapy

by Beatriz Sanchez-Correa, Isabel Valhondo, Fakhri Hassouneh, Nelson Lopez-Sejas, Alejandra Pera, Juan M. Bergua, Maria Jose Arcos, Helena Bañas, Ignacio Casas-Avilés, Esther Durán, Corona Alonso, Rafael Solana and Raquel Tarazona

Cancers 2019, 11(6), 877; https://doi.org/10.3390/cancers11060877 - 23 Jun 2019

Cited by 144 | Viewed by 13542

Abstract

Natural killer (NK) cells are lymphocytes of the innate immune response characterized by their role in the destruction of tumor cells. Activation of NK cells depend on a fine balance between activating and inhibitory signals mediated by different receptors. In recent years, a [...] Read more.

Natural killer (NK) cells are lymphocytes of the innate immune response characterized by their role in the destruction of tumor cells. Activation of NK cells depend on a fine balance between activating and inhibitory signals mediated by different receptors. In recent years, a family of paired receptors that interact with ligands of the Nectin/Nectin-like (Necl) family has attracted great interest. Two of these ligands, Necl-5 (usually termed CD155 or PVR) and Nectin-2 (CD112), frequently expressed on different types of tumor cells, are recognized by a group of receptors expressed on T and NK cells that exert opposite functions after interacting with their ligands. These receptors include DNAM-1 (CD226), TIGIT, TACTILE (CD96) and the recently described PVRIG. Whereas activation through DNAM-1 after recognition of CD155 or CD112 enhances NK cell-mediated cytotoxicity against a wide range of tumor cells, TIGIT recognition of these ligands exerts an inhibitory effect on NK cells by diminishing IFN-γ production, as well as NK cell-mediated cytotoxicity. PVRIG has also been identified as an inhibitory receptor that recognizes CD112 but not CD155. However, little is known about the role of TACTILE as modulator of immune responses in humans. TACTILE control of tumor growth and metastases has been reported in murine models, and it has been suggested that it negatively regulates the anti-tumor functions mediated by DNAM-1. In NK cells from patients with solid cancer and leukemia, it has been observed a decreased expression of DNAM-1 that may shift the balance in favor to the inhibitory receptors TIGIT or PVRIG, further contributing to the diminished NK cell-mediated cytotoxic capacity observed in these patients. Analysis of DNAM-1, TIGIT, TACTILE and PVRIG on human NK cells from solid cancer or leukemia patients will clarify the role of these receptors in cancer surveillance. Overall, it can be speculated that in cancer patients the TIGIT/PVRIG pathways are upregulated and represent novel targets for checkpoint blockade immunotherapy. Full article

(This article belongs to the Special Issue Natural Killer Cells and Cancer Therapy)

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22 pages, 3849 KiB

Open AccessArticle

Circulating miRNAs in Untreated Breast Cancer: An Exploratory Multimodality Morpho-Functional Study

by Mariarosaria Incoronato, Anna Maria Grimaldi, Peppino Mirabelli, Carlo Cavaliere, Chiara Anna Parente, Monica Franzese, Stefania Staibano, Gennaro Ilardi, Daniela Russo, Andrea Soricelli, Onofrio Antonio Catalano and Marco Salvatore

Cancers 2019, 11(6), 876; https://doi.org/10.3390/cancers11060876 - 22 Jun 2019

Cited by 35 | Viewed by 4788

Abstract

The aim of this study was to identify new disease-related circulating miRNAs with high diagnostic accuracy for breast cancer (BC) and to correlate their deregulation with the morpho-functional characteristics of the tumour, as assessed in vivo by positron emission tomography/magnetic resonance (PET/MR) imaging. [...] Read more.

The aim of this study was to identify new disease-related circulating miRNAs with high diagnostic accuracy for breast cancer (BC) and to correlate their deregulation with the morpho-functional characteristics of the tumour, as assessed in vivo by positron emission tomography/magnetic resonance (PET/MR) imaging. A total of 77 untreated female BC patients underwent same-day PET/MR and blood collection, and 78 healthy donors were recruited as negative controls. The expression profile of 84 human miRNAs was screened by using miRNA PCR arrays and validated by real-time PCR. The validated miRNAs were correlated with the quantitative imaging parameters extracted from the primary BC samples. Circulating miR-125b-5p and miR-143-3p were upregulated in BC plasma and able to discriminate BC patients from healthy subjects (miR-125-5p area under the receiver operating characteristic ROC curve (AUC) = 0.85 and miR-143-3p AUC = 0.80). Circulating CA15-3, a soluble form of the transmembrane glycoprotein Mucin 1 (MUC-1) that is upregulated in epithelial cancer cells of different origins, was combined with miR-125b-5p and improved the diagnostic accuracy from 70% (CA15-3 alone) to 89% (CA15-3 plus miR-125b-5p). MiR-143-3p showed a strong and significant correlation with the stage of the disease, apparent diffusion coefficient (ADC_mean), reverse efflux volume transfer constant (Kep_mean) and maximum standardized uptake value (SUV_max), and it might represent a biomarker of tumour aggressiveness. Similarly, miR-125b-5p was correlated with stage and grade 2 but inversely correlated with the forward volume transfer constant (Ktrans_mean) and proliferation index (Ki67), suggesting a potential role as a biomarker of a relatively more favourable prognosis. In situ hybridization (ISH) experiments revealed that miR-143-3p was expressed in endothelial tumour cells, miR-125-5p in cancer-associated fibroblasts, and neither in epithelial tumour cells. Our results suggested that miR-125-5p and miR-143-3p are potential biomarkers for the risk stratification of BC, and Kaplan-Maier plots confirmed this hypothesis. In addition, the combined use of miR-125-b-5p and CA15-3 enhanced the diagnostic accuracy up to 89%. This is the first study that correlates circulating miRNAs with in vivo quantified tumour biology through PET/MR biomarkers. This integration elucidates the link between the plasmatic increase in these two potential circulating biomarkers and the biology of untreated BC. In conclusion, while miR-143-3b and miR-125b-5p provide valuable information for prognosis, a combination of miR-125b-5p with the tumour marker CA15-3 improves sensitivity for BC detection, which warrants consideration by further validation studies. Full article

(This article belongs to the Special Issue Role of Medical Imaging in Cancers)

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21 pages, 1865 KiB

Open AccessReview

Can Dendritic Cell Vaccination Prevent Leukemia Relapse?

by Liam J. O’Brien, Camille Guillerey and Kristen J. Radford

Cancers 2019, 11(6), 875; https://doi.org/10.3390/cancers11060875 - 22 Jun 2019

Cited by 12 | Viewed by 5787

Abstract

Leukemias are clonal proliferative disorders arising from immature leukocytes in the bone marrow. While the advent of targeted therapies has improved survival in certain subtypes, relapse after initial therapy is a major problem. Dendritic cell (DC) vaccination has the potential to induce tumor-specific [...] Read more.

Leukemias are clonal proliferative disorders arising from immature leukocytes in the bone marrow. While the advent of targeted therapies has improved survival in certain subtypes, relapse after initial therapy is a major problem. Dendritic cell (DC) vaccination has the potential to induce tumor-specific T cells providing long-lasting, anti-tumor immunity. This approach has demonstrated safety but limited clinical success until recently, as DC vaccination faces several barriers in both solid and hematological malignancies. Importantly, vaccine-mediated stimulation of protective immune responses is hindered by the aberrant production of immunosuppressive factors by cancer cells which impede both DC and T cell function. Leukemias present the additional challenge of severely disrupted hematopoiesis owing to both cytogenic defects in hematopoietic progenitors and an abnormal hematopoietic stem cell niche in the bone marrow; these factors accentuate systemic immunosuppression and DC malfunction. Despite these obstacles, several recent clinical trials have caused great excitement by extending survival in Acute Myeloid Leukemia (AML) patients through DC vaccination. Here, we review the phenotype and functional capacity of DCs in leukemia and approaches to harness DCs in leukemia patients. We describe the recent clinical successes in AML and detail the multiple new strategies that might enhance prognosis in AML and other leukemias. Full article

(This article belongs to the Special Issue Tumour Associated Dendritic Cells)

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19 pages, 3448 KiB

Open AccessArticle

Tumor-Derived Extracellular Vesicles Inhibit Natural Killer Cell Function in Pancreatic Cancer

by Jiangang Zhao, Hans A. Schlößer, Zhefang Wang, Jie Qin, Jiahui Li, Felix Popp, Marie Christine Popp, Hakan Alakus, Seung-Hun Chon, Hinrich P. Hansen, Wolfram F. Neiss, Karl-Walter Jauch, Christiane J. Bruns and Yue Zhao

Cancers 2019, 11(6), 874; https://doi.org/10.3390/cancers11060874 - 22 Jun 2019

Cited by 83 | Viewed by 5887

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies. Tumor-derived extracellular vesicles (EVs) induce pre-metastatic niche formation to promote metastasis. We isolated EVs from a highly-metastatic pancreatic cancer cell line and patient-derived primary cancer cells by ultracentrifugation. The protein content of [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies. Tumor-derived extracellular vesicles (EVs) induce pre-metastatic niche formation to promote metastasis. We isolated EVs from a highly-metastatic pancreatic cancer cell line and patient-derived primary cancer cells by ultracentrifugation. The protein content of EVs was analyzed by mass spectrometry. The effects of PDAC-derived EVs on natural kill (NK) cells were investigated by flow cytometry. The serum EVs’ TGF-β1 levels were quantified by ELISA. We found that integrins were enriched in PDAC-derived EVs. The expression of NKG2D, CD107a, TNF-α, and INF-γ in NK cells was significantly downregulated after co-culture with EVs. NK cells also exhibited decreased levels of CD71 and CD98, as well as impaired glucose uptake ability. In addition, NK cell cytotoxicity against pancreatic cancer stem cells was attenuated. Moreover, PDAC-derived EVs induced the phosphorylation of Smad2/3 in NK cells. Serum EVs’ TGF-β1 was significantly increased in PDAC patients. Our findings emphasize the immunosuppressive role of PDAC-derived EVs and provide new insights into our understanding of NK cell dysfunction regarding pre-metastatic niche formation in PDAC. Full article

(This article belongs to the Special Issue Advances in Pancreatic Cancer Research)

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12 pages, 210 KiB

Open AccessReview

Multidisciplinary Management of Patients with Unresectable Hepatocellular Carcinoma: A Critical Appraisal of Current Evidence

by Pierre M. Gholam, Renuka Iyer and Matthew S. Johnson

Cancers 2019, 11(6), 873; https://doi.org/10.3390/cancers11060873 - 22 Jun 2019

Cited by 21 | Viewed by 3630

Abstract

Hepatocellular carcinoma (HCC) is a leading cause of new cancer diagnoses in the United States, with an incidence that is expected to rise. The etiology of HCC is varied and can lead to differences between patients in terms of presentation and natural history. [...] Read more.

Hepatocellular carcinoma (HCC) is a leading cause of new cancer diagnoses in the United States, with an incidence that is expected to rise. The etiology of HCC is varied and can lead to differences between patients in terms of presentation and natural history. Subsequently, physicians treating these patients need to consider a variety of disease and patient characteristics when they select from the many different treatment options that are available for these patients. At the same time, the treatment landscape for patients with HCC, particularly those with unresectable HCC, has been rapidly evolving as new, evidence-based options become available. The treatment plan for patients with HCC can include surgery, transplant, ablation, transarterial chemoembolization, transarterial radioembolization, radiation therapy, and/or systemic therapies. Implementing these different modalities, where the optimal sequence and/or combination has not been defined, requires coordination between physicians with different specialties, including interventional radiologists, hepatologists, and surgical and medical oncologists. As such, the implementation of a multidisciplinary team is necessary to develop a comprehensive care plan for patients, especially those with unresectable HCC. Full article

(This article belongs to the Special Issue Hepatocellular Cancer Treatment)

19 pages, 4912 KiB

Open AccessArticle

Evaluating a Single Domain Antibody Targeting Human PD-L1 as a Nuclear Imaging and Therapeutic Agent

by Katrijn Broos, Quentin Lecocq, Catarina Xavier, Jessica Bridoux, Tham T. Nguyen, Jurgen Corthals, Steve Schoonooghe, Eva Lion, Geert Raes, Marleen Keyaerts, Nick Devoogdt and Karine Breckpot

Cancers 2019, 11(6), 872; https://doi.org/10.3390/cancers11060872 - 21 Jun 2019

Cited by 47 | Viewed by 6734

Abstract

The PD-1:PD-L1 immune checkpoint axis is central in the escape of cancer cells from anticancer immune responses. Monoclonal antibodies (mAbs) specific for PD-L1 have been approved for treatment of various cancer types. Although PD-L1 blockade has proven its merit, there are still several [...] Read more.

The PD-1:PD-L1 immune checkpoint axis is central in the escape of cancer cells from anticancer immune responses. Monoclonal antibodies (mAbs) specific for PD-L1 have been approved for treatment of various cancer types. Although PD-L1 blockade has proven its merit, there are still several aspects that require further attention to fully capitalize on its potential. One of these is the development of antigen-binding moieties that enable PD-L1 diagnosis and therapy. We generated human PD-L1 binding single domain antibodies (sdAbs) and selected sdAb K2, a sdAb with a high affinity for PD-L1, as a lead compound. SPECT/CT imaging in mice following intravenous injection of Technetium-99m (^99mTc)-labeled sdAb K2 revealed high signal-to-noise ratios, strong ability to specifically detect PD-L1 in melanoma and breast tumors, and relatively low kidney retention, which is a unique property for radiolabeled sdAbs. We further showed using surface plasmon resonance that sdAb K2 binds to the same epitope on PD-L1 as the mAb avelumab, and antagonizes PD-1:PD-L1 interactions. Different human cell-based assays corroborated the PD-1:PD-L1 blocking activity, showing enhanced T-cell receptor signaling and tumor cell killing when PD-1^POS T cells interacted with PD-L1^POS tumor cells. Taken together, we present sdAb K2, which specifically binds to human PD-L1, as a new diagnostic and therapeutic agent in cancer management. Full article

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8 pages, 1203 KiB

Open AccessArticle

Meta-Enrichment Analyses to Identify Advanced Gastric Cancer Patients Who Achieve a Higher Response to S-1/Cisplatin

by Madoka Takeuchi, Jaffer A. Ajani, Xuemin Fang, Per Pfeiffer, Masahiro Takeuchi and Hanneke W. M. van Laarhoven

Cancers 2019, 11(6), 871; https://doi.org/10.3390/cancers11060871 - 21 Jun 2019

Viewed by 2440

Abstract

The Multicenter phase III comparison of cisplatin/S-1 with cisplatin/infusional fluorouracil in advanced gastric or gastroesophageal adenocarcinoma study (FLAGS) and the Diffuse Gastric and Esophagogastric Junction Cancer S-1 Trial (DIGEST) have shown that patients with advanced gastric cancer treated with S-1/Cisplatin (CS) have similar [...] Read more.

The Multicenter phase III comparison of cisplatin/S-1 with cisplatin/infusional fluorouracil in advanced gastric or gastroesophageal adenocarcinoma study (FLAGS) and the Diffuse Gastric and Esophagogastric Junction Cancer S-1 Trial (DIGEST) have shown that patients with advanced gastric cancer treated with S-1/Cisplatin (CS) have similar overall survival (OS) compared to 5-fluorouracil/cisplatin (CF). The purpose of this analysis was to identify patients who may specifically benefit from CS using meta-enrichment analysis of the combined two datasets. Eleven clinico-pathological factors were selected and a high response enrichable population was determined. The efficacy of CS in the combined data set of 1365 patients (n = 1019 from FLAGS and n = 346 from DIGEST) was analyzed. We identified 683 patients (n = 374 from CS, n = 309 from CF) as the high response enrichable population who were classified as those with Eastern Cooperative Oncology Group Performance Status (ECOG PS) 1, more than two metastatic sites and low neutrophil-lymphocyte ratio (log(NL ratio)). In the high response enrichable population, the median OS in the CS group was 241 days compared to 210 days in the CF group (hazard ratio 0.776; 95% confidence interval 0.658 to 0.915; p-value 0.004). Through meta-enrichment analysis, the high response enrichable population to CS was identified. Our findings show the clinical importance of selecting the appropriate treatment based on specific patient characteristics. Full article

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22 pages, 1915 KiB

Open AccessArticle

Synthesis and Enhanced Cellular Uptake In Vitro of Anti-HER2 Multifunctional Gold Nanoparticles

by Esteban Cruz and Veysel Kayser

Cancers 2019, 11(6), 870; https://doi.org/10.3390/cancers11060870 - 21 Jun 2019

Cited by 38 | Viewed by 7827

Abstract

Nanoparticle carriers offer the possibility of enhanced delivery of therapeutic payloads in tumor tissues due to tumor-selective accumulation through the enhanced permeability and retention effect (EPR). Gold nanoparticles (AuNP), in particular, possess highly appealing features for development as nanomedicines, such as biocompatibility, tunable [...] Read more.

Nanoparticle carriers offer the possibility of enhanced delivery of therapeutic payloads in tumor tissues due to tumor-selective accumulation through the enhanced permeability and retention effect (EPR). Gold nanoparticles (AuNP), in particular, possess highly appealing features for development as nanomedicines, such as biocompatibility, tunable optical properties and a remarkable ease of surface functionalization. Taking advantage of the latter, several strategies have been designed to increase treatment specificity of gold nanocarriers by attaching monoclonal antibodies on the surface, as a way to promote selective interactions with the targeted cells—an approach referred to as active-targeting. Here, we describe the synthesis of spherical gold nanoparticles surface-functionalized with an anti-HER2 antibody-drug conjugate (ADC) as an active targeting agent that carries a cytotoxic payload. In addition, we enhanced the intracellular delivery properties of the carrier by attaching a cell penetrating peptide to the active-targeted nanoparticles. We demonstrate that the antibody retains high receptor-affinity after the structural modifications performed for drug-conjugation and nanoparticle attachment. Furthermore, we show that antibody attachment increases cellular uptake in HER2 amplified cell lines selectively, and incorporation of the cell penetrating peptide leads to a further increase in cellular internalization. Nanoparticle-bound antibody-drug conjugates retain high antimitotic potency, which could contribute to a higher therapeutic index in high EPR tumors. Full article

(This article belongs to the Special Issue Therapeutic Monoclonal Antibodies and Antibody Products, Their Optimization and Drug Design in Cancers)

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13 pages, 2429 KiB

Open AccessArticle

Automated Definition of Skeletal Disease Burden in Metastatic Prostate Carcinoma: A 3D Analysis of SPECT/CT Images

by Francesco Fiz, Helmut Dittmann, Cristina Campi, Matthias Weissinger, Samine Sahbai, Matthias Reimold, Arnulf Stenzl, Michele Piana, Gianmario Sambuceti and Christian la Fougère

Cancers 2019, 11(6), 869; https://doi.org/10.3390/cancers11060869 - 21 Jun 2019

Cited by 1 | Viewed by 3925

Abstract

To meet the current need for skeletal tumor-load estimation in castration-resistant prostate cancer (CRPC), we developed a novel approach based on adaptive bone segmentation. In this study, we compared the program output with existing estimates and with the radiological outcome. Seventy-six whole-body single-photon [...] Read more.

To meet the current need for skeletal tumor-load estimation in castration-resistant prostate cancer (CRPC), we developed a novel approach based on adaptive bone segmentation. In this study, we compared the program output with existing estimates and with the radiological outcome. Seventy-six whole-body single-photon emission computed tomographies/x-ray computed tomography with 3,3-diphosphono-1,2-propanedicarboxylic acid from mCRPC patients were analyzed. The software identified the whole skeletal volume (S_Vol) and classified the voxels metastases (M_Vol) or normal bone (B_Vol). S_Vol was compared with the estimation of a commercial software. M_Vol was compared with manual assessment and with prostate specific antigen (PSA) levels. Counts/voxel were extracted from M_Vol and B_Vol. After six cycles of ²²³RaCl2-therapy every patient was re-evaluated as having progressive disease (PD), stable disease (SD), or a partial response (PR). S_Vol correlated with that of the commercial software (R = 0.99, p < 0.001). M_Vol correlated with the manually-counted lesions (R = 0.61, p < 0.001) and PSA (R = 0.46, p < 0.01). PD had a lower counts/voxel in M_Vol than PR/SD (715 ± 190 vs. 975 ± 215 and 1058 ± 255, p < 0.05 and p < 0.01) and B_Vol (PD 275 ± 60, PR 515 ± 188 and SD 528 ± 162 counts/voxel, p < 0.001). Segmentation-based tumor load correlated with radiological/laboratory indices. Uptake was linked with the clinical outcome, suggesting that metastases in PD patients have a lower affinity for bone-seeking radionuclides and might benefit less from bone-targeted radioisotope therapies. Full article

(This article belongs to the Special Issue Role of Medical Imaging in Cancers)

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17 pages, 4038 KiB

Open AccessArticle

Uptake of Ranibizumab but Not Bevacizumab into Uveal Melanoma Cells Correlates with a Sustained Decline in VEGF-A Levels and Metastatic Activities

by Aysegül Tura, Vera E. Pawlik, Martin Rudolf, Justus S. Ernesti, Jan-Niklas Stutzer, Salvatore Grisanti and Mahdy Ranjbar

Cancers 2019, 11(6), 868; https://doi.org/10.3390/cancers11060868 - 21 Jun 2019

Cited by 11 | Viewed by 3594

Abstract

Despite the implication of vascular endothelial growth factor-A (VEGF-A) in the pathophysiology of uveal melanoma (UM), the anti-VEGF-A antibody bevacizumab yielded conflicting results on UM growth. Here, we evaluated whether bevacizumab and ranibizumab, a humanized Fab-fragment against VEGF-A, can enter UM cells and [...] Read more.

Despite the implication of vascular endothelial growth factor-A (VEGF-A) in the pathophysiology of uveal melanoma (UM), the anti-VEGF-A antibody bevacizumab yielded conflicting results on UM growth. Here, we evaluated whether bevacizumab and ranibizumab, a humanized Fab-fragment against VEGF-A, can enter UM cells and induce a sustained physiological response. The primary and metastatic UM cell lines Mel-270 and OMM-2.5 were exposed to bevacizumab or ranibizumab for one day and were maintained further in untreated medium for a total of three days. Both antibodies significantly reduced the levels of extracellular VEGF-A and the angiogenic potential of the conditioned medium after one day. These inhibitory effects of bevacizumab diminished by day three. Ranibizumab suppressed the metabolic activity, proliferation, and intracellular VEGF-A levels in a cell-type and concentration-dependent manner, whereas bevacizumab exerted no effect. Both drugs were detected inside early endosomes within the UM cells, with the stronger and sustained colocalization of ranibizumab. Our results therefore demonstrated the more potent and persistent suppressive activity of ranibizumab on the UM cells, possibly due to its higher level of uptake and prolonged intracellular retention. Further research on the endosome dynamics in UM cells might provide valuable insight into the response of these heterogenous tumors to therapeutic antibodies. Full article

(This article belongs to the Special Issue Uveal Melanoma)

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34 pages, 722 KiB

Open AccessReview

Nobiletin and Derivatives: Functional Compounds from Citrus Fruit Peel for Colon Cancer Chemoprevention

by Joanna Xuan Hui Goh, Loh Teng-Hern Tan, Joo Kheng Goh, Kok Gan Chan, Priyia Pusparajah, Learn-Han Lee and Bey-Hing Goh

Cancers 2019, 11(6), 867; https://doi.org/10.3390/cancers11060867 - 21 Jun 2019

Cited by 104 | Viewed by 13142

Abstract

The search for effective methods of cancer treatment and prevention has been a continuous effort since the disease was discovered. Recently, there has been increasing interest in exploring plants and fruits for molecules that may have potential as either adjuvants or as chemopreventive [...] Read more.

The search for effective methods of cancer treatment and prevention has been a continuous effort since the disease was discovered. Recently, there has been increasing interest in exploring plants and fruits for molecules that may have potential as either adjuvants or as chemopreventive agents against cancer. One of the promising compounds under extensive research is nobiletin (NOB), a polymethoxyflavone (PMF) extracted exclusively from citrus peel. Not only does nobiletin itself exhibit anti-cancer properties, but its derivatives are also promising chemopreventive agents; examples of derivatives with anti-cancer activity include 3′-demethylnobiletin (3′-DMN), 4′-demethylnobiletin (4′-DMN), 3′,4′-didemethylnobiletin (3′,4′-DMN) and 5-demethylnobiletin (5-DMN). In vitro studies have demonstrated differential efficacies and mechanisms of NOB and its derivatives in inhibiting and killing of colon cancer cells. The chemopreventive potential of NOB has also been well demonstrated in several in vivo colon carcinogenesis animal models. NOB and its derivatives target multiple pathways in cancer progression and inhibit several of the hallmark features of colorectal cancer (CRC) pathophysiology, including arresting the cell cycle, inhibiting cell proliferation, inducing apoptosis, preventing tumour formation, reducing inflammatory effects and limiting angiogenesis. However, these substances have low oral bioavailability that limits their clinical utility, hence there have been numerous efforts exploring better drug delivery strategies for NOB and these are part of this review. We also reviewed data related to patents involving NOB to illustrate the extensiveness of each research area and its direction of commercialisation. Furthermore, this review also provides suggested directions for future research to advance NOB as the next promising candidate in CRC chemoprevention. Full article

(This article belongs to the Special Issue Role of Natural Bioactive Compounds in the Rise and Fall of Cancers)

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15 pages, 2678 KiB

Open AccessArticle

Validation of Immunohistochemistry for the Detection of BRAF V600E-Mutated Lung Adenocarcinomas

by Chien-Hung Gow, Min-Shu Hsieh, Yen-Ting Lin, Yi-Nan Liu and Jin-Yuan Shih

Cancers 2019, 11(6), 866; https://doi.org/10.3390/cancers11060866 - 21 Jun 2019

Cited by 20 | Viewed by 4025

Abstract

BRAF V600E mutation, a missense mutation in exon 15 resulting in valine substitution for glutamate at position 600 within the kinase domain of BRAF oncogene, is found in a subset of lung adenocarcinoma (ADC). The usefulness of immunohistochemistry (IHC) as an alternative diagnostic [...] Read more.

BRAF V600E mutation, a missense mutation in exon 15 resulting in valine substitution for glutamate at position 600 within the kinase domain of BRAF oncogene, is found in a subset of lung adenocarcinoma (ADC). The usefulness of immunohistochemistry (IHC) as an alternative diagnostic tool has not been validated. Moreover, the clinical information of patients with BRAF V600E-mutated lung ADC is limited. We retrospectively identified 31 lung ADCs diagnosed with BRAF V600E mutation by standard molecular sequencing methods and reviewed their clinical characteristics and pathological features. An anti-BRAF V600E monoclonal VE1 antibody for IHC was used to confirm the expression patterns. The series was comprised of 99 cases, 29 with BRAF V600E mutation and 70 without BRAF V600E but with other types or undetected mutations. The majority of BRAF V600E-mutated biopsied tissues were poorly differentiated and micropapillary patterns. Application of the IHC VE1 assay was highly feasible in primary/metastatic sites or effusion blocks, yielding positive findings in 28 of 29 (96.6%) BRAF V600E-mutated tumors and negative results in 69 of 70 (98.6%) tumors harboring other types or undetected mutations. Patients who received pemetrexed/platinum-based rather than mutation-targeted chemotherapy as the first-line therapy for metastatic disease showed median overall survival of 15.5 months. Our findings indicated that VE1 antibody-based IHC analysis demonstrated high sensitivity and specificity to detect BRAF V600E-mutated lung ADCs in tissues from primary or metastatic sites. Full article

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19 pages, 1178 KiB

Open AccessReview

The Role of Forkhead Box Proteins in Acute Myeloid Leukemia

by Carmelo Gurnari, Giulia Falconi, Eleonora De Bellis, Maria Teresa Voso and Emiliano Fabiani

Cancers 2019, 11(6), 865; https://doi.org/10.3390/cancers11060865 - 21 Jun 2019

Cited by 19 | Viewed by 3999

Abstract

Forkhead box (FOX) proteins are a group of transcriptional factors implicated in different cellular functions such as differentiation, proliferation and senescence. A growing number of studies have focused on the relationship between FOX proteins and cancers, particularly hematological neoplasms such as acute myeloid [...] Read more.

Forkhead box (FOX) proteins are a group of transcriptional factors implicated in different cellular functions such as differentiation, proliferation and senescence. A growing number of studies have focused on the relationship between FOX proteins and cancers, particularly hematological neoplasms such as acute myeloid leukemia (AML). FOX proteins are widely involved in AML biology, including leukemogenesis, relapse and drug sensitivity. Here we explore the role of FOX transcription factors in the major AML entities, according to “The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia”, and in the context of the most recurrent gene mutations identified in this heterogeneous disease. Moreover, we report the new evidences about the role of FOX proteins in drug sensitivity, mechanisms of chemoresistance, and possible targeting for personalized therapies. Full article

(This article belongs to the Special Issue Fox Proteins and Cancers: Old Proteins with Emerging New Tales)

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15 pages, 3499 KiB

Open AccessArticle

Plasma microRNA Levels Combined with CEA and CA19-9 in the Follow-Up of Colorectal Cancer Patients

by Martin Pesta, Radek Kucera, Ondrej Topolcan, Marie Karlikova, Katerina Houfkova, Jiri Polivka, Tereza Macanova, Iva Machova, David Slouka and Vlastimil Kulda

Cancers 2019, 11(6), 864; https://doi.org/10.3390/cancers11060864 - 21 Jun 2019

Cited by 30 | Viewed by 4251

Abstract

Colorectal cancer (CRC) ranks among the most common cancers worldwide. Surgical removal remains the best strategy for treatment of resectable tumors. An important part of caring for patients after surgery is monitoring for early detection of a possible relapse of the disease. Efforts [...] Read more.

Colorectal cancer (CRC) ranks among the most common cancers worldwide. Surgical removal remains the best strategy for treatment of resectable tumors. An important part of caring for patients after surgery is monitoring for early detection of a possible relapse of the disease. Efforts are being made to improve the sensitivity and specificity of routinely used carcinoembryonic antigen (CEA) with the use of additional biomarkers such as microRNAs. The aim of our study was to evaluate the prognostic potential of microRNAs and their use as markers of disease recurrence. The quantitative estimation of CEA, CA19-9, and 22 selected microRNAs (TaqMan Advanced miRNA Assays) was performed in 85 paired (preoperative and postoperative) blood plasma samples of CRC patients and in samples taken during the follow-up period. We have revealed a statistically significant decrease in plasma levels for miR-20a, miR-23a, miR-210, and miR-223a (p = 0.0093, p = 0.0013, p = 0.0392, and p = 0.0214, respectively) after surgical removal of the tumor tissue. A statistically significant relation to prognosis (overall survival; OS) was recorded for preoperative plasma levels of miR-20a, miR-21, and miR-23a (p = 0.0236, p = 0.0316, and p =0.0271, respectively) in a subgroup of patients who underwent palliative surgery. The best discrimination between patients with favorable and unfavorable outcomes was achieved by a combination of CEA, CA19-9 with miR-21, miR-20a, and miR-23a (p < 0.0001). The use of these microRNAs for early disease recurrence detection was affected by a low specificity in comparison with CEA and CA19-9. CEA and CA19-9 had high specificity but low sensitivity. Our results show the benefit of combining currently used standard biomarkers and microRNAs for precise prognosis estimation. Full article

(This article belongs to the Special Issue New Biomarkers in Cancers)

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12 pages, 958 KiB

Open AccessArticle

Development of a Prognostic Nomogram for Liver Metastasis of Uveal Melanoma Patients Selected by Liver MRI

by Pascale Mariani, Sylvain Dureau, Alexia Savignoni, Livia Lumbroso-Le Rouic, Christine Levy-Gabriel, Sophie Piperno-Neumann, Manuel J. Rodrigues, Laurence Desjardins, Nathalie Cassoux and Vincent Servois

Cancers 2019, 11(6), 863; https://doi.org/10.3390/cancers11060863 - 21 Jun 2019

Cited by 20 | Viewed by 2974

Abstract

Patients with liver metastases of uveal melanoma (LMUM) die from their metastatic evolution within 2 years. We established a nomogram to choose a treatment adapted to life expectancy. From 2002 to 2013, we reviewed 224 patients with LMUM selected by liver MRI. A [...] Read more.

Patients with liver metastases of uveal melanoma (LMUM) die from their metastatic evolution within 2 years. We established a nomogram to choose a treatment adapted to life expectancy. From 2002 to 2013, we reviewed 224 patients with LMUM selected by liver MRI. A nomogram was developed based on a Cox model. The predictive performance of the model was assessed according to the C-statistic, Kaplan–Meier curve, and calibration plots. The median follow-up was 49.2 months (range, 0.6–70.9). The survival rates at 6, 12, and 24 months were 0.88 (0.95 CI [0.84–0.93]), 0.68 (0.95 CI [0.62–0.75]), and 0.26 (0.95 CI [0.21–0.33]), respectively. The four factors selected for the nomogram with a worse prognosis were: A disease-free interval between the UM and LMUM groups of less than 6 months (HR = 3.39; 0.95 CI [1.90–6.05]), more than 10 LMUM (HR = 3.95; 0.95 CI [1.97–4.43]), a maximum LMUM of more than 1200 mm2 (HR = 2.47; 0.95 CI [1.53–3.98]), and a lactate dehydrogenase (LDH) value greater than 1.5 (HR = 3.72; 0.95 CI [2.30–6.00]). The model achieved relatively good discrimination and calibration (C-statistic 0.71). This nomogram could be useful for decision-making and risk stratification for therapeutic options. Full article

(This article belongs to the Special Issue Uveal Melanoma)

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20 pages, 999 KiB

Open AccessEditor’s ChoiceReview

Cancer Stem Cells and Radioresistance: DNA Repair and Beyond

by Alexander Schulz, Felix Meyer, Anna Dubrovska and Kerstin Borgmann

Cancers 2019, 11(6), 862; https://doi.org/10.3390/cancers11060862 - 21 Jun 2019

Cited by 186 | Viewed by 10660

Abstract

The current preclinical and clinical findings demonstrate that, in addition to the conventional clinical and pathological indicators that have a prognostic value in radiation oncology, the number of cancer stem cells (CSCs) and their inherent radioresistance are important parameters for local control after [...] Read more.

The current preclinical and clinical findings demonstrate that, in addition to the conventional clinical and pathological indicators that have a prognostic value in radiation oncology, the number of cancer stem cells (CSCs) and their inherent radioresistance are important parameters for local control after radiotherapy. In this review, we discuss the molecular mechanisms of CSC radioresistance attributable to DNA repair mechanisms and the development of CSC-targeted therapies for tumor radiosensitization. We also discuss the current challenges in preclinical and translational CSC research including the high inter- and intratumoral heterogeneity, plasticity of CSCs, and microenvironment-stimulated tumor cell reprogramming. Full article

(This article belongs to the Special Issue Tumor Radioresistance)

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17 pages, 263 KiB

Open AccessReview

Outcomes and Quality of Life of Systemic Therapy in Advanced Hepatocellular Carcinoma

by Kehua Zhou and Christos Fountzilas

Cancers 2019, 11(6), 861; https://doi.org/10.3390/cancers11060861 - 21 Jun 2019

Cited by 25 | Viewed by 4228

Abstract

Hepatocellular carcinoma (HCC) is one of the most commonly diagnosed cancers worldwide; most patients are diagnosed with advanced disease for which there is no known cure. Tremendous progress has been made over the past decade in the development of new agents for HCC, [...] Read more.

Hepatocellular carcinoma (HCC) is one of the most commonly diagnosed cancers worldwide; most patients are diagnosed with advanced disease for which there is no known cure. Tremendous progress has been made over the past decade in the development of new agents for HCC, including small-molecule kinase inhibitors such as sorafenib, lenvatinib, cabozantinib, regorafenib, and monoclonal antibodies like ramucirumab, nivolumab, and pembrolizumab. Ideal use of these agents in clinics has improved the long-term outcome of patients with advanced HCC as well as introduced unique toxicities that can affect quality of life. These toxicities usually are thought to be partially related to cirrhosis, a major risk factor for the development of HCC and a pathophysiological barrier complicating the optimal delivery of antineoplastic therapy. Additionally, side effects of medications together with advanced HCC symptoms not only decrease quality of life, but also cause treatment interruptions and dose reductions that can potentially decrease efficacy. Physicians caring for patients with advanced HCC are called to optimally manage HCC along with cirrhosis in order to prolong life while at the same time preserve the quality of life. In this review, we aimed to summarize outcomes and quality of life with the use of modern systemic treatments in advanced HCC and provide a physician reference for treatment toxicity and cirrhosis management. Full article

(This article belongs to the Special Issue Hepatocellular Cancer Treatment)

16 pages, 856 KiB

Open AccessReview

The 6th R of Radiobiology: Reactivation of Anti-Tumor Immune Response

by Jihane Boustani, Mathieu Grapin, Pierre-Antoine Laurent, Lionel Apetoh and Céline Mirjolet

Cancers 2019, 11(6), 860; https://doi.org/10.3390/cancers11060860 - 20 Jun 2019

Cited by 72 | Viewed by 14435

Abstract

Historically, the 4Rs and then the 5Rs of radiobiology explained the effect of radiation therapy (RT) fractionation on the treatment efficacy. These 5Rs are: Repair, Redistribution, Reoxygenation, Repopulation and, more recently, intrinsic Radiosensitivity. Advances in radiobiology have demonstrated that RT is able to [...] Read more.

Historically, the 4Rs and then the 5Rs of radiobiology explained the effect of radiation therapy (RT) fractionation on the treatment efficacy. These 5Rs are: Repair, Redistribution, Reoxygenation, Repopulation and, more recently, intrinsic Radiosensitivity. Advances in radiobiology have demonstrated that RT is able to modify the tumor micro environment (TME) and to induce a local and systemic (abscopal effect) immune response. Conversely, RT is able to increase some immunosuppressive barriers, which can lead to tumor radioresistance. Fractionation and dose can affect the immunomodulatory properties of RT. Here, we review how fractionation, dose and timing shape the RT-induced anti-tumor immune response and the therapeutic effect of RT. We discuss how immunomodulators targeting immune checkpoint inhibitors and the cGAS/STING (cyclic GMP-AMP Synthase/Stimulator of Interferon Genes) pathway can be successfully combined with RT. We then review current trials evaluating the RT/Immunotherapy combination efficacy and suggest new innovative associations of RT with immunotherapies currently used in clinic or in development with strategic schedule administration (fractionation, dose, and timing) to reverse immune-related radioresistance. Overall, our work will present the existing evidence supporting the claim that the reactivation of the anti-tumor immune response can be regarded as the 6th R of Radiobiology. Full article

(This article belongs to the Special Issue Tumor Radioresistance)

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Cancers, Volume 11, Issue 6 (June 2019) – 153 articles

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