Cancers

18 pages, 4933 KiB

Open AccessReview

Endometrial Cancer Stem Cells: Role, Characterization and Therapeutic Implications

by Gaia Giannone, Laura Attademo, Giulia Scotto, Sofia Genta, Eleonora Ghisoni, Valentina Tuninetti, Massimo Aglietta, Sandro Pignata and Giorgio Valabrega

Cancers 2019, 11(11), 1820; https://doi.org/10.3390/cancers11111820 - 19 Nov 2019

Cited by 70 | Viewed by 6261

Abstract

Endometrial cancer (EC) is the most frequent gynecological cancer. In patients with relapsed and advanced disease, prognosis is still dismal and development of resistance is common. In this context, endometrial Cancer Stem Cells (eCSC), stem-like cells capable to self-renewal and differentiation in mature [...] Read more.

Endometrial cancer (EC) is the most frequent gynecological cancer. In patients with relapsed and advanced disease, prognosis is still dismal and development of resistance is common. In this context, endometrial Cancer Stem Cells (eCSC), stem-like cells capable to self-renewal and differentiation in mature cancer cells, represent a potential field of expansion for drug development. The aim of this review is to characterize the role of eCSC in EC, their features and how they could be targeted. CSC are involved in progression, invasiveness and metastasis (though epithelial to mesenchimal transition, EMT), as well as chemoresistance in EC. Nevertheless, isolation of eCSC is still controversial. Indeed, CD133, Aldheyde dehydrogenase (ALDH), CD117, CD55 and CD44 are enriched in CSCs but there is no universal marker nowadays. The most frequently activated pathways in eCSC are Wingless-INT (Wnt)/β-catenin, Notch1, and Hedghog, with a high expression of self-renewal transcription factors like Octamer binding transcription factor 4 (OCT), B Lymphoma Mo-MLV Insertion Region 1 Homolog (BMI1), North American Network Operations Group Homebox protein (NANOG), and SRY-Box 2 (SOX2). These pathways have been targeted with selective drugs alone or in combination with chemotherapy and immunotherapy. Unfortunately, although preclinical results are encouraging, few clinical data are available. Full article

(This article belongs to the Special Issue Cancer Stem Cells and Personalized Medicine for Gynecologic Cancers)

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17 pages, 304 KiB

Open AccessReview

Reactivation of Hepatitis B Virus in Patients with Multiple Myeloma

by Yutaka Tsukune, Makoto Sasaki and Norio Komatsu

Cancers 2019, 11(11), 1819; https://doi.org/10.3390/cancers11111819 - 19 Nov 2019

Cited by 9 | Viewed by 4517

Abstract

Reactivation of hepatitis B virus (HBV) is a well-known complication in patients with hematological malignancies during or after cytotoxic chemotherapy. If the initiation of antiviral therapy is delayed in patients with HBV reactivation, these patients can develop severe hepatitis and may die of [...] Read more.

Reactivation of hepatitis B virus (HBV) is a well-known complication in patients with hematological malignancies during or after cytotoxic chemotherapy. If the initiation of antiviral therapy is delayed in patients with HBV reactivation, these patients can develop severe hepatitis and may die of fulminant hepatitis. The preventive strategy for HBV reactivation in patients with malignant lymphoma has already been established based on some prospective studies. As there was an increased number of novel agents being approved for the treatment of multiple myeloma (MM), the number of reported cases of HBV reactivation among MM patients has gradually increased. We conducted a Japanese nationwide retrospective study and revealed that HBV reactivation in MM patients is not rare and that autologous stem cell transplantation is a significant risk factor. In this study, around 20% of all patients with HBV reactivation developed HBV reactivation after 2 years from the initiation of therapy, unlike malignant lymphoma. This might be due to the fact that almost all of the patients received chemotherapy for a long duration. Therefore, a new strategy for the prevention of HBV reactivation in MM patients is required. Full article

(This article belongs to the Special Issue Latest Development in Multiple Myeloma)

19 pages, 3365 KiB

Open AccessArticle

WWOX Possesses N-Terminal Cell Surface-Exposed Epitopes WWOX_7-21 and WWOX_7-11 for Signaling Cancer Growth Suppression and Prevention In Vivo

by Wan-Jen Wang, Pei-Chuan Ho, Ganesan Nagarajan, Yu-An Chen, Hsiang-Ling Kuo, Dudekula Subhan, Wan-Pei Su, Jean-Yun Chang, Chen-Yu Lu, Katarina T. Chang, Sing-Ru Lin, Ming-Hui Lee and Nan-Shan Chang

Cancers 2019, 11(11), 1818; https://doi.org/10.3390/cancers11111818 - 19 Nov 2019

Cited by 11 | Viewed by 4222

Abstract

Membrane hyaluronidase Hyal-2 supports cancer cell growth. Inhibition of Hyal-2 by specific antibody against Hyal-2 or pY216-Hyal-2 leads to cancer growth suppression and prevention in vivo. By immunoelectron microscopy, tumor suppressor WWOX is shown to be anchored, in part, in the cell membrane [...] Read more.

Membrane hyaluronidase Hyal-2 supports cancer cell growth. Inhibition of Hyal-2 by specific antibody against Hyal-2 or pY216-Hyal-2 leads to cancer growth suppression and prevention in vivo. By immunoelectron microscopy, tumor suppressor WWOX is shown to be anchored, in part, in the cell membrane by Hyal-2. Alternatively, WWOX undergoes self-polymerization and localizes in the cell membrane. Proapoptotic pY33-WWOX binds Hyal-2, and TGF-β induces internalization of the pY33-WWOX/Hyal-2 complex to the nucleus for causing cell death. In contrast, when pY33 is downregulated and pS14 upregulated in WWOX, pS14-WWOX supports cancer growth in vivo. Here, we investigated whether membrane WWOX receives extracellular signals via surface-exposed epitopes, especially at the S14 area, that signals for cancer growth suppression and prevention. By using a simulated 3-dimentional structure and generated specific antibodies, WWOX epitopes were determined at amino acid #7 to 21 and #286 to 299. Synthetic WWOX7-21 peptide, or truncation to 5-amino acid WWOX7-11, significantly suppressed and prevented the growth and metastasis of melanoma and skin cancer cells in mice. Time-lapse microscopy revealed that WWOX7-21 peptide potently enhanced the explosion and death of 4T1 breast cancer stem cell spheres by ceritinib. This is due to rapid upregulation of proapoptotic pY33-WWOX, downregulation of prosurvival pERK, prompt increases in Ca²⁺ influx, and disruption of the IkBα/WWOX/ERK prosurvival signaling. In contrast, pS14-WWOX7-21 peptide dramatically increased cancer growth in vivo and protected cancer cells from ceritinib-mediated apoptosis in vitro, due to a prolonged ERK phosphorylation. Further, specific antibody against pS14-WWOX significantly enhanced the ceritinib-induced apoptosis. Together, the N-terminal epitopes WWOX7-21 and WWOX7-11 are potent in blocking cancer growth in vivo. WWOX7-21 and WWOX7-11 peptides and pS14-WWOX antibody are of therapeutic values in suppressing and preventing cancer growth in vivo. Full article

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17 pages, 1175 KiB

Open AccessReview

Biological Functions of the ING Proteins

by Arthur Dantas, Buthaina Al Shueili, Yang Yang, Arash Nabbi, Dieter Fink and Karl Riabowol

Cancers 2019, 11(11), 1817; https://doi.org/10.3390/cancers11111817 - 19 Nov 2019

Cited by 36 | Viewed by 5170

Abstract

The proteins belonging to the inhibitor of growth (ING) family of proteins serve as epigenetic readers of the H3K4Me3 histone mark of active gene transcription and target histone acetyltransferase (HAT) or histone deacetylase (HDAC) protein complexes, in order to alter local chromatin structure. [...] Read more.

The proteins belonging to the inhibitor of growth (ING) family of proteins serve as epigenetic readers of the H3K4Me3 histone mark of active gene transcription and target histone acetyltransferase (HAT) or histone deacetylase (HDAC) protein complexes, in order to alter local chromatin structure. These multidomain adaptor proteins interact with numerous other proteins to facilitate their localization and the regulation of numerous biochemical pathways that impinge upon biological functions. Knockout of some of the ING genes in murine models by various groups has verified their status as tumor suppressors, with ING1 knockout resulting in the formation of large clear-cell B-lymphomas and ING2 knockout increasing the frequency of ameloblastomas, among other phenotypic effects. ING4 knockout strongly affects innate immunity and angiogenesis, and INGs1, ING2, and ING4 have been reported to affect apoptosis in different cellular models. Although ING3 and ING5 knockouts have yet to be published, preliminary reports indicate that ING3 knockout results in embryonic lethality and that ING5 knockout may have postpartum effects on stem cell maintenance. In this review, we compile the known information on the domains of the INGs and the effects of altering ING protein expression, to better understand the functions of this adaptor protein family and its possible uses for targeted cancer therapy. Full article

(This article belongs to the Special Issue Inhibitor of Growth (ING) Genes)

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22 pages, 3112 KiB

Open AccessArticle

Repeated Fractions of X-Radiation to the Breast Fat Pads of Mice Augment Activation of the Autotaxin-Lysophosphatidate-Inflammatory Cycle

by Guanmin Meng, Melinda Wuest, Xiaoyun Tang, Jennifer Dufour, YuanYuan Zhao, Jonathan M. Curtis, Todd P. W. McMullen, David Murray, Frank Wuest and David N. Brindley

Cancers 2019, 11(11), 1816; https://doi.org/10.3390/cancers11111816 - 19 Nov 2019

Cited by 16 | Viewed by 3463

Abstract

Breast cancer patients are usually treated with multiple fractions of radiotherapy (RT) to the whole breast after lumpectomy. We hypothesized that repeated fractions of RT would progressively activate the autotaxin–lysophosphatidate-inflammatory cycle. To test this, a normal breast fat pad and a fat pad [...] Read more.

Breast cancer patients are usually treated with multiple fractions of radiotherapy (RT) to the whole breast after lumpectomy. We hypothesized that repeated fractions of RT would progressively activate the autotaxin–lysophosphatidate-inflammatory cycle. To test this, a normal breast fat pad and a fat pad containing a mouse 4T1 tumor were irradiated with X-rays using a small-animal “image-guided” RT platform. A single RT dose of 7.5 Gy and three daily doses of 7.5 Gy increased ATX activity and decreased plasma adiponectin concentrations. The concentrations of IL-6 and TNFα in plasma and of VEGF, G-CSF, CCL11 and CXCL10 in the irradiated fat pad were increased, but only after three fractions of RT. In 4T1 breast tumor-bearing mice, three fractions of 7.5 Gy augmented tumor-induced increases in plasma ATX activity and decreased adiponectin levels in the tumor-associated mammary fat pad. There were also increased expressions of multiple inflammatory mediators in the tumor-associated mammary fat pad and in tumors, which was accompanied by increased infiltration of CD45+ leukocytes into tumor-associated adipose tissue. This work provides novel evidence that increased ATX production is an early response to RT and that repeated fractions of RT activate the autotaxin–lysophosphatidate-inflammatory cycle. This wound healing response to RT-induced damage could decrease the efficacy of further fractions of RT. Full article

(This article belongs to the Special Issue Lysophosphatidic Acid Signalling in Cancer)

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17 pages, 1351 KiB

Open AccessReview

Nucleocytoplasmic Shuttling of STATs. A Target for Intervention?

by Sabrina Ernst and Gerhard Müller-Newen

Cancers 2019, 11(11), 1815; https://doi.org/10.3390/cancers11111815 - 19 Nov 2019

Cited by 13 | Viewed by 4673

Abstract

Signal transducer and activator of transcription (STAT) proteins are transcription factors that in the latent state are located predominantly in the cytoplasm. Activation of STATs through phosphorylation of a single tyrosine residue results in nuclear translocation. The requirement of tyrosine phosphorylation for nuclear [...] Read more.

Signal transducer and activator of transcription (STAT) proteins are transcription factors that in the latent state are located predominantly in the cytoplasm. Activation of STATs through phosphorylation of a single tyrosine residue results in nuclear translocation. The requirement of tyrosine phosphorylation for nuclear accumulation is shared by all STAT family members but mechanisms of nuclear translocation vary between different STATs. These differences offer opportunities for specific intervention. To achieve this, the molecular mechanisms of nucleocytoplasmic shuttling of STATs need to be understood in more detail. In this review we will give an overview on the various aspects of nucleocytoplasmic shuttling of latent and activated STATs with a special focus on STAT3 and STAT5. Potential targets for cancer treatment will be identified and discussed. Full article

(This article belongs to the Special Issue Targeting STAT3 and STAT5 in Cancer)

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14 pages, 2799 KiB

Open AccessArticle

A Novel Calcium-Mediated EMT Pathway Controlled by Lipids: An Opportunity for Prostate Cancer Adjuvant Therapy

by Sandy Figiel, Fanny Bery, Aurélie Chantôme, Delphine Fontaine, Côme Pasqualin, Véronique Maupoil, Isabelle Domingo, Roseline Guibon, Franck Bruyère, Marie Potier-Cartereau, Christophe Vandier, Gaëlle Fromont and Karine Mahéo

Cancers 2019, 11(11), 1814; https://doi.org/10.3390/cancers11111814 - 18 Nov 2019

Cited by 26 | Viewed by 4230

Abstract

The composition of periprostatic adipose tissue (PPAT) has been shown to play a role in prostate cancer (PCa) progression. We recently reported an inverse association between PCa aggressiveness and elevated PPAT linoleic acid (LA) and eicosapentaenoic acid (EPA) content. In the present study, [...] Read more.

The composition of periprostatic adipose tissue (PPAT) has been shown to play a role in prostate cancer (PCa) progression. We recently reported an inverse association between PCa aggressiveness and elevated PPAT linoleic acid (LA) and eicosapentaenoic acid (EPA) content. In the present study, we identified a new signaling pathway with a positive feedback loop between the epithelial-to-mesenchymal transition (EMT) transcription factor Zeb1 and the Ca²⁺-activated K⁺ channel SK3, which leads to an amplification of Ca²⁺ entry and cellular migration. Using in vitro experiments and ex vivo cultures of human PCa slices, we demonstrated that LA and EPA exert anticancer effects, by modulating Ca²⁺ entry, which was involved in Zeb1 regulation and cancer cellular migration. This functional approach using human prostate tumors highlights the clinical relevance of our observations, and may allow us to consider the possibility of targeting cancer spread by altering the lipid microenvironment. Full article

(This article belongs to the Special Issue Targeting Calcium Signaling in Cancer Cells)

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12 pages, 1721 KiB

Open AccessArticle

Evaluation of the Accuracy of Liquid-Based Oral Brush Cytology in Screening for Oral Squamous Cell Carcinoma

by Lena Deuerling, Kristin Gaida, Heinrich Neumann and Torsten W. Remmerbach

Cancers 2019, 11(11), 1813; https://doi.org/10.3390/cancers11111813 - 18 Nov 2019

Cited by 22 | Viewed by 7617

Abstract

This study evaluates the accuracy of the results of liquid-based oral brush cytology and compares it to the histology and/or the clinical follow-ups of the respective patients. A total of 1352 exfoliated specimens were collected with an Orcellex brush from an identical number [...] Read more.

This study evaluates the accuracy of the results of liquid-based oral brush cytology and compares it to the histology and/or the clinical follow-ups of the respective patients. A total of 1352 exfoliated specimens were collected with an Orcellex brush from an identical number of oral lesions, then cytological diagnoses were made using liquid-based cytology. The final diagnoses in the study were 105 histologically proven squamous cell carcinomas (SCCs), 744 potentially malignant lesions and 503 cases of traumatic, inflammatory or benign hyperplastic oral lesions. The sensitivity and specificity of the liquid-based brush biopsy were 95.6% (95% CI 94.5–96.7%) and 84.9% (95% CI 83.0–86.8%), respectively. This led to the conclusion that brush biopsy is potentially a highly sensitive and reliable method to make cytological diagnoses of oral neoplasia. The main advantage of a brush biopsy over a scalpel biopsy is that it is less invasive and is more tolerated by the patients. Therefore, more lesions can be screened and more cancers can be detected at an early stage. Full article

(This article belongs to the Special Issue Cytologic Features of Tumor)

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21 pages, 3671 KiB

Open AccessArticle

Synergistic Autophagy Effect of miR-212-3p in Zoledronic Acid-Treated In Vitro and Orthotopic In Vivo Models and in Patient-Derived Osteosarcoma Cells

by Ju Yeon Oh, Eun Ho Kim, Yeon-Joo Lee, Sei Sai, Sun Ha Lim, Jang Woo Park, Hye Kyung Chung, Joon Kim, Guillaume Vares, Akihisa Takahashi, Youn Kyoung Jeong, Mi-Sook Kim and Chang-Bae Kong

Cancers 2019, 11(11), 1812; https://doi.org/10.3390/cancers11111812 - 18 Nov 2019

Cited by 13 | Viewed by 3900 | Correction

Abstract

Osteosarcoma (OS) originates from osteoid bone tissues and is prone to metastasis, resulting in a high mortality rate. Although several treatments are available for OS, an effective cure does not exist for most patients with advanced OS. Zoledronic acid (ZOL) is a third-generation [...] Read more.

Osteosarcoma (OS) originates from osteoid bone tissues and is prone to metastasis, resulting in a high mortality rate. Although several treatments are available for OS, an effective cure does not exist for most patients with advanced OS. Zoledronic acid (ZOL) is a third-generation bisphosphonate that inhibits osteoclast-mediated bone resorption and has shown efficacy in treating bone metastases in patients with various types of solid tumors. Here, we sought to clarify the mechanisms through which ZOL inhibits OS cell proliferation. ZOL treatment inhibited OS cell proliferation, viability, and colony formation. Autophagy inhibition by RNA interference against Beclin-1 or ATG5 inhibited ZOL-induced OS cell death. ZOL induced autophagy by repressing the protein kinase B/mammalian target of rapamycin/p70S6 kinase pathway and extracellular signal-regulated kinase signaling-dependent autophagy in OS cell lines and patient-derived OS cells. Microarrays of miRNA showed that ZOL increased the levels of miR-212-3p, which is known to play an important role in autophagy, in OS in vitro and in vivo systems. Collectively, our data provided mechanistic insight into how increased miR-212-3p through ZOL treatment induces autophagy synergistically in OS cells, providing a preclinical rationale for conducting a broad-scale clinical evaluation of ZOL + miR-212-3p in treating OS. Full article

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20 pages, 1457 KiB

Open AccessArticle

Mitigating Effect of 1-Palmitoyl-2-Linoleoyl-3-Acetyl-Rac-Glycerol (PLAG) on a Murine Model of 5-Fluorouracil-Induced Hematological Toxicity

by Jinseon Jeong, Yong-Jae Kim, Do Young Lee, Ki-Young Sohn, Sun Young Yoon and Jae Wha Kim

Cancers 2019, 11(11), 1811; https://doi.org/10.3390/cancers11111811 - 18 Nov 2019

Cited by 8 | Viewed by 3537

Abstract

5-Fluorouracil (5-FU) is an antimetabolite chemotherapy widely used for the treatment of various cancers. However, many cancer patients experience hematological side effects following 5-FU treatment. Here, we investigated the protective effects of 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) as a mitigator against 5-FU-induced hematologic toxicity, including neutropenia, [...] Read more.

5-Fluorouracil (5-FU) is an antimetabolite chemotherapy widely used for the treatment of various cancers. However, many cancer patients experience hematological side effects following 5-FU treatment. Here, we investigated the protective effects of 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) as a mitigator against 5-FU-induced hematologic toxicity, including neutropenia, monocytopenia, thrombocytopenia, and thrombocytosis, in Balb/c mice injected with 5-FU (100 mg/kg, i.p.). Administration of PLAG significantly and dose-dependently reduced the duration of neutropenia and improved the nadirs of absolute neutrophil counts (ANCs). Moreover, while the ANCs of all mice in the control fell to the severely neutropenic range, none of the mice in the PLAG 200 and 400 mg/kg-treated groups experienced severe neutropenia. Administration of PLAG significantly delayed the mean first day of monocytopenia and reduced the duration of monocytopenia. PLAG also effectively reduced extreme changes in platelet counts induced by 5-FU treatment, thus preventing 5-FU-induced thrombocytopenia and thrombocytosis. PLAG significantly decreased plasma levels of the chemokine (C–X–C motif) ligand 1 (CXCL1), CXCL2, interleukin (IL)-6, and C-reactive protein (CRP), which were elevated consistently with the occurrence time of neutropenia, monocytopenia, and thrombocytopenia. When compared with olive oil and palmitic linoleic hydroxyl glycerol (PLH), only PLAG effectively mitigated 5-FU-induced hematological toxicity, indicating that it has a distinctive mechanism of action. In conclusion, PLAG may have therapeutic potential as a mitigator for 5-FU-induced neutropenia and other hematological disorders. Full article

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19 pages, 5878 KiB

Open AccessArticle

The Gasdermin E Gene Has Potential as a Pan-Cancer Biomarker, While Discriminating between Different Tumor Types

by Joe Ibrahim, Ken Op de Beeck, Erik Fransen, Marc Peeters and Guy Van Camp

Cancers 2019, 11(11), 1810; https://doi.org/10.3390/cancers11111810 - 18 Nov 2019

Cited by 28 | Viewed by 4673

Abstract

Due to the elevated rates of incidence and mortality of cancer, early and accurate detection is crucial for achieving optimal treatment. Molecular biomarkers remain important screening and detection tools, especially in light of novel blood-based assays. DNA methylation in cancer has been linked [...] Read more.

Due to the elevated rates of incidence and mortality of cancer, early and accurate detection is crucial for achieving optimal treatment. Molecular biomarkers remain important screening and detection tools, especially in light of novel blood-based assays. DNA methylation in cancer has been linked to tumorigenesis, but its value as a biomarker has not been fully explored. In this study, we have investigated the methylation patterns of the Gasdermin E gene across 14 different tumor types using The Cancer Genome Atlas (TCGA) methylation data (N = 6502). We were able to identify six CpG sites that could effectively distinguish tumors from normal samples in a pan-cancer setting (AUC = 0.86). This combination of pan-cancer biomarkers was validated in six independent datasets (AUC = 0.84–0.97). Moreover, we tested 74,613 different combinations of six CpG probes, where we identified tumor-specific signatures that could differentiate one tumor type versus all the others (AUC = 0.79–0.98). In all, methylation patterns exhibited great variation between cancer and normal tissues, but were also tumor specific. Our analyses highlight that a Gasdermin E methylation biomarker assay, not only has the potential for being a methylation-specific pan-cancer detection marker, but it also possesses the capacity to discriminate between different types of tumors. Full article

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

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21 pages, 583 KiB

Open AccessReview

Bulk and Single-Cell Next-Generation Sequencing: Individualizing Treatment for Colorectal Cancer

by Ioannis D. Kyrochristos, Demosthenes E. Ziogas, Anna Goussia, Georgios K. Glantzounis and Dimitrios H. Roukos

Cancers 2019, 11(11), 1809; https://doi.org/10.3390/cancers11111809 - 18 Nov 2019

Cited by 18 | Viewed by 5960

Abstract

The increasing incidence combined with constant rates of early diagnosis and mortality of colorectal cancer (CRC) over the past decade worldwide, as well as minor overall survival improvements in the industrialized world, suggest the need to shift from conventional research and clinical practice [...] Read more.

The increasing incidence combined with constant rates of early diagnosis and mortality of colorectal cancer (CRC) over the past decade worldwide, as well as minor overall survival improvements in the industrialized world, suggest the need to shift from conventional research and clinical practice to the innovative development of screening, predictive and therapeutic tools. Explosive integration of next-generation sequencing (NGS) systems into basic, translational and, more recently, basket trials is transforming biomedical and cancer research, aiming for substantial clinical implementation as well. Shifting from inter-patient tumor variability to the precise characterization of intra-tumor genetic, genomic and transcriptional heterogeneity (ITH) via multi-regional bulk tissue NGS and emerging single-cell transcriptomics, coupled with NGS of circulating cell-free DNA (cfDNA), unravels novel strategies for therapeutic response prediction and drug development. Remarkably, underway and future genomic/transcriptomic studies and trials exploring spatiotemporal clonal evolution represent most rational expectations to discover novel prognostic, predictive and therapeutic tools. This review describes latest advancements and future perspectives of integrated sequencing systems for genome and transcriptome exploration to overcome unmet research and clinical challenges towards Precision Oncology. Full article

(This article belongs to the Special Issue Application of Next-Generation Sequencing in Cancers)

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10 pages, 1880 KiB

Open AccessArticle

hENT1 Testing in Pancreatic Ductal Adenocarcinoma: Are We Ready? A Multimodal Evaluation of hENT1 Status

by Jerome Raffenne, Remy Nicolle, Francesco Puleo, Delphine Le Corre, Camille Boyez, Raphael Marechal, Jean François Emile, Peter Demetter, Armelle Bardier, Pierre Laurent-Puig, Louis de Mestier, Valerie Paradis, Anne Couvelard, Jean Luc VanLathem, John R. MacKey, Jean-Baptiste Bachet, Magali Svrcek and Jerome Cros

Cancers 2019, 11(11), 1808; https://doi.org/10.3390/cancers11111808 - 18 Nov 2019

Cited by 26 | Viewed by 3377

Abstract

Gemcitabine is still one of the standard chemotherapy regimens for pancreatic ductal adenocarcinoma (PDAC). Gemcitabine uptake into tumor cells is mainly through the human equilibrative nucleoside transport 1 (hENT1). It was therefore proposed as a potential predictive biomarker of gemcitabine efficacy but reports [...] Read more.

Gemcitabine is still one of the standard chemotherapy regimens for pancreatic ductal adenocarcinoma (PDAC). Gemcitabine uptake into tumor cells is mainly through the human equilibrative nucleoside transport 1 (hENT1). It was therefore proposed as a potential predictive biomarker of gemcitabine efficacy but reports are conflicting, with an important heterogeneity in methods to assess hENT1 expression. A multicenter cohort of 471 patients with a resected PDAC was used to assess simultaneously the predictive value of the 2 best described hENT1 antibodies (10D7G2 and SP120). Three additional antibodies and the predictive value of hENT1 mRNA were also tested on 251 and 302 patients, respectively. hENT1 expression was assessed in 54 patients with matched primary tumors and metastases samples. The 10D7G2 clone was the only hENT1 antibody whose high expression was associated with a prolonged progression free survival and overall survival in patients who received adjuvant gemcitabine. hENT1 mRNA level was also predictive of gemcitabine benefit. hENT1 status was concordant in 83% of the cases with the best concordance in synchronous metastases. The 10D7G2 clone has the best predictive value of gemcitabine benefit in PDAC patients. Since it is not commercially available, hENT1 mRNA level could represent an alternative to assess hENT1 status. Full article

(This article belongs to the Special Issue Molecular Biomarkers and Precision Medicine for Pancreatic, Liver and Biliary Tract Cancers)

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13 pages, 6099 KiB

Open AccessArticle

Sensitive and Specific Detection of Ewing Sarcoma Minimal Residual Disease in Ovarian and Testicular Tissues in an In Vitro Model

by Laure Chaput, Victoria Grèze, Pascale Halle, Nina Radosevic-Robin, Bruno Pereira, Lauren Véronèse, Hervé Lejeune, Philippe Durand, Guillaume Martin, Sandra Sanfilippo, Michel Canis, Justyna Kanold, Andrei Tchirkov and Florence Brugnon

Cancers 2019, 11(11), 1807; https://doi.org/10.3390/cancers11111807 - 17 Nov 2019

Cited by 5 | Viewed by 3147

Abstract

Ewing sarcoma (EWS) is a common pediatric solid tumor with high metastatic potential. Due to toxic effects of treatments on reproductive functions, the cryopreservation of ovarian tissue (OT) or testicular tissue (TT) is recommended to preserve fertility. However, the risk of reintroducing residual [...] Read more.

Ewing sarcoma (EWS) is a common pediatric solid tumor with high metastatic potential. Due to toxic effects of treatments on reproductive functions, the cryopreservation of ovarian tissue (OT) or testicular tissue (TT) is recommended to preserve fertility. However, the risk of reintroducing residual metastatic tumor cells should be evaluated before fertility restoration. Our goal was to validate a sensitive and specific approach for EWS minimal residual disease (MRD) detection in frozen germinal tissues. Thawed OT (n = 12) and TT (n = 14) were contaminated with tumor RD-ES cells (10, 100, and 1000 cells) and EWS-FLI1 tumor-specific transcript was quantified with RT-qPCR. All contaminated samples were found to be positive, with a strong correlation between RD-ES cell numbers and EWS-FLI1 levels in OT (r = 0.93) and TT (r = 0.96) (p < 0.001). No transcript was detected in uncontaminated control samples. The invasive potential of Ewing cells was evaluated using co-culture techniques. After co-culturing, tumor cells were detected in OT/TT with histology, FISH, and RT-qPCR. In addition, four OT and four TT samples from children with metastatic EWS were tested, and no MRD was found using RT-qPCR and histology. We demonstrated the high sensitivity and specificity of RT-qPCR to detect EWS MRD in OT/TT samples. Clinical trial: NCT 02400970. Full article

(This article belongs to the Special Issue Ewing Sarcoma)

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12 pages, 1688 KiB

Open AccessArticle

Complex Formation with Monomeric α-Tubulin and Importin 13 Fosters c-Jun Protein Stability and Is Required for c-Jun’s Nuclear Translocation and Activity

by Melanie Kappelmann-Fenzl, Silke Kuphal, Rosemarie Krupar, Dirk Schadendorf, Viktor Umansky, Lily Vardimon, Claus Hellerbrand and Anja-Katrin Bosserhoff

Cancers 2019, 11(11), 1806; https://doi.org/10.3390/cancers11111806 - 17 Nov 2019

Cited by 6 | Viewed by 4384

Abstract

Microtubules are highly dynamic structures, which consist of α- and β-tubulin heterodimers. They are essential for a number of cellular processes, including intracellular trafficking and mitosis. Tubulin-binding chemotherapeutics are used to treat different types of tumors, including malignant melanoma. The transcription factor c-Jun [...] Read more.

Microtubules are highly dynamic structures, which consist of α- and β-tubulin heterodimers. They are essential for a number of cellular processes, including intracellular trafficking and mitosis. Tubulin-binding chemotherapeutics are used to treat different types of tumors, including malignant melanoma. The transcription factor c-Jun is a central driver of melanoma development and progression. Here, we identify the microtubule network as a main regulator of c-Jun activity. Monomeric α-tubulin fosters c-Jun protein stability by protein–protein interaction. In addition, this complex formation is necessary for c-Jun’s nuclear localization sequence binding to importin 13, and consequent nuclear import and activity of c-Jun. A reduction in monomeric α-tubulin levels by treatment with the chemotherapeutic paclitaxel resulted in a decline in the nuclear accumulation of c-Jun in melanoma cells in an experimental murine model and in patients’ tissues. These findings add important knowledge to the mechanism of the action of microtubule-targeting drugs and indicate the newly discovered regulation of c-Jun by the microtubule cytoskeleton as a novel therapeutic target for melanoma and potentially also other types of cancer. Full article

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15 pages, 3082 KiB

Open AccessArticle

Imaging Collagen Alterations in STICs and High Grade Ovarian Cancers in the Fallopian Tubes by Second Harmonic Generation Microscopy

by Eric C. Rentchler, Kristal L. Gant, Ronny Drapkin, Manish Patankar and Paul J. Campagnola

Cancers 2019, 11(11), 1805; https://doi.org/10.3390/cancers11111805 - 16 Nov 2019

Cited by 22 | Viewed by 4506

Abstract

The majority of high-grade serous ovarian cancers originate in the fallopian tubes, however, the corresponding structural changes in the extracellular matrix (ECM) have not been well-characterized. This information could provide new insight into the carcinogenesis and provide the basis for new diagnostic tools. [...] Read more.

The majority of high-grade serous ovarian cancers originate in the fallopian tubes, however, the corresponding structural changes in the extracellular matrix (ECM) have not been well-characterized. This information could provide new insight into the carcinogenesis and provide the basis for new diagnostic tools. We have previously used the collagen-specific Second Harmonic Generation (SHG) microscopy to probe collagen fiber alterations in high-grade serous ovarian cancer and in other ovarian tumors, and showed they could be uniquely identified by machine learning approaches. Here we couple SHG imaging of serous tubal intra-epithelial carcinomas (STICs), high-grade cancers, and normal regions of the fallopian tubes, using three distinct image analysis approaches to form a classification scheme based on the respective collagen fiber morphology. Using a linear discriminant analysis, we achieved near 100% classification accuracy between high-grade disease and the other tissues, where the STICs and normal regions were differentiated with ~75% accuracy. Importantly, the collagen in high-grade disease in both the fallopian tube and the ovary itself have a similar collagen morphology, further substantiating the metastasis between these sites. This analysis provides a new method of classification, but also quantifies the structural changes in the disease, which may provide new insight into metastasis. Full article

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

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16 pages, 1580 KiB

Open AccessArticle

Penetrance of the TP53 R337H Mutation and Pediatric Adrenocortical Carcinoma Incidence Associated with Environmental Influences in a 12-Year Observational Cohort in Southern Brazil

by Tatiana E. J. Costa, Viviane K. Q. Gerber, Humberto C. Ibañez, Viviane S. Melanda, Ivy Z. S. Parise, Flora M. Watanabe, Mara A. D. Pianovski, Carmem M. C. M. Fiori, Ana L. M. R. Fabro, Denise B. da Silva, Diancarlos P. Andrade, Heloisa Komechen, Monalisa C. Mendes, Edna Carboni, Ana Paula Kuczynski, Emanuelle N. Souza, Mariana M. Paraizo, Marilea V. C. Ibañez, Laura M. Castilho, Amanda F. Cruz, Thuila F. da Maia, Cleber Machado-Souza, Roberto Rosati, Claudia S. Oliveira, Guilherme A. Parise, Jaqueline D. C. Passos, José R. S. Barbosa, Mirna M. O. Figueiredo, Leniza Lima, Tiago Tormen, Cesar C. Sabbaga, Sylvio G. A. Ávilla, Leila Grisa, Airton Aranha, Karina C. F. Tosin, Karin R. P. Ogradowski, Geneci Lima, Edith F. Legal, Tania H. Anegawa, Tânia L. Mazzuco, André L. Grion, José H. G. Balbinotti, Karin L. Dammski, Rosiane G. Melo, Nilton Kiesel Filho, Gislaine Custódio and Bonald C. Figueiredo Show full author list Hide full author list

Cancers 2019, 11(11), 1804; https://doi.org/10.3390/cancers11111804 - 16 Nov 2019

Cited by 19 | Viewed by 4734

Abstract

The TP53 R337H mutation is associated with increased incidence of pediatric adrenocortical tumor (ACT). The different environmental conditions where R337H carriers live have not been systematically analyzed. Here, the R337H frequencies, ACT incidences, and R337H penetrance for ACT were calculated using the 2006 [...] Read more.

The TP53 R337H mutation is associated with increased incidence of pediatric adrenocortical tumor (ACT). The different environmental conditions where R337H carriers live have not been systematically analyzed. Here, the R337H frequencies, ACT incidences, and R337H penetrance for ACT were calculated using the 2006 cohort with 4165 R337H carriers living in Paraná state (PR) subregions. The effectiveness of a second surveillance for R337H probands selected from 42,438 tested newborns in PR (2016 cohort) was tested to detect early stage I tumor among educated families without periodical exams. Estimation of R337H frequencies and ACT incidence in Santa Catarina state (SC) used data from 50,115 tested newborns without surveillance, ACT cases from a SC hospital, and a public cancer registry. R337H carrier frequencies in the population were 0.245% (SC) and 0.306% (PR), and 87% and 95% in ACTs, respectively. The ACT incidence was calculated as ~6.4/million children younger than 10 years per year in PR (95% CI: 5.28; 7.65) and 4.15/million in SC (CI 95%: 2.95; 5.67). The ACT penetrance in PR for probands followed from birth to 12 years was 3.9%. R337H carriers living in an agricultural subregion (C1) had a lower risk of developing pediatric ACT than those living in industrial and large urban subregion (relative risk = 2.4). One small ACT (21g) without recurrence (1/112) was detected by the parents in the 2016 cohort. ACT incidence follows R337H frequency in each population, but remarkably environmental factors modify these rates. Full article

(This article belongs to the Special Issue Adrenocortical Carcinoma)

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17 pages, 1730 KiB

Open AccessReview

CD147 Is a Promising Target of Tumor Progression and a Prognostic Biomarker

by Alexandra Landras, Coralie Reger de Moura, Fanelie Jouenne, Celeste Lebbe, Suzanne Menashi and Samia Mourah

Cancers 2019, 11(11), 1803; https://doi.org/10.3390/cancers11111803 - 16 Nov 2019

Cited by 102 | Viewed by 11504

Abstract

Microenvironment plays a crucial role in tumor development and progression. Cancer cells modulate the tumor microenvironment, which also contribute to resistance to therapy. Identifying biomarkers involved in tumorigenesis and cancer progression represents a great challenge for cancer diagnosis and therapeutic strategy development. CD147 [...] Read more.

Microenvironment plays a crucial role in tumor development and progression. Cancer cells modulate the tumor microenvironment, which also contribute to resistance to therapy. Identifying biomarkers involved in tumorigenesis and cancer progression represents a great challenge for cancer diagnosis and therapeutic strategy development. CD147 is a glycoprotein involved in the regulation of the tumor microenvironment and cancer progression by several mechanisms—in particular, by the control of glycolysis and also by its well-known ability to induce proteinases leading to matrix degradation, tumor cell invasion, metastasis and angiogenesis. Accumulating evidence has demonstrated the role of CD147 expression in tumor progression and prognosis, suggesting it as a relevant tumor biomarker for cancer diagnosis and prognosis, as well as validating its potential as a promising therapeutic target in cancers. Full article

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

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28 pages, 871 KiB

Open AccessReview

Long Non-Coding RNA: Dual Effects on Breast Cancer Metastasis and Clinical Applications

by Qi-Yuan Huang, Guo-Feng Liu, Xian-Ling Qian, Li-Bo Tang, Qing-Yun Huang and Li-Xia Xiong

Cancers 2019, 11(11), 1802; https://doi.org/10.3390/cancers11111802 - 16 Nov 2019

Cited by 47 | Viewed by 5501

Abstract

As a highly heterogeneous malignancy, breast cancer (BC) has become the most significant threat to female health. Distant metastasis and therapy resistance of BC are responsible for most of the cases of mortality and recurrence. Distant metastasis relies on an array of processes, [...] Read more.

As a highly heterogeneous malignancy, breast cancer (BC) has become the most significant threat to female health. Distant metastasis and therapy resistance of BC are responsible for most of the cases of mortality and recurrence. Distant metastasis relies on an array of processes, such as cell proliferation, epithelial-to-mesenchymal transition (EMT), mesenchymal-to-epithelial transition (MET), and angiogenesis. Long non-coding RNA (lncRNA) refers to a class of non-coding RNA with a length of over 200 nucleotides. Currently, a rising number of studies have managed to investigate the association between BC and lncRNA. In this study, we summarized how lncRNA has dual effects in BC metastasis by regulating invasion, migration, and distant metastasis of BC cells. We also emphasize that lncRNA has crucial regulatory effects in the stemness and angiogenesis of BC. Clinically, some lncRNAs can regulate chemotherapy sensitivity in BC patients and may function as novel biomarkers to diagnose or predict prognosis for BC patients. The exact impact on clinical relevance deserves further study. This review can be an approach to understanding the dual effects of lncRNAs in BC, thereby linking lncRNAs to quasi-personalized treatment in the future. Full article

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17 pages, 275 KiB

Open AccessArticle

Efficacy of Cancer Immunotherapy: An Umbrella Review of Meta-Analyses of Randomized Controlled Trials

by Jong Yeob Kim, Keum Hwa Lee, Michael Eisenhut, Hans J. van der Vliet, Andreas Kronbichler, Gwang Hun Jeong, Jae Il Shin and Gabriele Gamerith

Cancers 2019, 11(11), 1801; https://doi.org/10.3390/cancers11111801 - 15 Nov 2019

Cited by 20 | Viewed by 4976

Abstract

We conducted a systematic review for evidence of the clinical efficacy of cancer immunotherapies. We searched PubMed from inception to 14 February 2018 for meta-analyses of randomized controlled trials (RCTs) of cancer immunotherapies. Re-analyses were performed to estimate the summary effect size under [...] Read more.

We conducted a systematic review for evidence of the clinical efficacy of cancer immunotherapies. We searched PubMed from inception to 14 February 2018 for meta-analyses of randomized controlled trials (RCTs) of cancer immunotherapies. Re-analyses were performed to estimate the summary effect size under random-effects, the 95% confidence interval (CI), heterogeneity, and the 95% prediction interval, and we determined the strength of the evidence. We examined publication bias and excess significance bias. 63 articles corresponding to 247 meta-analyses were eligible. Nine meta-analyses were classified to have convincing evidence, and 75 were classified as suggestive evidence. The clinical benefit of immunotherapy was supported by convincing evidence in the following settings: anti-PD-1/PD-L1 monoclonal antibody (mAb) therapy for treating advanced melanoma and non-small cell lung cancer (NSCLC), the combination of rituximab and chemotherapy for treating chronic lymphocytic leukemia and B-cell non-Hodgkin’s lymphoma, adoptive cell immunotherapy for NSCLC, and the combination of interferon α and chemotherapy for metastatic melanoma. A further meta-analysis of 16 RCTs showed that anti-PD-1/PD-L1 mAb therapy had a benefit in patients with solid tumors (overall survival; hazard ratio = 0.73, 95% CI: 0.68–0.79; p < 0.001), supported by convincing evidence. In the future, rigorous approaches are needed when interpreting meta-analyses to gain better insight into the true efficacy of cancer immunotherapy. Full article

16 pages, 9975 KiB

Open AccessReview

Mouse Models for Immunotherapy in Hepatocellular Carcinoma

by Enya Li, Li Lin, Chia-Wei Chen and Da-Liang Ou

Cancers 2019, 11(11), 1800; https://doi.org/10.3390/cancers11111800 - 15 Nov 2019

Cited by 27 | Viewed by 15447

Abstract

Liver cancer is one of the dominant causes of cancer-related mortality, and the survival rate of liver cancer is among the lowest for all cancers. Immunotherapy for hepatocellular carcinoma (HCC) has yielded some encouraging results, but the percentage of patients responding to single-agent [...] Read more.

Liver cancer is one of the dominant causes of cancer-related mortality, and the survival rate of liver cancer is among the lowest for all cancers. Immunotherapy for hepatocellular carcinoma (HCC) has yielded some encouraging results, but the percentage of patients responding to single-agent therapies remains low. Therefore, potential directions for improved immunotherapies include identifying new immune targets and checkpoints and customizing treatment procedures for individual patients. The development of combination therapies for HCC is also crucial and urgent and, thus, further studies are required. Mice have been utilized in immunotherapy research due to several advantages, for example, being low in cost, having high success rates for inducing tumor growth, and so on. Moreover, immune-competent mice are used in immunotherapy research to clarify the role that the immune system plays in cancer growth. In this review paper, the advantages and disadvantages of mouse models for immunotherapy, the equipment that are used for monitoring HCC, and the cell strains used for inducing HCC are reviewed. Full article

(This article belongs to the Special Issue Models of Experimental Liver Cancer)

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23 pages, 3598 KiB

Open AccessArticle

Blocking Activin Receptor Ligands Is Not Sufficient to Rescue Cancer-Associated Gut Microbiota—A Role for Gut Microbial Flagellin in Colorectal Cancer and Cachexia?

by Satu Pekkala, Anniina Keskitalo, Emilia Kettunen, Sanna Lensu, Noora Nykänen, Teijo Kuopio, Olli Ritvos, Jaakko Hentilä, Tuuli A. Nissinen and Juha J. Hulmi

Cancers 2019, 11(11), 1799; https://doi.org/10.3390/cancers11111799 - 15 Nov 2019

Cited by 12 | Viewed by 4923

Abstract

Colorectal cancer (CRC) and cachexia are associated with the gut microbiota and microbial surface molecules. We characterized the CRC-associated microbiota and investigated whether cachexia affects the microbiota composition. Further, we examined the possible relationship between the microbial surface molecule flagellin and CRC. CRC [...] Read more.

Colorectal cancer (CRC) and cachexia are associated with the gut microbiota and microbial surface molecules. We characterized the CRC-associated microbiota and investigated whether cachexia affects the microbiota composition. Further, we examined the possible relationship between the microbial surface molecule flagellin and CRC. CRC cells (C26) were inoculated into mice. Activin receptor (ACVR) ligands were blocked, either before tumor formation or before and after, to increase muscle mass and prevent muscle loss. The effects of flagellin on C26-cells were studied in vitro. The occurrence of similar phenomena were studied in murine and human tumors. Cancer modulated the gut microbiota without consistent effects of blocking the ACVR ligands. However, continued treatment for muscle loss modified the association between microbiota and weight loss. Several abundant microbial taxa in cancer were flagellated. Exposure of C26-cells to flagellin increased IL6 and CCL2/MCP-1 mRNA and IL6 excretion. Murine C26 tumors expressed more IL6 and CCL2/MCP-1 mRNA than C26-cells, and human CRC tumors expressed more CCL2/MCP-1 than healthy colon sites. Additionally, flagellin decreased caspase-1 activity and the production of reactive oxygen species, and increased cytotoxicity in C26-cells. Conditioned media from flagellin-treated C26-cells deteriorated C2C12-myotubes and decreased their number. In conclusion, cancer increased flagellated microbes that may promote CRC survival and cachexia by inducing inflammatory proteins such as MCP-1. Cancer-associated gut microbiota could not be rescued by blocking ACVR ligands. Full article

(This article belongs to the Special Issue Cancer Cachexia)

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21 pages, 2065 KiB

Open AccessArticle

Tumor Mutational Burden and Efficacy of Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis

by Jong Yeob Kim, Andreas Kronbichler, Michael Eisenhut, Sung Hwi Hong, Hans J. van der Vliet, Jeonghyun Kang, Jae Il Shin and Gabriele Gamerith

Cancers 2019, 11(11), 1798; https://doi.org/10.3390/cancers11111798 - 15 Nov 2019

Cited by 114 | Viewed by 6785

Abstract

Tumor mutational burden (TMB) is a genomic biomarker that predicts favorable responses to immune checkpoint inhibitors (ICIs). Here, we set out to assess the predictive value of TMB on long-term survival outcomes in patients undergoing ICIs. We systematically searched PubMed, Embase, CENTRAL and [...] Read more.

Tumor mutational burden (TMB) is a genomic biomarker that predicts favorable responses to immune checkpoint inhibitors (ICIs). Here, we set out to assess the predictive value of TMB on long-term survival outcomes in patients undergoing ICIs. We systematically searched PubMed, Embase, CENTRAL and clinicaltrials.gov from inception to 6 August 2019. We included retrospective studies or clinical trials of ICIs that reported hazard ratios (HRs) for overall survival (OS) and/or progression-free survival (PFS) according to TMB. Data on 5712 patients from 26 studies were included. Among patients who received ICIs, high TMB groups showed better OS (HR 0.53, 95% CI 0.42 to 0.67) and PFS (HR 0.52, 95% CI 0.40 to 0.67) compared to low TMB groups. In patients with high TMB, those who received ICIs had a better OS (HR 0.69, 95% CI 0.50 to 0.95) and PFS (HR = 0.66, 95% CI = 0.47 to 0.92) compared to those who received chemotherapy alone, while in patients with low TMB, such ICI benefits of OS or PFS were not statistically significant. In conclusion, TMB may be an effective biomarker to predict survival in patients undergoing ICI treatment. The role of TMB in identifying patient groups who may benefit from ICIs should be determined in future randomized controlled trials. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

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19 pages, 2869 KiB

Open AccessArticle

G-Quadruplex Binders Induce Immunogenic Cell Death Markers in Aggressive Breast Cancer Cells

by Sarah Di Somma, Jussara Amato, Nunzia Iaccarino, Bruno Pagano, Antonio Randazzo, Giuseppe Portella and Anna Maria Malfitano

Cancers 2019, 11(11), 1797; https://doi.org/10.3390/cancers11111797 - 15 Nov 2019

Cited by 24 | Viewed by 4562

Abstract

Background: DNA G-quadruplex (G4) structures represent potential anti-cancer targets. In this study, we compared the effect of two G4-targeting compounds, C066-3108 and the gold standard BRACO-19. Methods: In breast and prostate cancer cells, cytotoxicity induced by both molecules was measured by a sulforhodamine [...] Read more.

Background: DNA G-quadruplex (G4) structures represent potential anti-cancer targets. In this study, we compared the effect of two G4-targeting compounds, C066-3108 and the gold standard BRACO-19. Methods: In breast and prostate cancer cells, cytotoxicity induced by both molecules was measured by a sulforhodamine B assay. In breast cancer cells, cycle, apoptosis, the formation of G4 structures, calreticulin and high mobility group box 1 (HMGB1), as well as T cell activation, were analyzed by flow cytometry and adenosine triphosphate (ATP) by luminescence. Results: Both ligands inhibited cell survival and induced DNA damage. In MCF-7 cells, G4 ligands increased the subG0/G1 phase of the cell cycle inducing apoptosis and reduced intracellular ATP. In untreated MCF-7 cells, we observed a slight presence of G4 structures associated with the G2/M phase. In MDA-MB231 cells, G4 ligands decreased the G1 and enhanced the G2/M phase. We observed a decrease of intracellular ATP, calreticulin cell surface exposure and an increase of HMGB1, accompanied by T cell activation. Both compounds induced G4 structure formation in the subG0/G1 phase. Conclusions: Our data report similar effects for both compounds and the first evidence that G4 ligands induce the release of danger signals associated with immunogenic cell death and induction of T cell activation. Full article

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9 pages, 10853 KiB

Open AccessArticle

Non-Invasive Targeted Hepatic Irradiation and SPECT/CT Functional Imaging to Study Radiation-Induced Liver Damage in Small Animal Models

by Rafi Kabarriti, N. Patrik Brodin, Hillary Yaffe, Mark Barahman, Wade R. Koba, Laibin Liu, Patrik Asp, Wolfgang A. Tomé and Chandan Guha

Cancers 2019, 11(11), 1796; https://doi.org/10.3390/cancers11111796 - 15 Nov 2019

Cited by 6 | Viewed by 3392

Abstract

Radiation therapy (RT) has traditionally not been widely used in the management of hepatic malignancies for fear of toxicity in the form of radiation-induced liver disease (RILD). Pre-clinical hepatic irradiation models can provide clinicians with better understanding of the radiation tolerance of the [...] Read more.

Radiation therapy (RT) has traditionally not been widely used in the management of hepatic malignancies for fear of toxicity in the form of radiation-induced liver disease (RILD). Pre-clinical hepatic irradiation models can provide clinicians with better understanding of the radiation tolerance of the liver, which in turn may lead to the development of more effective cancer treatments. Previous models of hepatic irradiation are limited by either invasive laparotomy procedures, or the need to irradiate the whole or large parts of the liver using external skin markers. In the setting of modern-day radiation oncology, a truly translational animal model would require the ability to deliver RT to specific parts of the liver, through non-invasive image guidance methods. To this end, we developed a targeted hepatic irradiation model on the Small Animal Radiation Research Platform (SARRP) using contrast-enhanced cone-beam computed tomography image guidance. Using this model, we showed evidence of the early development of region-specific RILD through functional single photon emission computed tomography (SPECT) imaging. Full article

(This article belongs to the Special Issue Animal Models for Radiotherapy Research)

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18 pages, 3838 KiB

Open AccessArticle

Emodin Inhibits EBV Reactivation and Represses NPC Tumorigenesis

by Chung-Chun Wu, Mei-Shu Chen, Yu-Jhen Cheng, Ying-Chieh Ko, Su-Fang Lin, Ing-Ming Chiu and Jen-Yang Chen

Cancers 2019, 11(11), 1795; https://doi.org/10.3390/cancers11111795 - 15 Nov 2019

Cited by 25 | Viewed by 4332

Abstract

Nasopharyngeal carcinoma (NPC) is a unique malignancy derived from the epithelium of the nasopharynx. Despite great advances in the development of radiotherapy and chemotherapy, relapse and metastasis in NPC patients remain major causes of mortality. Evidence accumulated over recent years indicates that Epstein-Barr [...] Read more.

Nasopharyngeal carcinoma (NPC) is a unique malignancy derived from the epithelium of the nasopharynx. Despite great advances in the development of radiotherapy and chemotherapy, relapse and metastasis in NPC patients remain major causes of mortality. Evidence accumulated over recent years indicates that Epstein-Barr virus (EBV) lytic replication plays an important role in the pathogenesis of NPC and inhibition of EBV reactivation is now being considered as a goal for the therapy of EBV-associated cancers. With this in mind, a panel of dietary compounds was screened and emodin was found to have potential anti-EBV activity. Through Western blotting, immunofluorescence, and flow cytometric analysis, we show that emodin inhibits the expression of EBV lytic proteins and blocks virion production in EBV- positive epithelial cell lines. In investigating the underlying mechanism, reporter assays indicated that emodin represses Zta promoter (Zp) and Rta promoter (Rp) activities, triggered by various inducers. Mapping of the Zp construct reveals that the SP1 binding region is important for emodin-triggered repression and emodin is shown to be able to inhibit SP1 expression, suggesting that it likely inhibits EBV reactivation by suppression of SP1 expression. Moreover, we also show that emodin inhibits the tumorigenic properties induced by repeated EBV reactivation, including micronucleus formation, cell proliferation, migration, and matrigel invasiveness. Emodin administration also represses the tumor growth in mice which is induced by EBV activation. Taken together, our results provide a potential chemopreventive agent in restricting EBV reactivation and NPC recurrence. Full article

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24 pages, 956 KiB

Open AccessReview

HDAC Inhibitors in Acute Myeloid Leukemia

by Edurne San José-Enériz, Naroa Gimenez-Camino, Xabier Agirre and Felipe Prosper

Cancers 2019, 11(11), 1794; https://doi.org/10.3390/cancers11111794 - 14 Nov 2019

Cited by 144 | Viewed by 14942

Abstract

Acute myeloid leukemia (AML) is a hematological malignancy characterized by uncontrolled proliferation, differentiation arrest, and accumulation of immature myeloid progenitors. Although clinical advances in AML have been made, especially in young patients, long-term disease-free survival remains poor, making this disease an unmet therapeutic [...] Read more.

Acute myeloid leukemia (AML) is a hematological malignancy characterized by uncontrolled proliferation, differentiation arrest, and accumulation of immature myeloid progenitors. Although clinical advances in AML have been made, especially in young patients, long-term disease-free survival remains poor, making this disease an unmet therapeutic challenge. Epigenetic alterations and mutations in epigenetic regulators contribute to the pathogenesis of AML, supporting the rationale for the use of epigenetic drugs in patients with AML. While hypomethylating agents have already been approved in AML, the use of other epigenetic inhibitors, such as histone deacetylases (HDAC) inhibitors (HDACi), is under clinical development. HDACi such as Panobinostat, Vorinostat, and Tricostatin A have been shown to promote cell death, autophagy, apoptosis, or growth arrest in preclinical AML models, yet these inhibitors do not seem to be effective as monotherapies, but rather in combination with other drugs. In this review, we discuss the rationale for the use of different HDACi in patients with AML, the results of preclinical studies, and the results obtained in clinical trials. Although so far the results with HDACi in clinical trials in AML have been modest, there are some encouraging data from treatment with the HDACi Pracinostat in combination with DNA demethylating agents. Full article

(This article belongs to the Special Issue Epigenetic Dysregulation in Cancer: From Mechanism to Therapy)

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30 pages, 857 KiB

Open AccessReview

Proteostasis in the Endoplasmic Reticulum: Road to Cure

by Su Min Nam and Young Joo Jeon

Cancers 2019, 11(11), 1793; https://doi.org/10.3390/cancers11111793 - 14 Nov 2019

Cited by 31 | Viewed by 5974

Abstract

The endoplasmic reticulum (ER) is an interconnected organelle that is responsible for the biosynthesis, folding, maturation, stabilization, and trafficking of transmembrane and secretory proteins. Therefore, cells evolve protein quality-control equipment of the ER to ensure protein homeostasis, also termed proteostasis. However, disruption in [...] Read more.

The endoplasmic reticulum (ER) is an interconnected organelle that is responsible for the biosynthesis, folding, maturation, stabilization, and trafficking of transmembrane and secretory proteins. Therefore, cells evolve protein quality-control equipment of the ER to ensure protein homeostasis, also termed proteostasis. However, disruption in the folding capacity of the ER caused by a large variety of pathophysiological insults leads to the accumulation of unfolded or misfolded proteins in this organelle, known as ER stress. Upon ER stress, unfolded protein response (UPR) of the ER is activated, integrates ER stress signals, and transduces the integrated signals to relive ER stress, thereby leading to the re-establishment of proteostasis. Intriguingly, severe and persistent ER stress and the subsequently sustained unfolded protein response (UPR) are closely associated with tumor development, angiogenesis, aggressiveness, immunosuppression, and therapeutic response of cancer. Additionally, the UPR interconnects various processes in and around the tumor microenvironment. Therefore, it has begun to be delineated that pharmacologically and genetically manipulating strategies directed to target the UPR of the ER might exhibit positive clinical outcome in cancer. In the present review, we summarize recent advances in our understanding of the UPR of the ER and the UPR of the ER–mitochondria interconnection. We also highlight new insights into how the UPR of the ER in response to pathophysiological perturbations is implicated in the pathogenesis of cancer. We provide the concept to target the UPR of the ER, eventually discussing the potential of therapeutic interventions for targeting the UPR of the ER for cancer treatment. Full article

(This article belongs to the Special Issue Therapeutic Targeting of the Unfolded Protein Response in Cancer)

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15 pages, 584 KiB

Open AccessFeature PaperReview

Animal Models of Hepatocellular Carcinoma Prevention

by Ram C. Shankaraiah, Laura Gramantieri, Francesca Fornari, Silvia Sabbioni, Elisa Callegari and Massimo Negrini

Cancers 2019, 11(11), 1792; https://doi.org/10.3390/cancers11111792 - 14 Nov 2019

Cited by 11 | Viewed by 4868

Abstract

Hepatocellular carcinoma (HCC) is a deadly disease and therapeutic efficacy in advanced HCC is limited. Since progression of chronic liver disease to HCC involves a long latency period of a few decades, a significant window of therapeutic opportunities exists for prevention of HCC [...] Read more.

Hepatocellular carcinoma (HCC) is a deadly disease and therapeutic efficacy in advanced HCC is limited. Since progression of chronic liver disease to HCC involves a long latency period of a few decades, a significant window of therapeutic opportunities exists for prevention of HCC and improve patient prognosis. Nonetheless, there has been no clinical advancement in instituting HCC chemopreventive strategies. Some of the major challenges are heterogenous genetic aberrations of HCC, significant modulation of tumor microenvironment and incomplete understanding of HCC tumorigenesis. To this end, animal models of HCC are valuable tools to evaluate biology of tumor initiation and progression with specific insight into molecular and genetic mechanisms involved. In this review, we describe various animal models of HCC that facilitate effective ways to study therapeutic prevention strategies that have translational potential to be evaluated in a clinical context. Full article

(This article belongs to the Special Issue Models of Experimental Liver Cancer)

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20 pages, 663 KiB

Open AccessReview

Breast Cancer in Young Women: Status Quo and Advanced Disease Management by a Predictive, Preventive, and Personalized Approach

by Erik Kudela, Marek Samec, Peter Kubatka, Marcela Nachajova, Zuzana Laucekova, Alena Liskova, Karol Dokus, Kamil Biringer, Denisa Simova, Eva Gabonova, Zuzana Dankova, Kristina Biskupska Bodova, Pavol Zubor and Daniela Trog

Cancers 2019, 11(11), 1791; https://doi.org/10.3390/cancers11111791 - 14 Nov 2019

Cited by 37 | Viewed by 7124

Abstract

Why does healthcare of breast cancer (BC) patients, especially in a young population, matter and why are innovative strategies by predictive, preventive, and personalized medicine (PPPM) strongly recommended to replace current reactive medical approach in BC management? Permanent increase in annual numbers of [...] Read more.

Why does healthcare of breast cancer (BC) patients, especially in a young population, matter and why are innovative strategies by predictive, preventive, and personalized medicine (PPPM) strongly recommended to replace current reactive medical approach in BC management? Permanent increase in annual numbers of new BC cases with particularly quick growth of premenopausal BC patients, an absence of clearly described risk factors for those patients, as well as established screening tools and programs represent important reasons to focus on BC in young women. Moreover, "young" BC cases are frequently "asymptomatic", difficult to diagnose, and to treat effectively on time. The objective of this article is to update the knowledge on BC in young females, its unique molecular signature, newest concepts in diagnostics and therapy, and to highlight the concepts of predictive, preventive, and personalized medicine with a well-acknowledged potential to advance the overall disease management. Full article

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