Cancers

10 pages, 1578 KiB

Open AccessArticle

Prognostic Biomarkers in Pancreatic Cancer: Avoiding Errata When Using the TCGA Dataset

by Remy Nicolle, Jerome Raffenne, Valerie Paradis, Anne Couvelard, Aurelien de Reynies, Yuna Blum and Jerome Cros

Cancers 2019, 11(1), 126; https://doi.org/10.3390/cancers11010126 - 21 Jan 2019

Cited by 25 | Viewed by 7355

Abstract

Data from the Cancer Genome Atlas (TCGA) are now easily accessible through web-based platforms with tools to assess the prognostic value of molecular alterations. Pancreatic tumors have heterogeneous biology and aggressiveness ranging from the deadly adenocarcinoma (PDAC) to the better prognosis, neuroendocrine tumors. [...] Read more.

Data from the Cancer Genome Atlas (TCGA) are now easily accessible through web-based platforms with tools to assess the prognostic value of molecular alterations. Pancreatic tumors have heterogeneous biology and aggressiveness ranging from the deadly adenocarcinoma (PDAC) to the better prognosis, neuroendocrine tumors. We assessed the availability of the pancreatic cancer TCGA data (TCGA_PAAD) from several repositories and investigated the nature of each sample and how non-PDAC samples impact prognostic biomarker studies. While the clinical and genomic data (n = 185) were fairly consistent across all repositories, RNAseq profiles varied from 176 to 185. As a result, 35 RNAseq profiles (18.9%) corresponded to a normal, inflamed pancreas or non-PDAC neoplasms. This information was difficult to obtain. By considering gene expression data as continuous values, the expression of the 5312 and 4221 genes were significantly associated with the progression-free and overall survival respectively. Considering the cohort was not curated, only 4 and 14, respectively, had prognostic value in the PDAC-only cohort. Similarly, mutations in key genes or well-described miRNA lost their prognostic significance in the PDAC-only cohort. Therefore, we propose a web-based application to assess biomarkers in the curated TCGA_PAAD dataset. In conclusion, TCGA_PAAD curation is critical to avoid important biological and clinical biases from non-PDAC samples. Full article

(This article belongs to the Special Issue Application of Bioinformatics in Cancers)

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12 pages, 1548 KiB

Open AccessArticle

Influence of Vitamin D in Advanced Non-Small Cell Lung Cancer Patients Treated with Nivolumab

by Jessica Cusato, Carlo Genova, Cristina Tomasello, Paolo Carrega, Selene Ottonello, Gabriella Pietra, Maria Cristina Mingari, Irene Cossu, Erika Rijavec, Anna Leggieri, Giovanni Di Perri, Maria Giovanna Dal Bello, Simona Coco, Simona Boccardo, Guido Ferlazzo, Francesco Grossi and Antonio D’Avolio

Cancers 2019, 11(1), 125; https://doi.org/10.3390/cancers11010125 - 21 Jan 2019

Cited by 12 | Viewed by 5048

Abstract

Nivolumab is one of the most commonly used monoclonal antibodies for advanced non-small cell lung cancer treatment, to the extent that the presence of its anti-antibody is considered a negative prognostic factor. Vitamin D (VD) modulates expression of the genes involved in drug [...] Read more.

Nivolumab is one of the most commonly used monoclonal antibodies for advanced non-small cell lung cancer treatment, to the extent that the presence of its anti-antibody is considered a negative prognostic factor. Vitamin D (VD) modulates expression of the genes involved in drug metabolism and elimination. Immune system regulation and immunodeficiency is frequent in non-small cell lung cancer patients. To date, no data have been reported about the relationship between nivolumab and VD. The aim of this study was to quantify plasma 25-hydroxyVD (25-VD) and 1,25-VD, nivolumab, and its anti-antibody before starting treatment (baseline) and at 15, 45 and 60 days of therapy. VD-pathway-associated gene single nucleotide polymorphisms (SNPs) were also evaluated. Molecules were quantified through enzyme-linked immunosorbent assay, and SNPs through real-time PCR. Forty-five patients were enrolled. Median nivolumab concentrations were 12.5 μg/mL, 22.3 μg/mL and 27.1 μg/mL at 15, 45 and 60 days respectively. No anti-nivolumab antibodies were found. Correlations were observed between nivolumab concentrations and 25-VD levels. Nivolumab concentrations were affected by VD-pathway-related gene SNPs. VDBP AC/CC genotype and baseline 25-VD < 10 ng/mL predicted a nivolumab concentration cut-off value of <18.7 μg/mL at 15 days, which was associated with tumor progression. This is the first study showing VD marker predictors of nivolumab concentrations in a real-life context of non-small cell lung cancer treatment. 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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9 pages, 1025 KiB

Open AccessArticle

Detection of TP53 Mutations in Tissue or Liquid Rebiopsies at Progression Identifies ALK+ Lung Cancer Patients with Poor Survival

by Petros Christopoulos, Steffen Dietz, Martina Kirchner, Anna-Lena Volckmar, Volker Endris, Olaf Neumann, Simon Ogrodnik, Claus-Peter Heussel, Felix J. Herth, Martin Eichhorn, Michael Meister, Jan Budczies, Michael Allgäuer, Jonas Leichsenring, Tomasz Zemojtel, Helge Bischoff, Peter Schirmacher, Michael Thomas, Holger Sültmann and Albrecht Stenzinger

Cancers 2019, 11(1), 124; https://doi.org/10.3390/cancers11010124 - 21 Jan 2019

Cited by 36 | Viewed by 5692

Abstract

Anaplastic lymphoma kinase (ALK) sequencing can identify resistance mechanisms and guide next-line therapy in ALK+ non-small-cell lung cancer (NSCLC), but the clinical significance of other rebiopsy findings remains unclear. We analysed all stage-IV ALK+ NSCLC patients with longitudinally assessable TP53 status treated in [...] Read more.

Anaplastic lymphoma kinase (ALK) sequencing can identify resistance mechanisms and guide next-line therapy in ALK+ non-small-cell lung cancer (NSCLC), but the clinical significance of other rebiopsy findings remains unclear. We analysed all stage-IV ALK+ NSCLC patients with longitudinally assessable TP53 status treated in our institutions (n = 62). Patients with TP53 mutations at baseline (TP53mutbas, n = 23) had worse overall survival (OS) than patients with initially wild-type tumours (TP53wtbas, n = 39, 44 vs. 62 months in median, p = 0.018). Within the generally favourable TP53wtbas group, detection of TP53 mutations at progression defined a “converted” subgroup (TP53mutconv, n = 9) with inferior OS, similar to that of TP53mutbas and shorter than that of patients remaining TP53 wild-type (TP53wtprogr, 45 vs. 94 months, p = 0.043). Progression-free survival (PFS) under treatment with tyrosine kinase inhibitors (TKI) for TP53mutconv was comparable to that of TP53mutbas and also shorter than that of TP53wtprogr cases (5 and 8 vs. 13 months, p = 0.0039). Fewer TP53wtprogr than TP53mutbas or TP53mutconv cases presented with metastatic disease at diagnosis (67% vs. 91% or 100%, p < 0.05). Thus, acquisition of TP53 mutations at progression is associated with more aggressive disease, shorter TKI responses and inferior OS in ALK+ NSCLC, comparable to primary TP53 mutated cases. Full article

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17 pages, 3257 KiB

Open AccessArticle

PKA at a Cross-Road of Signaling Pathways Involved in the Regulation of Glioblastoma Migration and Invasion by the Neuropeptides VIP and PACAP

by Souheyla Bensalma, Soumaya Turpault, Annie-Claire Balandre, Madryssa De Boisvilliers, Afsaneh Gaillard, Corinne Chadéneau and Jean-Marc Muller

Cancers 2019, 11(1), 123; https://doi.org/10.3390/cancers11010123 - 21 Jan 2019

Cited by 13 | Viewed by 4720

Abstract

Glioblastoma (GBM) remains an incurable disease, mainly due to the high migration and invasion potency of GBM cells inside the brain. PI3K/Akt, Sonic Hedgehog (SHH), and PKA pathways play major regulatory roles in the progression of GBM. The vasoactive intestinal peptide (VIP) family [...] Read more.

Glioblastoma (GBM) remains an incurable disease, mainly due to the high migration and invasion potency of GBM cells inside the brain. PI3K/Akt, Sonic Hedgehog (SHH), and PKA pathways play major regulatory roles in the progression of GBM. The vasoactive intestinal peptide (VIP) family of neuropeptides and their receptors, referred in this article as the “VIP-receptor system”, has been reported to regulate proliferation, differentiation, and migration in a number of tumor cell types and more particularly in GBM cells. These neuropeptides are potent activators of the cAMP/PKA pathway. The present study aimed to investigate the cross-talks between the above cited signaling cascades. Regulation by VIP-related neuropeptides of GBM migration and invasion was evaluated ex vivo in rat brain slices explanted in culture. Effects of different combinations of VIP-related neuropeptides and of pharmacological and siRNA inhibitors of PKA, Akt, and of the SHH/GLI1 pathways were tested on GBM migration rat C6 and human U87 GBM cell lines using the wound-healing technique. Quantification of nuclear GLI1, phospho-Akt, and phospho-PTEN was assessed by western-immunoblotting. The VIP-receptor system agonists VIP and PACAP-38 significantly reduced C6 cells invasion in the rat brain parenchyma ex vivo, and C6 and U87 migration in vitro. A VIP-receptor system antagonist, VIP_10-28 increased C6 cell invasion in the rat brain parenchyma ex vivo, and C6 and migration in vitro. These effects on cell migration were abolished by selective inhibitors of the PI3K/Akt and of the SHH pathways. Furthermore, VIP and PACAP-38 reduced the expression of nuclear GLI1 while VIP_10-28 increased this expression. Selective inhibitors of Akt and PKA abolished VIP, PACAP-38, and VIP_10-28 effects on nuclear GLI1 expression in C6 cells. PACAP-38 induced a time-dependent inhibition of phospho-Akt expression and an increased phosphorylation of PTEN in C6 cells. All together, these data indicate that triggering the VIP-receptor system reduces migration and invasion in GBM cells through a PKA-dependent blockade of the PI3K/Akt and of the SHH/GLI1 pathways. Therefore, the VIP-receptor system displays anti-oncogenic properties in GBM cells and PKA is a central core in this process. Full article

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

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17 pages, 1680 KiB

Open AccessArticle

Location-Dependent Patient Outcome and Recurrence Patterns in IDH1-Wildtype Glioblastoma

by Christine Jungk, Rolf Warta, Andreas Mock, Sara Friauf, Bettina Hug, David Capper, Amir Abdollahi, Jürgen Debus, Martin Bendszus, Andreas von Deimling, Andreas Unterberg and Christel Herold-Mende

Cancers 2019, 11(1), 122; https://doi.org/10.3390/cancers11010122 - 21 Jan 2019

Cited by 25 | Viewed by 4557

Abstract

Recent studies suggest that glioblastomas (GBMs) contacting the subventricular zone (SVZ) as the main adult neurogenic niche confer a dismal prognosis but disregard the unique molecular and prognostic phenotype associated with isocitrate dehydrogenase 1 (IDH1) mutations. We therefore examined location-dependent prognostic factors, growth, [...] Read more.

Recent studies suggest that glioblastomas (GBMs) contacting the subventricular zone (SVZ) as the main adult neurogenic niche confer a dismal prognosis but disregard the unique molecular and prognostic phenotype associated with isocitrate dehydrogenase 1 (IDH1) mutations. We therefore examined location-dependent prognostic factors, growth, and recurrence patterns in a consecutive cohort of 285 IDH1-wildtype GBMs. Based on pre-operative contrast-enhanced MRI, patients were allotted to four location-dependent groups with (SVZ+; groups I, II) and without (SVZ−; groups III, IV) SVZ involvement or with (cortex+; groups I, III) and without (cortex−; groups II, IV) cortical involvement and compared for demographic, treatment, imaging, and survival data at first diagnosis and recurrence. SVZ involvement was associated with lower Karnofsky performance score (p < 0.001), lower frequency of complete resections at first diagnosis (p < 0.0001), and lower non-surgical treatment intensity at recurrence (p < 0.001). Multivariate survival analysis employing a Cox proportional hazards model identified SVZ involvement as an independent prognosticator of inferior overall survival (p < 0.001) and survival after relapse (p = 0.041). In contrast, multifocal growth at first diagnosis (p = 0.031) and recurrence (p < 0.001), as well as distant recurrences (p < 0.0001), was more frequent in cortex+ GBMs. These findings offer the prospect for location-tailored prognostication and treatment based on factors assessable on pre-operative MRI. Full article

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

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12 pages, 2355 KiB

Open AccessArticle

The Oncogene Addiction Switch from NOTCH to PI3K Requires Simultaneous Targeting of NOTCH and PI3K Pathway Inhibition in Glioblastoma

by Norihiko Saito, Nozomi Hirai, Kazuya Aoki, Ryo Suzuki, Satoshi Fujita, Haruo Nakayama, Morito Hayashi, Keisuke Ito, Takatoshi Sakurai and Satoshi Iwabuchi

Cancers 2019, 11(1), 121; https://doi.org/10.3390/cancers11010121 - 20 Jan 2019

Cited by 15 | Viewed by 4715

Abstract

The NOTCH pathway regulates neural stem cells and glioma initiating cells (GICs). However, blocking NOTCH activity with γ-secretase inhibitors (GSIs) fails to alter the growth of GICs, as GSIs seem to be active in only a fraction of GICs lines with constitutive NOTCH [...] Read more.

The NOTCH pathway regulates neural stem cells and glioma initiating cells (GICs). However, blocking NOTCH activity with γ-secretase inhibitors (GSIs) fails to alter the growth of GICs, as GSIs seem to be active in only a fraction of GICs lines with constitutive NOTCH activity. Here we report loss of PTEN function as a critical event leading to resistance to NOTCH inhibition, which causes the transfer of oncogene addiction from the NOTCH pathway to the PI3K pathway. Drug cytotoxicity testing of eight GICs showed a differential growth response to GSI, and the GICs were thus stratified into two groups: sensitive and resistant. In the sensitive group, GICs with loss of PTEN function appeared less sensitive to GSI treatment. Here we show that NOTCH regulates PTEN expression and the activity of the PI3K pathway in GICs, as treatment with GSI attenuated the NOTCH pathway and increased PTEN expression. NOTCH regulates PTEN expression via Hes-1, as knockdown of Notch or Hes1 increased expression of PTEN. This novel observation suggests that both pathways must be simultaneously inhibited in order to improve therapeutic efficacy in human glioblastomas (GBMs). Full article

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

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17 pages, 1213 KiB

Open AccessArticle

Combination of Different Fecal Immunochemical Tests in Colorectal Cancer Screening: Any Gain in Diagnostic Performance?

by Anton Gies, Katarina Cuk, Petra Schrotz-King and Hermann Brenner

Cancers 2019, 11(1), 120; https://doi.org/10.3390/cancers11010120 - 20 Jan 2019

Cited by 4 | Viewed by 4082

Abstract

A variety of fecal immunochemical tests (FITs) are used for colorectal cancer screening. FIT performance could be improved further. It is unclear, whether the combination of different FITs with different analytical characteristics (such as, different antibodies for the detection of fecal hemoglobin) can [...] Read more.

A variety of fecal immunochemical tests (FITs) are used for colorectal cancer screening. FIT performance could be improved further. It is unclear, whether the combination of different FITs with different analytical characteristics (such as, different antibodies for the detection of fecal hemoglobin) can yield a better diagnostic performance. Fecal samples were obtained from 2042 participants of screening colonoscopy. All participants with advanced neoplasm (AN, colorectal cancer (n = 16) or advanced adenoma (n = 200)) and 300 randomly selected participants without AN were included. Nine quantitative FITs were evaluated simultaneously. Sensitivity and specificity was calculated for single tests (n = 9) and for their pairwise test combinations (n = 36) (requiring either both FITs (P++) or at least one FIT (P+) to be positive for defining a positive test result). Mean age of the participants (n = 516) was 63 (range: 50–79) years and 56% were men. At cutoffs yielding a specificity of 96.7% for single FITs, the median gain in specificity by P++ combination was +1.0%, whereas the median loss in sensitivity for AN was −4.2%. For P+ combination the median gain in sensitivity for AN was +2.8%, at a prize of median loss of −1.0% of specificity. Combinations of different FITs do not yield any relevant gain in diagnostic performance. Full article

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15 pages, 630 KiB

Open AccessEditor’s ChoiceReview

Platinum Resistance in Ovarian Cancer: Role of DNA Repair

by Giovanna Damia and Massimo Broggini

Cancers 2019, 11(1), 119; https://doi.org/10.3390/cancers11010119 - 20 Jan 2019

Cited by 190 | Viewed by 12320

Abstract

Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer. It is initially responsive to cisplatin and carboplatin, two DNA damaging agents used in first line therapy. However, almost invariably, patients relapse with a tumor resistant to subsequent treatment with platinum containing drugs. [...] Read more.

Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer. It is initially responsive to cisplatin and carboplatin, two DNA damaging agents used in first line therapy. However, almost invariably, patients relapse with a tumor resistant to subsequent treatment with platinum containing drugs. Several mechanisms associated with the development of acquired drug resistance have been reported. Here we focused our attention on DNA repair mechanisms, which are fundamental for recognition and removal of platinum adducts and hence for the ability of these drugs to exert their activity. We analyzed the major DNA repair pathways potentially involved in drug resistance, detailing gene mutation, duplication or deletion as well as polymorphisms as potential biomarkers for drug resistance development. We dissected potential ways to overcome DNA repair-associated drug resistance thanks to the development of new combinations and/or drugs directly targeting DNA repair proteins or taking advantage of the vulnerability arising from DNA repair defects in EOCs. Full article

(This article belongs to the Special Issue Cancer Chemoresistance)

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19 pages, 1513 KiB

Open AccessArticle

Oral Administration of Fermented Papaya (FPP^®) Controls the Growth of a Murine Melanoma through the In Vivo Induction of a Natural Antioxidant Response

by Mariantonia Logozzi, Davide Mizzoni, Rossella Di Raimo, Daniele Macchia, Massimo Spada and Stefano Fais

Cancers 2019, 11(1), 118; https://doi.org/10.3390/cancers11010118 - 20 Jan 2019

Cited by 7 | Viewed by 4468

Abstract

Prolonged oxidative stress may play a key role in tumor development. Antioxidant molecules are contained in many foods and seem to have a potential role in future anti-tumor strategies. Among the natural antioxidants the beneficial effect of Fermented Papaya (FPP^®) is [...] Read more.

Prolonged oxidative stress may play a key role in tumor development. Antioxidant molecules are contained in many foods and seem to have a potential role in future anti-tumor strategies. Among the natural antioxidants the beneficial effect of Fermented Papaya (FPP^®) is well known. The aim of this study was to investigate the effects of orally administered FPP^® in either the prevention or treatment of a murine model of melanoma. The tumor growth was analyzed together with the blood levels of both oxidants (ROS) and anti-oxidants (SOD-1 and GSH). The results showed that FPP^® controlled tumor growth, reducing the tumor mass of about three to seven times vs. untreated mice. The most significant effect was obtained with sublingual administration of FPP^® close to the inoculation of melanoma. At the time of the sacrifice none of mice treated with FPP^® had metastases and the subcutaneous tumors were significantly smaller and amelanotic, compared to untreated mice. Moreover, the FPP^® anti-tumor effect was consistent with the decrease of total ROS levels and the increase in the blood levels of GSH and SOD-1. This study shows that a potent anti-oxidant treatment through FPP^® may contribute to both preventing and inhibiting tumors growth. Full article

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14 pages, 2385 KiB

Open AccessPerspective

A Barter Economy in Tumors: Exchanging Metabolites through Gap Junctions

by Pawel Swietach and Stefania Monterisi

Cancers 2019, 11(1), 117; https://doi.org/10.3390/cancers11010117 - 20 Jan 2019

Cited by 8 | Viewed by 3859

Abstract

To produce physiological functions, many tissues require their cells to be connected by gap junctions. Such diffusive coupling is important in establishing a cytoplasmic syncytium through which cells can exchange signals, substrates and metabolites. Often the benefits of connectivity become apparent solely at [...] Read more.

To produce physiological functions, many tissues require their cells to be connected by gap junctions. Such diffusive coupling is important in establishing a cytoplasmic syncytium through which cells can exchange signals, substrates and metabolites. Often the benefits of connectivity become apparent solely at the multicellular level, leading to the notion that cells work for a common good rather than exclusively in their self-interest. In some tumors, gap junctional connectivity between cancer cells is reduced or absent, but there are notable cases where it persists or re-emerges in late-stage disease. Diffusive coupling will blur certain phenotypic differences between cells, which may seem to go against the establishment of population heterogeneity, a central pillar of cancer that stems from genetic instability. Here, building on our previous measurements of gap junctional coupling between cancer cells, we use a computational model to simulate the role of connexin-assembled channels in exchanging lactate and bicarbonate ions down their diffusion gradients. Based on the results of these simulations, we propose that an overriding benefit of gap junctional connectivity may relate to lactate/bicarbonate exchange, which would support an elevated metabolic rate in hypoxic tumors. In this example of barter, hypoxic cancer cells provide normoxic neighbors with lactate for mitochondrial oxidation; in exchange, bicarbonate ions, which are more plentiful in normoxic cells, are supplied to hypoxic neighbors to neutralize the H⁺ ions co-produced glycolytically. Both cells benefit, and so does the tumor. Full article

(This article belongs to the Special Issue Gap Junctions and Connexins in Cancer Formation, Progression, and Therapy)

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8 pages, 687 KiB

Open AccessArticle

Vonoprazan-Based Third-Line Therapy Has a Higher Eradication Rate against Sitafloxacin-Resistant Helicobacter pylori

by Yoshimasa Saito, Kaho Konno, Moeka Sato, Masaru Nakano, Yukako Kato, Hidetsugu Saito and Hiroshi Serizawa

Cancers 2019, 11(1), 116; https://doi.org/10.3390/cancers11010116 - 19 Jan 2019

Cited by 26 | Viewed by 5002

Abstract

Eradication of Helicobacter pylori (H. pylori) is an effective strategy for preventing various gastrointestinal diseases such as gastric cancer and mucosa-associated lymphoid tissue (MALT) lymphoma. However, the eradication success rate is decreasing because of a recent increase in drug-resistant strains of [...] Read more.

Eradication of Helicobacter pylori (H. pylori) is an effective strategy for preventing various gastrointestinal diseases such as gastric cancer and mucosa-associated lymphoid tissue (MALT) lymphoma. However, the eradication success rate is decreasing because of a recent increase in drug-resistant strains of H. pylori. Here, we evaluated the success rate of eradication therapy with vonoprazan (VPZ), a new potassium-competitive acid blocker, against drug-resistant H. pylori. In total, 793 patients who received H. pylori eradication therapy were investigated retrospectively. All underwent esomeprazole (EPZ)-based triple therapy (n = 386) or VPZ-based triple therapy (n = 407) for first-, second- and third-line H. pylori eradication for 7 days. The overall success rates of first- and third-line H. pylori eradication were significantly higher for VPZ-based triple therapy (88.4% and 93.0%, respectively, per protocol (PP)) than for EPZ-based triple therapy (69.5% and 56.5%, respectively, PP). Moreover, the success rates of first- and third-line eradication of clarithromycin (CLR)- and sitafloxacin (STFX)-resistant H. pylori were significantly higher for VPZ-based triple therapy (72.0% and 91.7%, PP) than for EPZ-based triple therapy (38.5% and 20.0%, PP). In addition, patient age did not affect the eradication rate of VPZ-based first-line therapy, whereas the success rate of EPZ-based therapy was lower in patients under 65 years of age. Our results clearly demonstrated that VPZ-based therapy achieved a higher eradication rate even against CLR- and STFX-resistant H. pylori, and that patient age did not affect the eradication rate of VPZ-based therapy. These findings suggest that dual therapy using VPZ and amoxicillin may be sufficient for standard H. pylori eradication, and may thus also be beneficial for avoiding antibiotic misuse. Full article

(This article belongs to the Special Issue Helicobacter pylori Associated Cancer)

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18 pages, 3126 KiB

Open AccessArticle

Transfection with GLS2 Glutaminase (GAB) Sensitizes Human Glioblastoma Cell Lines to Oxidative Stress by a Common Mechanism Involving Suppression of the PI3K/AKT Pathway

by Ewelina Majewska, Javier Márquez, Jan Albrecht and Monika Szeliga

Cancers 2019, 11(1), 115; https://doi.org/10.3390/cancers11010115 - 19 Jan 2019

Cited by 16 | Viewed by 4894

Abstract

GLS-encoded glutaminase promotes tumorigenesis, while GLS2-encoded glutaminase displays tumor-suppressive properties. In glioblastoma (GBM), the most aggressive brain tumor, GLS is highly expressed and in most cases GLS2 is silenced. Previously, it was shown that transfection with a sequence encoding GAB, the [...] Read more.

GLS-encoded glutaminase promotes tumorigenesis, while GLS2-encoded glutaminase displays tumor-suppressive properties. In glioblastoma (GBM), the most aggressive brain tumor, GLS is highly expressed and in most cases GLS2 is silenced. Previously, it was shown that transfection with a sequence encoding GAB, the main GLS2 isoform, decreased the survival, growth, and ability to migrate of human GBM cells T98G and increased their sensitivity towards an alkylating agent temozolomide (TMZ) and oxidative stress compared to the controls, by a not well-defined mechanism. In this study we report that GAB transfection inhibits growth and increases susceptibility towards TMZ and H₂O₂-mediated oxidative stress of two other GBM cell lines, U87MG and LN229. We also show that in GAB-transfected cells treated with H₂O₂, the PI3K/AKT pathway is less induced compared to the pcDNA-transfected counterparts and that pretreatment with PDGF-BB, an activator of AKT, protects GAB-transfected cells from death caused by the H₂O₂ treatment. In conclusion, our results show that (i) GAB suppresses the malignant phenotype of the GBM cells of different tumorigenic potentials and genetic backgrounds and (ii) the GAB-mediated increase of sensitivity to oxidative stress is causally related to the inhibition of the PI3K/AKT pathway. The upregulation of the GLS2 expression and the inhibition of the PI3K/AKT pathway may become a novel combined therapeutic strategy for anti-glioma preclinical investigations. Full article

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13 pages, 2525 KiB

Open AccessArticle

Expression of Proteolytic Enzymes by Small Cell Lung Cancer Circulating Tumor Cell Lines

by Barbara Rath, Lukas Klameth, Adelina Plangger, Maximilian Hochmair, Ernst Ulsperger, Ihor Huk, Robert Zeillinger and Gerhard Hamilton

Cancers 2019, 11(1), 114; https://doi.org/10.3390/cancers11010114 - 19 Jan 2019

Cited by 17 | Viewed by 5371

Abstract

Small cell lung cancer (SCLC) is an aggressive type of lung cancer which disseminates vigorously and has a dismal prognosis. Metastasis of SCLC is linked to an extremely high number of circulating tumor cells (CTCs), which form chemoresistant spheroids, termed tumorospheres. Intravasation and [...] Read more.

Small cell lung cancer (SCLC) is an aggressive type of lung cancer which disseminates vigorously and has a dismal prognosis. Metastasis of SCLC is linked to an extremely high number of circulating tumor cells (CTCs), which form chemoresistant spheroids, termed tumorospheres. Intravasation and extravasation during tumor spread requires the activity of a number of proteases to disintegrate the stroma and vascular tissue. Generation of several permanent SCLC CTC lines allowed us to screen for the expression of 35 proteases using Western blot arrays. Cell culture supernatants of two CTC lines, namely BHGc7 and 10, were analyzed for secreted proteases, including matrix metalloproteinases (MMPs), ADAM/TS, cathepsins, kallikreins, and others, and compared to proteases expressed by SCLC cell lines (GLC14, GLC16, NCI-H526 and SCLC26A). In contrast to NCI-H526 and SCLC26A, MMP-9 was highly expressed in the two CTC lines and in GLC16 derived of a relapse. Furthermore, cathepsins (S, V, X/Z/P, A and D) were highly expressed in the CTC lines, whereas ADAM/TS and kallikreins were not detectable. In conclusion, SCLC CTCs express MMP-9 and a range of cathepsins for proteolysis and, aside from tissue degradation, these enzymes are involved in cell signaling, survival, and the chemoresistance of tumor cells. Full article

(This article belongs to the Special Issue Circulating Tumor Cells (CTCs))

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11 pages, 1349 KiB

Open AccessReview

Prognostic Role of High-Grade Tumor Budding in Pancreatic Ductal Adenocarcinoma: A Systematic Review and Meta-Analysis with a Focus on Epithelial to Mesenchymal Transition

by Rita T. Lawlor, Nicola Veronese, Alessia Nottegar, Giuseppe Malleo, Lee Smith, Jacopo Demurtas, Liang Cheng, Laura D. Wood, Nicola Silvestris, Roberto Salvia, Aldo Scarpa and Claudio Luchini

Cancers 2019, 11(1), 113; https://doi.org/10.3390/cancers11010113 - 19 Jan 2019

Cited by 47 | Viewed by 5618

Abstract

This study aims at clarifying the prognostic role of high-grade tumor budding (TB) in pancreatic ductal adenocarcinoma (PDAC) with the first systematic review and meta-analysis on this topic. Furthermore, we analyzed with a systematic review the relationship between TB and a recently suggested [...] Read more.

This study aims at clarifying the prognostic role of high-grade tumor budding (TB) in pancreatic ductal adenocarcinoma (PDAC) with the first systematic review and meta-analysis on this topic. Furthermore, we analyzed with a systematic review the relationship between TB and a recently suggested TB-associated mechanism: the epithelial to mesenchymal transition (EMT). Analyzing a total of 613 patients, 251 of them (40.9%) with high grade-TB, we found an increased risk of all-cause mortality (RR, 1.46; 95% CI, 1.13–1.88, p = 0.004; HR, 2.65; 95% CI, 1.79–3.91; p < 0.0001) and of recurrence (RR, 1.61; 95% CI, 1.05–2.47, p = 0.03) for PDAC patients with high-grade TB. Moreover, we found that EMT is a central process in determining the presence of TB in PDAC. Thanks to this meta-analysis, we demonstrate the potential clinical significance of high-grade TB for prognostic stratification of PDAC. TB also shows a clear association with the process of EMT. Based on the results of the present study, TB should be conveyed in pathology reports and taken into account by future oncologic staging systems. Full article

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

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23 pages, 1498 KiB

Open AccessReview

Hypoxic Radioresistance: Can ROS Be the Key to Overcome It?

by Hui Wang, Heng Jiang, Melissa Van De Gucht and Mark De Ridder

Cancers 2019, 11(1), 112; https://doi.org/10.3390/cancers11010112 - 18 Jan 2019

Cited by 110 | Viewed by 9163

Abstract

Radiotherapy is a mainstay treatment for many types of cancer and kills cancer cells via generation of reactive oxygen species (ROS). Incorporating radiation with pharmacological ROS inducers, therefore, has been widely investigated as an approach to enhance aerobic radiosensitization. However, this strategy was [...] Read more.

Radiotherapy is a mainstay treatment for many types of cancer and kills cancer cells via generation of reactive oxygen species (ROS). Incorporating radiation with pharmacological ROS inducers, therefore, has been widely investigated as an approach to enhance aerobic radiosensitization. However, this strategy was overlooked in hypoxic counterpart, one of the most important causes of radiotherapy failure, due to the notion that hypoxic cells are immune to ROS insults because of the shortage of ROS substrate oxygen. Paradoxically, evidence reveals that ROS are produced more in hypoxic than normoxic cells and serve as signaling molecules that render cells adaptive to hypoxia. As a result, hypoxic tumor cells heavily rely on antioxidant systems to sustain the ROS homeostasis. Thereby, they become sensitive to insults that impair the ROS detoxification network, which has been verified in diverse models with or without radiation. Of note, hypoxic radioresistance has been overviewed in different contexts. To the best of our knowledge, this review is the first to systemically summarize the interplay among radiation, hypoxia, and ROS, and to discuss whether perturbation of ROS homeostasis could provide a new avenue to tackle hypoxic radioresistance. Full article

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32 pages, 5628 KiB

Open AccessReview

A Review on a Deep Learning Perspective in Brain Cancer Classification

by Gopal S. Tandel, Mainak Biswas, Omprakash G. Kakde, Ashish Tiwari, Harman S. Suri, Monica Turk, John R. Laird, Christopher K. Asare, Annabel A. Ankrah, N. N. Khanna, B. K. Madhusudhan, Luca Saba and Jasjit S. Suri

Cancers 2019, 11(1), 111; https://doi.org/10.3390/cancers11010111 - 18 Jan 2019

Cited by 268 | Viewed by 20766

Abstract

A World Health Organization (WHO) Feb 2018 report has recently shown that mortality rate due to brain or central nervous system (CNS) cancer is the highest in the Asian continent. It is of critical importance that cancer be detected earlier so that many [...] Read more.

A World Health Organization (WHO) Feb 2018 report has recently shown that mortality rate due to brain or central nervous system (CNS) cancer is the highest in the Asian continent. It is of critical importance that cancer be detected earlier so that many of these lives can be saved. Cancer grading is an important aspect for targeted therapy. As cancer diagnosis is highly invasive, time consuming and expensive, there is an immediate requirement to develop a non-invasive, cost-effective and efficient tools for brain cancer characterization and grade estimation. Brain scans using magnetic resonance imaging (MRI), computed tomography (CT), as well as other imaging modalities, are fast and safer methods for tumor detection. In this paper, we tried to summarize the pathophysiology of brain cancer, imaging modalities of brain cancer and automatic computer assisted methods for brain cancer characterization in a machine and deep learning paradigm. Another objective of this paper is to find the current issues in existing engineering methods and also project a future paradigm. Further, we have highlighted the relationship between brain cancer and other brain disorders like stroke, Alzheimer’s, Parkinson’s, and Wilson’s disease, leukoriaosis, and other neurological disorders in the context of machine learning and the deep learning paradigm. Full article

(This article belongs to the Special Issue Application of Bioinformatics in Cancers)

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21 pages, 4573 KiB

Open AccessArticle

Alternating Electric Fields (TTFields) Activate Ca_v1.2 Channels in Human Glioblastoma Cells

by Eric Neuhaus, Lisa Zirjacks, Katrin Ganser, Lukas Klumpp, Uwe Schüler, Daniel Zips, Franziska Eckert and Stephan M. Huber

Cancers 2019, 11(1), 110; https://doi.org/10.3390/cancers11010110 - 18 Jan 2019

Cited by 45 | Viewed by 6748

Abstract

Tumor treating fields (TTFields) represent a novel FDA-approved treatment modality for patients with newly diagnosed or recurrent glioblastoma multiforme. This therapy applies intermediate frequency alternating electric fields with low intensity to the tumor volume by the use of non-invasive transducer electrode arrays. Mechanistically, [...] Read more.

Tumor treating fields (TTFields) represent a novel FDA-approved treatment modality for patients with newly diagnosed or recurrent glioblastoma multiforme. This therapy applies intermediate frequency alternating electric fields with low intensity to the tumor volume by the use of non-invasive transducer electrode arrays. Mechanistically, TTFields have been proposed to impair formation of the mitotic spindle apparatus and cytokinesis. In order to identify further potential molecular targets, here the effects of TTFields on Ca²⁺-signaling, ion channel activity in the plasma membrane, cell cycle, cell death, and clonogenic survival were tested in two human glioblastoma cell lines in vitro by fura-2 Ca²⁺ imaging, patch-clamp cell-attached recordings, flow cytometry and pre-plated colony formation assay. In addition, the expression of voltage-gated Ca²⁺ (Ca_v) channels was determined by real-time RT-PCR and their significance for the cellular TTFields response defined by knock-down and pharmacological blockade. As a result, TTFields stimulated in a cell line-dependent manner a Ca_v1.2-mediated Ca²⁺ entry, G₁ or S phase cell cycle arrest, breakdown of the inner mitochondrial membrane potential and DNA degradation, and/or decline of clonogenic survival suggesting a tumoricidal action of TTFields. Moreover, inhibition of Ca_v1.2 by benidipine aggravated in one glioblastoma line the TTFields effects suggesting that Ca_v1.2-triggered signaling contributes to cellular TTFields stress response. In conclusion, the present study identified Ca_v1.2 channels as TTFields target in the plasma membrane and provides the rationale to combine TTFields therapy with Ca²⁺ antagonists that are already in clinical use. Full article

(This article belongs to the Special Issue Ion Channels in Cancer)

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22 pages, 1600 KiB

Open AccessReview

Cancer-Associated Intermediate Conductance Ca²⁺-Activated K⁺ Channel K_Ca3.1

by Corinna J. Mohr, Friederike A. Steudel, Dominic Gross, Peter Ruth, Wing-Yee Lo, Reiner Hoppe, Werner Schroth, Hiltrud Brauch, Stephan M. Huber and Robert Lukowski

Cancers 2019, 11(1), 109; https://doi.org/10.3390/cancers11010109 - 17 Jan 2019

Cited by 45 | Viewed by 6725

Abstract

Several tumor entities have been reported to overexpress K_Ca3.1 potassium channels due to epigenetic, transcriptional, or post-translational modifications. By modulating membrane potential, cell volume, or Ca²⁺ signaling, K_Ca3.1 has been proposed to exert pivotal oncogenic functions in tumorigenesis, [...] Read more.

Several tumor entities have been reported to overexpress K_Ca3.1 potassium channels due to epigenetic, transcriptional, or post-translational modifications. By modulating membrane potential, cell volume, or Ca²⁺ signaling, K_Ca3.1 has been proposed to exert pivotal oncogenic functions in tumorigenesis, malignant progression, metastasis, and therapy resistance. Moreover, K_Ca3.1 is expressed by tumor-promoting stroma cells such as fibroblasts and the tumor vasculature suggesting a role of K_Ca3.1 in the adaptation of the tumor microenvironment. Combined, this features K_Ca3.1 as a candidate target for innovative anti-cancer therapy. However, immune cells also express K_Ca3.1 thereby contributing to T cell activation. Thus, any strategy targeting K_Ca3.1 in anti-cancer therapy may also modulate anti-tumor immune activity and/or immunosuppression. The present review article highlights the potential of K_Ca3.1 as an anti-tumor target providing an overview of the current knowledge on its function in tumor pathogenesis with emphasis on vasculo- and angiogenesis as well as anti-cancer immune responses. Full article

(This article belongs to the Special Issue Ion Channels in Cancer)

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12 pages, 932 KiB

Open AccessReview

Cancer Immunotherapy: Silencing Intracellular Negative Immune Regulators of Dendritic Cells

by Yao-Hua Liu, I-Jeng Yeh, Ming-Derg Lai, Kuan-Ting Liu, Po-Lin Kuo and Meng-Chi Yen

Cancers 2019, 11(1), 108; https://doi.org/10.3390/cancers11010108 - 17 Jan 2019

Cited by 4 | Viewed by 4537

Abstract

Dendritic cells (DCs) are capable of activating adaptive immune responses, or inducing immune suppression or tolerance. In the tumor microenvironment, the function of DCs is polarized into immune suppression that attenuates the effect of T cells, promoting differentiation of regulatory T cells and [...] Read more.

Dendritic cells (DCs) are capable of activating adaptive immune responses, or inducing immune suppression or tolerance. In the tumor microenvironment, the function of DCs is polarized into immune suppression that attenuates the effect of T cells, promoting differentiation of regulatory T cells and supporting tumor progression. Therefore, blocking negative immune regulators in DCs is considered a strategy of cancer immunotherapy. Antibodies can target molecules on the cell surface, but not intracellular molecules of DCs. The delivery of short-hairpin RNAs (shRNA) and small-interfering RNAs (siRNA) should be a strategy to silence specific intracellular targets in DCs. This review provides an overview of the known negative immune regulators of DCs. Moreover, a combination of shRNA/siRNA and DC vaccines, DNA vaccines in animal models, and clinical trials are also discussed. Full article

(This article belongs to the Special Issue Cancer Vaccines: Research and Applications)

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21 pages, 11989 KiB

Open AccessArticle

FOSB–PCDHB13 Axis Disrupts the Microtubule Network in Non-Small Cell Lung Cancer

by Chen-Hung Ting, Kang-Yun Lee, Sheng-Ming Wu, Po-Hao Feng, Yao-Fei Chan, Yi-Chun Chen and Jyh-Yih Chen

Cancers 2019, 11(1), 107; https://doi.org/10.3390/cancers11010107 - 17 Jan 2019

Cited by 17 | Viewed by 5140

Abstract

Non-small cell lung cancer (NSCLC) is among the leading causes of human mortality. One reason for high rates of NSCLC mortality is that drug resistance is a major problem for both conventional chemotherapies and less-toxic targeted therapies. Thus, novel mechanistic insights into disease [...] Read more.

Non-small cell lung cancer (NSCLC) is among the leading causes of human mortality. One reason for high rates of NSCLC mortality is that drug resistance is a major problem for both conventional chemotherapies and less-toxic targeted therapies. Thus, novel mechanistic insights into disease pathogenesis may benefit the development of urgently needed therapies. Here we show that FBJ murine osteosarcoma viral oncogene homolog B (FOSB) was induced by an antimicrobial peptide, tilapia piscidin-4 (TP4), through the dysregulation of mitochondrial Ca²⁺ homeostasis in NSCLC cells. Transcriptomic, chromatin immunoprecipitation quantitative PCR, and immunocytochemical studies reveal that protocadherin-β13 (PCDHB13) as a target of FOSB that was functionally associated with microtubule. Overexpression of either PCDHB13 or FOSB attenuated NSCLC growth and survival in vitro and in vivo. Importantly, downregulation of both FOSB and PCDHB13 was observed in NSCLC patients and was negatively correlated with pathological grade. These findings introduce the FOSB–PCDHB13 axis as a novel tumor suppressive pathway in NSCLC. Full article

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15 pages, 1387 KiB

Open AccessEditor’s ChoiceReview

Connexins and Integrins in Exosomes

by Motomu Shimaoka, Eiji Kawamoto, Arong Gaowa, Takayuki Okamoto and Eun Jeong Park

Cancers 2019, 11(1), 106; https://doi.org/10.3390/cancers11010106 - 17 Jan 2019

Cited by 57 | Viewed by 6752

Abstract

Connexins and integrins, the two structurally and functionally distinct families of transmembrane proteins, have been shown to be inter-connected by various modes of cross-talk in cells, such as direct physical coupling via lateral contact, indirect physical coupling via actin and actin-binding proteins, and [...] Read more.

Connexins and integrins, the two structurally and functionally distinct families of transmembrane proteins, have been shown to be inter-connected by various modes of cross-talk in cells, such as direct physical coupling via lateral contact, indirect physical coupling via actin and actin-binding proteins, and functional coupling via signaling cascades. This connexin-integrin cross-talk exemplifies a biologically important collaboration between channels and adhesion receptors in cells. Exosomes are biological lipid-bilayer nanoparticles secreted from virtually all cells via endosomal pathways into the extracellular space, thereby mediating intercellular communications across a broad range of health and diseases, including cancer progression and metastasis, infection and inflammation, and metabolic deregulation. Connexins and integrins are embedded in the exosomal membranes and have emerged as critical regulators of intercellular communication. This concise review article will explain and discuss recent progress in better understanding the roles of connexins, integrins, and their cross-talk in cells and exosomes. Full article

(This article belongs to the Special Issue Gap Junctions and Connexins in Cancer Formation, Progression, and Therapy)

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12 pages, 4113 KiB

Open AccessArticle

Varlitinib Downregulates HER/ERK Signaling and Induces Apoptosis in Triple Negative Breast Cancer Cells

by Chun-Yu Liu, Pei-Yi Chu, Chun-Teng Huang, Ji-Lin Chen, Hsiu-Ping Yang, Wan-Lun Wang, Ka-Yi Lau, Chia-Han Lee, Tien-Yun Lan, Tzu-Ting Huang, Po-Han Lin, Ming-Shen Dai and Ling-Ming Tseng

Cancers 2019, 11(1), 105; https://doi.org/10.3390/cancers11010105 - 17 Jan 2019

Cited by 23 | Viewed by 7106

Abstract

Triple-negative breast cancer (TNBC) is a complex disease associated with the aggressive phenotype and poor prognosis. TNBC harbors heterogeneous molecular subtypes with no approved specific targeted therapy. It has been reported that HER receptors are overexpressed in breast cancer including TNBC. In this [...] Read more.

Triple-negative breast cancer (TNBC) is a complex disease associated with the aggressive phenotype and poor prognosis. TNBC harbors heterogeneous molecular subtypes with no approved specific targeted therapy. It has been reported that HER receptors are overexpressed in breast cancer including TNBC. In this study, we evaluated the efficacy of varlitinib, a reversible small molecule pan-HER inhibitor in TNBC. Our results showed that varlitinib reduced cell viability and induced cell apoptosis in most TNBC cell lines but not in MDA-MB-231 cells. MEK and ERK inhibition overcame resistance to varlitinib in MDA-MB-231 cells. Varlitinib inhibited HER signaling which led to inhibition of migration, invasion and mammosphere formation of TNBC cells as well as significant suppression of tumor growth of MDA-MB-468 xenograft mouse model. In summary, these results suggest that HER signaling plays an important role in TNBC progression and that pan-HER inhibition is potentially an effective treatment for TNBC patients. Full article

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19 pages, 7139 KiB

Open AccessArticle

Transfer of Extracellular Vesicle-Associated-RNAs Induces Drug Resistance in ALK-Translocated Lung Adenocarcinoma

by Hoi-Hin Kwok, Ziyu Ning, Peony Wing-Chi Chong, Thomas Shek-Kong Wan, Margaret Heung-Ling Ng, Gloria Y.F. Ho, Mary Sau-Man Ip and David Chi-Leung Lam

Cancers 2019, 11(1), 104; https://doi.org/10.3390/cancers11010104 - 17 Jan 2019

Cited by 21 | Viewed by 4276

Abstract

Anaplastic lymphoma kinase (ALK) translocation is an actionable mutation in lung adenocarcinoma. Nonetheless tumour consists of heterogeneous cell subpopulations with diverse phenotypes and genotypes, and cancer cells can actively release extracellular vesicles (EVs) to modulate the phenotype of other cells in [...] Read more.

Anaplastic lymphoma kinase (ALK) translocation is an actionable mutation in lung adenocarcinoma. Nonetheless tumour consists of heterogeneous cell subpopulations with diverse phenotypes and genotypes, and cancer cells can actively release extracellular vesicles (EVs) to modulate the phenotype of other cells in the tumour microenvironment. We hypothesized that EVs derived from a drug-resistant subpopulation of cells could induce drug resistance in recipient cells. We have established ALK-translocated lung adenocarcinoma cell lines and subclones. The subclones have been characterized and the expression of EV-RNAs determined by quantitative polymerase chain reaction. The effects of EV transfer on drug resistance were examined in vitro. Serum EV-RNA was assayed serially in two patients prescribed ALK-tyrosine kinase inhibitor (ALK-TKI) treatment. We demonstrated that the EVs from an ALK-TKI-resistant subclone could induce drug resistance in the originally sensitive subclone. EV-RNA profiling revealed that miRNAs miR-21-5p and miR-486-3p, and lncRNAs MEG3 and XIST were differentially expressed in the EVs secreted by the resistant subclones. These circulating EV-RNA levels have been found to correlate with disease progression of EML4-ALK-translocated lung adenocarcinoma in patients prescribed ALK-TKI treatment. The results from this study suggest that EVs released by a drug-resistant subpopulation can induce drug resistance in other subpopulations and may sustain intratumoural heterogeneity. Full article

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

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11 pages, 388 KiB

Open AccessArticle

Increased Mortality in SDHB but Not in SDHD Pathogenic Variant Carriers

by Johannes A. Rijken, Leonie T. van Hulsteijn, Olaf M. Dekkers, Nicolasine D. Niemeijer, C. René Leemans, Karin Eijkelenkamp, Anouk N.A. van der Horst-Schrivers, Michiel N. Kerstens, Anouk van Berkel, Henri J.L.M. Timmers, Henricus P.M. Kunst, Peter H.L.T. Bisschop, Koen M.A. Dreijerink, Marieke F. van Dooren, Frederik J. Hes, Jeroen C. Jansen, Eleonora P.M. Corssmit and Erik F. Hensen

Cancers 2019, 11(1), 103; https://doi.org/10.3390/cancers11010103 - 17 Jan 2019

Cited by 15 | Viewed by 5148

Abstract

Germline mutations in succinate dehydrogenase subunit B and D (SDHB and SDHD) are predisposed to hereditary paraganglioma (PGL) and pheochromocytoma (PHEO). The phenotype of pathogenic variants varies according to the causative gene. In this retrospective study, we estimate the mortality of [...] Read more.

Germline mutations in succinate dehydrogenase subunit B and D (SDHB and SDHD) are predisposed to hereditary paraganglioma (PGL) and pheochromocytoma (PHEO). The phenotype of pathogenic variants varies according to the causative gene. In this retrospective study, we estimate the mortality of a nationwide cohort of SDHB variant carriers and that of a large cohort of SDHD variant carriers and compare it to the mortality of a matched cohort of the general Dutch population. A total of 192 SDHB variant carriers and 232 SDHD variant carriers were included in this study. The Standard Mortality Ratio (SMR) for SDHB mutation carriers was 1.89, increasing to 2.88 in carriers affected by PGL. For SDHD variant carriers the SMR was 0.93 and 1.06 in affected carriers. Compared to the general population, mortality seems to be increased in SDHB variant carriers, especially in those affected by PGL. In SDHD variant carriers, the mortality is comparable to that of the general Dutch population, even if they are affected by PGL. This insight emphasizes the significance of DNA-testing in all PGL and PHEO patients, since different clinical risks may warrant gene-specific management strategies. Full article

(This article belongs to the Special Issue Pheochromocytoma (PHEO) and Paraganglioma (PGL))

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24 pages, 4519 KiB

Open AccessArticle

Inhibition of Pannexin 1 Reduces the Tumorigenic Properties of Human Melanoma Cells

by Taylor J. Freeman, Samar Sayedyahossein, Danielle Johnston, Rafael E. Sanchez-Pupo, Brooke O’Donnell, Kenneth Huang, Zameena Lakhani, Daniel Nouri-Nejad, Kevin J. Barr, Luke Harland, Steven Latosinsky, Aaron Grant, Lina Dagnino and Silvia Penuela

Cancers 2019, 11(1), 102; https://doi.org/10.3390/cancers11010102 - 16 Jan 2019

Cited by 34 | Viewed by 6013

Abstract

Pannexin 1 (PANX1) is a channel-forming glycoprotein expressed in many tissues including the skin. PANX1 channels allow the passage of ions and molecules up to 1 kDa, including ATP and other metabolites. In this study, we show that PANX1 is highly expressed in [...] Read more.

Pannexin 1 (PANX1) is a channel-forming glycoprotein expressed in many tissues including the skin. PANX1 channels allow the passage of ions and molecules up to 1 kDa, including ATP and other metabolites. In this study, we show that PANX1 is highly expressed in human melanoma tumors at all stages of disease progression, as well as in patient-derived cells and established melanoma cell lines. Reducing PANX1 protein levels using shRNA or inhibiting channel function with the channel blockers, carbenoxolone (CBX) and probenecid (PBN), significantly decreased cell growth and migration, and increased melanin production in A375-P and A375-MA2 cell lines. Further, treatment of A375-MA2 tumors in chicken embryo xenografts with CBX or PBN significantly reduced melanoma tumor weight and invasiveness. Blocking PANX1 channels with PBN reduced ATP release in A375-P cells, suggesting a potential role for PANX1 in purinergic signaling of melanoma cells. In addition, cell-surface biotinylation assays indicate that there is an intracellular pool of PANX1 in melanoma cells. PANX1 likely modulates signaling through the Wnt/β-catenin pathway, because β-catenin levels were significantly decreased upon PANX1 silencing. Collectively, our findings identify a role for PANX1 in controlling growth and tumorigenic properties of melanoma cells contributing to signaling pathways that modulate melanoma progression. Full article

(This article belongs to the Special Issue Ion Channels in Cancer)

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17 pages, 2517 KiB

Open AccessArticle

SP1 and STAT3 Functionally Synergize to Induce the RhoU Small GTPase and a Subclass of Non-canonical WNT Responsive Genes Correlating with Poor Prognosis in Breast Cancer

by Emanuele Monteleone, Valeria Orecchia, Paola Corrieri, Davide Schiavone, Lidia Avalle, Enrico Moiso, Aurora Savino, Ivan Molineris, Paolo Provero and Valeria Poli

Cancers 2019, 11(1), 101; https://doi.org/10.3390/cancers11010101 - 16 Jan 2019

Cited by 18 | Viewed by 3887

Abstract

Breast cancer is a heterogeneous disease whose clinical management is very challenging. Although specific molecular features characterize breast cancer subtypes with different prognosis, the identification of specific markers predicting disease outcome within the single subtypes still lags behind. Both the non-canonical Wingless-type MMTV [...] Read more.

Breast cancer is a heterogeneous disease whose clinical management is very challenging. Although specific molecular features characterize breast cancer subtypes with different prognosis, the identification of specific markers predicting disease outcome within the single subtypes still lags behind. Both the non-canonical Wingless-type MMTV Integration site (WNT) and the Signal Transducer and Activator of Transcription (STAT)3 pathways are often constitutively activated in breast tumors, and both can induce the small GTPase Ras Homolog Family Member U RhoU. Here we show that RhoU transcription can be triggered by both canonical and non-canonical WNT ligands via the activation of c-JUN N-terminal kinase (JNK) and the recruitment of the Specificity Protein 1 (SP1) transcription factor to the RhoU promoter, identifying for the first time SP1 as a JNK-dependent mediator of WNT signaling. RhoU down-regulation by silencing or treatment with JNK, SP1 or STAT3 inhibitors leads to impaired migration and invasion in basal-like MDA-MB-231 and BT-549 cells, suggesting that STAT3 and SP1 can cooperate to induce high RhoU expression and enhance breast cancer cells migration. Moreover, in vivo concomitant binding of STAT3 and SP1 defines a subclass of genes belonging to the non-canonical WNT and the Interleukin (IL)-6/STAT3 pathways and contributing to breast cancer aggressiveness, suggesting the relevance of developing novel targeted therapies combining inhibitors of the STAT3 and WNT pathways or of their downstream mediators. Full article

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20 pages, 608 KiB

Open AccessFeature PaperReview

Thrombin Generation and Cancer: Contributors and Consequences

by Caroline J. Reddel, Chuen Wen Tan and Vivien M. Chen

Cancers 2019, 11(1), 100; https://doi.org/10.3390/cancers11010100 - 16 Jan 2019

Cited by 61 | Viewed by 5735

Abstract

The high occurrence of cancer-associated thrombosis is associated with elevated thrombin generation. Tumour cells increase the potential for thrombin generation both directly, through the expression and release of procoagulant factors, and indirectly, through signals that activate other cell types (including platelets, leukocytes and [...] Read more.

The high occurrence of cancer-associated thrombosis is associated with elevated thrombin generation. Tumour cells increase the potential for thrombin generation both directly, through the expression and release of procoagulant factors, and indirectly, through signals that activate other cell types (including platelets, leukocytes and erythrocytes). Furthermore, cancer treatments can worsen these effects. Coagulation factors, including tissue factor, and inhibitors of coagulation are altered and extracellular vesicles (EVs), which can promote and support thrombin generation, are released by tumour and other cells. Some phosphatidylserine-expressing platelet subsets and platelet-derived EVs provide the surface required for the assembly of coagulation factors essential for thrombin generation in vivo. This review will explore the causes of increased thrombin production in cancer, and the availability and utility of tests and biomarkers. Increased thrombin production not only increases blood coagulation, but also promotes tumour growth and metastasis and as a consequence, thrombin and its contributors present opportunities for treatment of cancer-associated thrombosis and cancer itself. Full article

(This article belongs to the Special Issue The Role of Thrombosis and Haemostasis in Cancer)

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20 pages, 2230 KiB

Open AccessArticle

Opposing Regulation of Cancer Properties via KRT19-Mediated Differential Modulation of Wnt/β-Catenin/Notch Signaling in Breast and Colon Cancers

by Subbroto Kumar Saha, Yingfu Yin, Hee Sung Chae and Ssang-Goo Cho

Cancers 2019, 11(1), 99; https://doi.org/10.3390/cancers11010099 - 15 Jan 2019

Cited by 25 | Viewed by 7549

Abstract

Although Keratin 19 (KRT19) has been reported as a tumor cell marker and found to interact with other proteins that modulate cancer properties, its role in cancer prognosis remains to be fully elucidated. We found that KRT19 expression was increased in both colon [...] Read more.

Although Keratin 19 (KRT19) has been reported as a tumor cell marker and found to interact with other proteins that modulate cancer properties, its role in cancer prognosis remains to be fully elucidated. We found that KRT19 expression was increased in both colon and breast cancer, but that knockdown of KRT19 showed opposing effects on cancer properties. In colon cancer, KRT19 knockdown resulted in suppression of cancer via downregulation of Wnt/Notch signaling without altering NUMB transcription. In breast cancer, KRT19 knockdown led to an increase in cancer properties because of attenuated Wnt and enhanced Notch signaling. In colon cancer, KRT19 interacted with β-catenin but not with RAC1, allowing the LEF/TCF transcription factor to bind primarily to the LEF1 and TCF7 promoter regions, whereas in breast cancer, KRT19 interacted with the β-catenin/RAC1 complex and led to apparent upregulation of NUMB expression and NUMB-mediated suppression of Notch signaling. These results reveal a novel differential role of KRT19 in carcinogenesis, due to differential modulation of Wnt/β-catenin/Notch signaling crosstalk through various interactions of KRT19 with only β-catenin or with the β-catenin/RAC1 complex, which might have implications for clinical cancer research. Full article

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20 pages, 3445 KiB

Open AccessArticle

Overcoming Intrinsic and Acquired Cetuximab Resistance in RAS Wild-Type Colorectal Cancer: An In Vitro Study on the Expression of HER Receptors and the Potential of Afatinib

by Ines De Pauw, Filip Lardon, Jolien Van den Bossche, Hasan Baysal, Patrick Pauwels, Marc Peeters, Jan Baptist Vermorken and An Wouters

Cancers 2019, 11(1), 98; https://doi.org/10.3390/cancers11010098 - 15 Jan 2019

Cited by 11 | Viewed by 6158

Abstract

The epidermal growth factor receptor (EGFR) is an important therapeutic target in colorectal cancer (CRC). After the initial promising results of EGFR-targeted therapies such as cetuximab, therapeutic resistance poses a challenging problem and limits the success of effective anti-EGFR cancer therapies in the [...] Read more.

The epidermal growth factor receptor (EGFR) is an important therapeutic target in colorectal cancer (CRC). After the initial promising results of EGFR-targeted therapies such as cetuximab, therapeutic resistance poses a challenging problem and limits the success of effective anti-EGFR cancer therapies in the clinic. In order to overcome resistance to these EGFR-targeted therapies, new treatment options are necessary. The objective of this study was to investigate the expression of human epidermal growth factor (HER) receptors and the efficacy of afatinib, a second-generation irreversible EGFR-tyrosine kinase inhibitor, in RAS wild-type CRC cell lines with different cetuximab sensitivities. CRC cell lines with different sensitivities to cetuximab showed rather low EGFR expression but high HER2 and HER3 expression. These results were in line with the The Cancer Genome Atlas (TCGA) data from CRC patients, where higher mRNA levels of HER2 and HER3 were also detected compared to EGFR. Therefore, the targets of afatinib were indeed expressed on the CRC cell lines used in this study and in CRC patients. Furthermore, cetuximab resistance had no significant influence on the expression levels of HER receptors in CRC cell lines (p ≥ 0.652). This study also demonstrated that afatinib was able to induce a concentration-dependent cytotoxic effect in RAS wild-type CRC cell lines with different cetuximab sensitivities. Neither cetuximab resistance (p = 0.233) nor hypoxia (p = 0.157) significantly influenced afatinib’s cytotoxic effect. In conclusion, our preclinical data support the hypothesis that treatment with afatinib might be a promising novel therapeutic strategy for CRC patients experiencing intrinsic and acquired cetuximab resistance. Full article

(This article belongs to the Special Issue Epidermal Growth Factor Receptor Signaling in Cancer)

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26 pages, 2327 KiB

Open AccessArticle

On the Mechanism of Hyperthermia-Induced BRCA2 Protein Degradation

by Nathalie van den Tempel, Alex N. Zelensky, Hanny Odijk, Charlie Laffeber, Christine K. Schmidt, Inger Brandsma, Jeroen Demmers, Przemek M. Krawczyk and Roland Kanaar

Cancers 2019, 11(1), 97; https://doi.org/10.3390/cancers11010097 - 15 Jan 2019

Cited by 15 | Viewed by 4626

Abstract

The DNA damage response (DDR) is a designation for a number of pathways that protects our DNA from various damaging agents. In normal cells, the DDR is extremely important for maintaining genome integrity, but in cancer cells these mechanisms counteract therapy-induced DNA damage. [...] Read more.

The DNA damage response (DDR) is a designation for a number of pathways that protects our DNA from various damaging agents. In normal cells, the DDR is extremely important for maintaining genome integrity, but in cancer cells these mechanisms counteract therapy-induced DNA damage. Inhibition of the DDR could therefore be used to increase the efficacy of anti-cancer treatments. Hyperthermia is an example of such a treatment—it inhibits a sub-pathway of the DDR, called homologous recombination (HR). It does so by inducing proteasomal degradation of BRCA2 —one of the key HR factors. Understanding the precise mechanism that mediates this degradation is important for our understanding of how hyperthermia affects therapy and how homologous recombination and BRCA2 itself function. In addition, mechanistic insight into the process of hyperthermia-induced BRCA2 degradation can yield new therapeutic strategies to enhance the effects of local hyperthermia or to inhibit HR. Here, we investigate the mechanisms driving hyperthermia-induced BRCA2 degradation. We find that BRCA2 degradation is evolutionarily conserved, that BRCA2 stability is dependent on HSP90, that ubiquitin might not be involved in directly targeting BRCA2 for protein degradation via the proteasome, and that BRCA2 degradation might be modulated by oxidative stress and radical scavengers. Full article

(This article belongs to the Special Issue Hyperthermia-based Anticancer Treatments)

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