Cancers

13 pages, 1186 KiB

Open AccessArticle

Frequency of Circulating Tumor Cells (CTC) in Patients with Brain Metastases: Implications as a Risk Assessment Marker in Oligo-Metastatic Disease

by Annkathrin Hanssen¹, Carlotta Riebensahm^1,†, Malte Mohme^2,†, Simon A. Joosse¹

, Janna-Lisa Velthaus³, Lars Arne Berger³

, Christian Bernreuther⁴, Markus Glatzel⁴, Sonja Loges^1,3, Katrin Lamszus², Manfred Westphal², Sabine Riethdorf¹, Klaus Pantel¹

and Harriet Wikman^1,*

¹ Department of Tumor Biology, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany

² Department of Neurosurgery University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany

³ Department of Internal Medicine II and Clinic (Oncology Centre) University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany

⁴ Institute of Neuropathology University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany

^† These authors contributed equally to this work.

Cancers 2018, 10(12), 527; https://doi.org/10.3390/cancers10120527 - 19 Dec 2018

Cited by 46 | Viewed by 5816

Abstract

Forty percent of non-small cell lung cancer (NSCLC) patients develop brain metastases, resulting in a dismal prognosis. However, patients in an oligo-metastatic brain disease setting seem to have better outcomes. Here, we investigate the possibility of using circulating tumor cells (CTCs) as biomarkers [...] Read more.

Forty percent of non-small cell lung cancer (NSCLC) patients develop brain metastases, resulting in a dismal prognosis. However, patients in an oligo-metastatic brain disease setting seem to have better outcomes. Here, we investigate the possibility of using circulating tumor cells (CTCs) as biomarkers to differentiate oligo-metastatic patients for better risk assessment. Using the CellSearch^® system, few CTCs were detected among NSCLC patients with brain metastases (n = 52, 12.5% ≥ two and 8.9% ≥ five CTC/7.5 mL blood) and especially oligo-metastatic brain patients (n = 34, 5.9%, and 2.9%). Still, thresholds of both ≥ two and ≥ five CTCs were independent prognostic indicators for shorter overall survival time among all of the NSCLC patients (n = 90, two CTC ≥ HR: 1.629, p = 0.024, 95% CI: 1.137–6.465 and five CTC ≥ HR: 2.846, p = 0.0304, CI: 1.104–7.339), as well as among patients with brain metastases (two CTC ≥ HR: 4.694, p = 0.004, CI: 1.650–13.354, and five CTC ≥ HR: 4.963, p = 0.003, CI: 1.752–14.061). Also, oligo-brain NSCLC metastatic patients with CTCs had a very poor prognosis (p = 0.019). Similarly, in other tumor entities, only 9.6% of patients with brain metastases (n = 52) had detectable CTCs. Our data indicate that although patients with brain metastases more seldom harbor CTCs, they are still predictive for overall survival, and CTCs might be a useful biomarker to identify oligo-metastatic NSCLC patients who might benefit from a more intense therapy. Full article

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

▼ Show Figures

Figure 1

18 pages, 2709 KiB

Open AccessArticle

Ponatinib Inhibits Multiple Signaling Pathways Involved in STAT3 Signaling and Attenuates Colorectal Tumor Growth

by Fiona H. Tan¹, Tracy L. Putoczki^1,2,3, Jieqiong Lou⁴, Elizabeth Hinde⁴, Frédéric Hollande⁵, Julie Giraud⁶, Stanley S. Stylli^1,7

, Lucia Paradiso¹, Hong-Jian Zhu¹, Oliver M. Sieber^1,3,8,9

and Rodney B. Luwor^1,*

¹ Department of Surgery, The University of Melbourne, The Royal Melbourne Hospital, Parkville VIC 3050, Australia

² Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville VIC 3052, Australia

³ Department of Medical Biology, The University of Melbourne, Parkville VIC 3050, Australia

⁴ Department of Biochemistry and Molecular Biology, Bio21, The University of Melbourne, Parkville VIC 3010, Australia

⁵ Department of Clinical Pathology, Victorian Comprehensive Cancer Centre, The University of Melbourne, Melbourne VIC 3000, Australia

⁶ CNRS, Institut de Génomique Fonctionnelle, Universités de Montpellier 1 & 2, UMR-5203, INSERM U661, 34094 Montpellier, France

⁷ Department of Neurosurgery, The Royal Melbourne Hospital, Parkville VIC 3050, Australia

⁸ Systems Biology and Personalised Medicine Division, The Walter and Eliza Hall Institute of Medical Research, Parkville VIC 3052, Australia

⁹ School of Biomedical Sciences, Monash University, Clayton VIC 3168, Australia

Cancers 2018, 10(12), 526; https://doi.org/10.3390/cancers10120526 - 19 Dec 2018

Cited by 17 | Viewed by 5300

Abstract

Signal transducer and activator of transcription 3 (STAT3) signaling is a major driver of colorectal cancer (CRC) growth, however therapeutics, which can effectively target this pathway, have so far remained elusive. Here, we performed an extensive screen for STAT3 inhibitors among a library [...] Read more.

Signal transducer and activator of transcription 3 (STAT3) signaling is a major driver of colorectal cancer (CRC) growth, however therapeutics, which can effectively target this pathway, have so far remained elusive. Here, we performed an extensive screen for STAT3 inhibitors among a library of 1167 FDA-approved agents, identifying Ponatinib as a lead candidate. We found that Ponatinib inhibits STAT3 activity driven by EGF/EGFR, IL-6/IL-6R and IL-11/IL-11R, three major ligand/receptor systems involved in CRC development and progression. Ponatinib was able to inhibit CRC migration and tumor growth in vivo. In addition, Ponatinib displayed a greater ability to inhibit STAT3 activity and mediated superior anti-proliferative efficacy compared to five FDA approved SRC and Janus Kinase (JAK) inhibitors. Finally, long-term exposure of CRC cells to Ponatinib, Dasatinib and Bosutinib resulted in acquired resistance to Dasatinib and Bosutinib occurring within six weeks. However, acquired resistance to Ponatinib was observed after long-term exposure of >4 months. Overall, our results identify a novel anti-STAT3 property of Ponatinib and thus, Ponatinib offers a potential therapeutic strategy for CRC. Full article

▼ Show Figures

Figure 1

19 pages, 2795 KiB

Open AccessArticle

CBP/β-Catenin/FOXM1 Is a Novel Therapeutic Target in Triple Negative Breast Cancer

by Alexander Ring¹, Cu Nguyen², Goar Smbatyan², Debu Tripathy³

, Min Yu⁴, Michael Press⁵, Michael Kahn^2,* and Julie E. Lang^5,6,*

¹ Department of Oncology and Hematology, UniversitätsSpital Zürich, Rämistrasse 100, 0832 Zürich 1, The Netherlands

² Department of Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA

³ Department of Breast Medical Oncology, UT-MD Anderson Cancer Center, Houston, TX 77030, USA

⁴ Department of Stem Cell Biology and Regenerative Medicine, University of Southern California, Los Angeles, CA 90033, USA

⁵ University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA

⁶ Department of Surgery, University of Southern California, Los Angeles, CA 90033, USA

Cancers 2018, 10(12), 525; https://doi.org/10.3390/cancers10120525 - 19 Dec 2018

Cited by 43 | Viewed by 6665

Abstract

Background: Triple negative breast cancers (TNBCs) are an aggressive BC subtype, characterized by high rates of drug resistance and a high proportion of cancer stem cells (CSC). CSCs are thought to be responsible for tumor initiation and drug resistance. cAMP-response element-binding (CREB) binding [...] Read more.

Background: Triple negative breast cancers (TNBCs) are an aggressive BC subtype, characterized by high rates of drug resistance and a high proportion of cancer stem cells (CSC). CSCs are thought to be responsible for tumor initiation and drug resistance. cAMP-response element-binding (CREB) binding protein (CREBBP or CBP) has been implicated in CSC biology and may provide a novel therapeutic target in TNBC. Methods: RNA Seq pre- and post treatment with the CBP-binding small molecule ICG-001 was used to characterize CBP-driven gene expression in TNBC cells. In vitro and in vivo TNBC models were used to determine the therapeutic effect of CBP inhibition via ICG-001. Tissue microarrays (TMAs) were used to investigate the potential of CBP and associated proteins as biomarkers in TNBC. Results: The CBP/ß-catenin/FOXM1 transcriptional complex drives gene expression in TNBC and is associated with increased CSC numbers, drug resistance and poor survival outcome. Targeting of CBP/β-catenin/FOXM1 with ICG-001 eliminated CSCs and sensitized TNBC tumors to chemotherapy. Immunohistochemistry of TMAs demonstrated a significant correlation between FOXM1 expression and TNBC subtype. Conclusion: CBP/β-catenin/FOXM1 transcriptional activity plays an important role in TNBC drug resistance and CSC phenotype. CBP/β-catenin/FOXM1 provides a molecular target for precision therapy in triple negative breast cancer and could form a rationale for potential clinical trials. Full article

▼ Show Figures

Graphical abstract

15 pages, 244 KiB

Open AccessFeature PaperReview

BRCA Mutations and Breast Cancer Prevention

by Joanne Kotsopoulos^1,2

¹ Women’s College Research Institute, Women’s College Hospital, 76 Grenville Street, 6th Floor, Toronto, ON M5S 1B2, Canada

² Dalla Lana School of Public Health, University of Toronto, 155 College St, Toronto, ON M5T 3M7, Canada

Cancers 2018, 10(12), 524; https://doi.org/10.3390/cancers10120524 - 19 Dec 2018

Cited by 80 | Viewed by 14132

Abstract

Women who inherit a deleterious BRCA1 or BRCA2 mutation face substantially increased risks of developing breast cancer, which is estimated at 70%. Although annual screening with magnetic resonance imaging (MRI) and mammography promotes the earlier detection of the disease, the gold standard for [...] Read more.

Women who inherit a deleterious BRCA1 or BRCA2 mutation face substantially increased risks of developing breast cancer, which is estimated at 70%. Although annual screening with magnetic resonance imaging (MRI) and mammography promotes the earlier detection of the disease, the gold standard for the primary prevention of breast cancer remains bilateral mastectomy. In the current paper, I review the evidence regarding the management of healthy BRCA mutation carriers, including key risk factors and protective factors, and also discuss potential chemoprevention options. I also provide an overview of the key findings from the literature published to date, with a focus on data from studies that are well-powered, and preferably prospective in nature. Full article

(This article belongs to the Special Issue BRCA Mutations and Cancer)

20 pages, 959 KiB

Open AccessReview

Obesity-Linked Cancers: Current Knowledge, Challenges and Limitations in Mechanistic Studies and Rodent Models

by Yang Xin Zi Xu¹

and Suresh Mishra^1,2,*

¹ Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3E 3P4, Canada

² Department of Internal Medicine, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3E 3P4, Canada

Cancers 2018, 10(12), 523; https://doi.org/10.3390/cancers10120523 - 18 Dec 2018

Cited by 16 | Viewed by 8561

Abstract

The worldwide prevalence of obesity has doubled during the last 50 years, and according to the World Obesity Federation, one third of the people on Earth will be obese by the year 2025. Obesity is described as a chronic, relapsing and multifactorial disease [...] Read more.

The worldwide prevalence of obesity has doubled during the last 50 years, and according to the World Obesity Federation, one third of the people on Earth will be obese by the year 2025. Obesity is described as a chronic, relapsing and multifactorial disease that causes metabolic, biomechanical, and psychosocial health consequences. Growing evidence suggests that obesity is a risk factor for multiple cancer types and rivals smoking as the leading preventable cause for cancer incidence and mortality. The epidemic of obesity will likely generate a new wave of obesity-related cancers with high aggressiveness and shortened latency. Observational studies have shown that from cancer risk to disease prognosis, an individual with obesity is consistently ranked worse compared to their lean counterpart. Mechanistic studies identified similar sets of abnormalities under obesity that may lead to cancer development, including ectopic fat storage, altered adipokine profiles, hormone fluctuations and meta-inflammation, but could not explain how these common mechanisms produce over 13 different cancer types. A major hurdle in the mechanistic underpinning of obesity-related cancer is the lack of suitable pre-clinical models that spontaneously develop obesity-linked cancers like humans. Current approaches and animal models fall short when discerning the confounders that often coexist in obesity. In this mini-review, we will briefly survey advances in the different obesity-linked cancers and discuss the challenges and limitations in the rodent models employed to study their relationship. We will also provide our perspectives on the future of obesity-linked cancer research. Full article

(This article belongs to the Special Issue Obesity as a Risk Factor for Cancer)

▼ Show Figures

Figure 1

16 pages, 1079 KiB

Open AccessReview

NK Cell-Based Glioblastoma Immunotherapy

by Irene Golán^†

, Laura Rodríguez de la Fuente^†

and Jose A. Costoya^*

¹ Molecular Oncology Laboratory MOL, Departamento de Fisioloxia, CiMUS, Facultade de Medicina, Universidade de Santiago de Compostela, IDIS, 15782 Santiago de Compostela, Spain

^† These authors contributed equally.

Cancers 2018, 10(12), 522; https://doi.org/10.3390/cancers10120522 - 18 Dec 2018

Cited by 66 | Viewed by 6938

Abstract

Glioblastoma (GB) is the most aggressive and most common malignant primary brain tumor diagnosed in adults. GB shows a poor prognosis and, unfortunately, current therapies are unable to improve its clinical outcome, imposing the need for innovative therapeutic approaches. The main reason for [...] Read more.

Glioblastoma (GB) is the most aggressive and most common malignant primary brain tumor diagnosed in adults. GB shows a poor prognosis and, unfortunately, current therapies are unable to improve its clinical outcome, imposing the need for innovative therapeutic approaches. The main reason for the poor prognosis is the great cell heterogeneity of the tumor mass and its high capacity for invading healthy tissues. Moreover, the glioblastoma microenvironment is capable of suppressing the action of the immune system through several mechanisms such as recruitment of cell modulators. Development of new therapies that avoid this immune evasion could improve the response to the current treatments for this pathology. Natural Killer (NK) cells are cellular components of the immune system more difficult to deceive by tumor cells and with greater cytotoxic activity. Their use in immunotherapy gains strength because they are a less toxic alternative to existing therapy, but the current research focuses on mimicking the NK attack strategy. Here, we summarize the most recent studies regarding molecular mechanisms involved in the GB and immune cells interaction and highlight the relevance of NK cells in the new therapeutic challenges. Full article

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

▼ Show Figures

Graphical abstract

19 pages, 6677 KiB

Open AccessArticle

The Human Papillomavirus (HPV) E6 Oncoprotein Regulates CD40 Expression via the AT-Hook Transcription Factor AKNA

by Joaquin Manzo-Merino^1,2,3,*

, Alfredo Lagunas-Martínez³, Carla O. Contreras-Ochoa³, Marcela Lizano^2,4

, Leonardo J. Castro-Muñoz²

, Crysele Calderón-Corona³, Kirvis Torres-Poveda^3,5, Alicia Román-Gonzalez³, Rogelio Hernández-Pando⁶, Margarita Bahena-Román³ and Vicente Madrid-Marina^3,*

¹ CONACyT-Instituto Nacional de Cancerología, Mexico City 14080, Mexico

² Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología-Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City 14080, Mexico

³ Chronic Infections and Cancer Division, Centro de Investigación Sobre Enfermedades Infecciosas (CISEI), Instituto Nacional de Salud Pública, Secretaría de Salud, Avenida Universidad 655, Col. Santa María Ahuacatitlan, Cuernavaca, Morelos 62100, Mexico

⁴ Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico

⁵ CONACyT-Instituto Nacional de Salud Pública (INSP), Cuernavaca, Morelos 62100, Mexico

⁶ Section of Experimental Pathology, Department of Pathology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City 14080, Mexico

Cancers 2018, 10(12), 521; https://doi.org/10.3390/cancers10120521 - 17 Dec 2018

Cited by 9 | Viewed by 4309

Abstract

Persistent infection with high-risk Human Papillomavirus (HR-HPV) is the main requisite for cervical cancer development. Normally, HPV is limited to the site of infection and regulates a plethora of cellular elements to avoid the immune surveillance by inducing an anti-inflammatory state, allowing the [...] Read more.

Persistent infection with high-risk Human Papillomavirus (HR-HPV) is the main requisite for cervical cancer development. Normally, HPV is limited to the site of infection and regulates a plethora of cellular elements to avoid the immune surveillance by inducing an anti-inflammatory state, allowing the progress through the viral cycle and the carcinogenic process. Recent findings suggest that the AT-hook transcriptional factor AKNA could play a role in the development of cervical cancer. AKNA is strongly related to the expression of co-stimulatory molecules such CD40/CD40L to achieve an anti-tumoral immune response. To date, there is no evidence demonstrating the effect of the HPV E6 oncoprotein on the AT-hook factor AKNA. In this work, minimal expression of AKNA in cervical carcinoma compared to normal tissue was found. We show the ability of E6 from high-risk HPVs 16 and 18 to interact with and down-regulate AKNA as well as its co-stimulatory molecule CD40 in a proteasome dependent manner. We also found that p53 interacts with AKNA and promotes AKNA expression. Our results indicate that the de-regulation of CD40 and AKNA is induced by the HPV E6 oncoprotein, and this event involves the action of p53 suggesting that the axis E6/p53A/AKNA might play an important role in the de-regulation of the immune system during the carcinogenic process induced by HR-HPV. Full article

▼ Show Figures

Figure 1

42 pages, 5883 KiB

Open AccessArticle

Oncogenic Activation of Nrf2, Though as a Master Antioxidant Transcription Factor, Liberated by Specific Knockout of the Full-Length Nrf1α that Acts as a Dominant Tumor Repressor

by Lu Qiu¹, Meng Wang¹, Shaofan Hu¹, Xufang Ru¹, Yonggang Ren¹, Zhengwen Zhang², Siwang Yu³ and Yiguo Zhang^1,*

¹ The Laboratory of Cell Biochemistry and Topogenetic Regulation, College of Bioengineering and Faculty of Sciences, Chongqing University, No. 174 Shazheng Street, Shapingba District, Chongqing 400044, China

² Institute of Neuroscience and Psychology, School of Life Sciences, University of Glasgow, 42 Western Common Road, Glasgow G22 5PQ, Scotland, United Kingdom

³ State Key Laboratory of Natural and Biomimetic Drugs, Department of Molecular and Cellular Pharmacology, Peking University School of Pharmaceutical Sciences, No. 38 Xueyuan Rd., Haidian District, Beijing 100191, China

Cancers 2018, 10(12), 520; https://doi.org/10.3390/cancers10120520 - 17 Dec 2018

Cited by 30 | Viewed by 7582

Abstract

Liver-specific knockout of Nrf1 in the mouse leads to spontaneous development of non- alcoholic steatohepatitis with dyslipidemia, and then its deterioration results in hepatoma, but the underlying mechanism remains elusive to date. A similar pathological model is reconstructed here by using human Nrf1α-specific [...] Read more.

Liver-specific knockout of Nrf1 in the mouse leads to spontaneous development of non- alcoholic steatohepatitis with dyslipidemia, and then its deterioration results in hepatoma, but the underlying mechanism remains elusive to date. A similar pathological model is reconstructed here by using human Nrf1α-specific knockout cell lines. Our evidence has demonstrated that a marked increase of the inflammation marker COX2 definitely occurs in Nrf1α^−/⁻ cells. Loss of Nrf1α leads to hyperactivation of Nrf2, which results from substantial decreases in Keap1, PTEN and most of 26S proteasomal subunits in Nrf1α^−/⁻ cells. Further investigation of xenograft model mice showed that malignant growth of Nrf1α^−/⁻-derived tumors is almost abolished by silencing of Nrf2, while Nrf1α^+/⁺-tumor is markedly repressed by an inactive mutant (i.e., Nrf2^−/⁻^ΔTA), but largely unaffected by a priori constitutive activator (i.e., caNrf2^ΔN). Mechanistic studies, combined with transcriptomic sequencing, unraveled a panoramic view of opposing and unifying inter-regulatory cross-talks between Nrf1α and Nrf2 at different layers of the endogenous regulatory networks from multiple signaling towards differential expression profiling of target genes. Collectively, Nrf1α manifests a dominant tumor-suppressive effect by confining Nrf2 oncogenicity. Though as a tumor promoter, Nrf2 can also, in turn, directly activate the transcriptional expression of Nrf1 to form a negative feedback loop. In view of such mutual inter-regulation by between Nrf1α and Nrf2, it should thus be taken severe cautions to interpret the experimental results from loss of Nrf1α, Nrf2 or both. Full article

▼ Show Figures

Figure 1

15 pages, 2764 KiB

Open AccessArticle

EphA3 Pay-Loaded Antibody Therapeutics for the Treatment of Glioblastoma

by Carolin Offenhäuser^1,†, Fares Al-Ejeh^1,†

, Simon Puttick^2,3, Kathleen S. Ensbey¹, Zara C. Bruce¹, Paul R. Jamieson¹, Fiona M. Smith¹, Brett W. Stringer¹

, Benjamin Carrington¹, Adrian V. Fuchs^2,4, Craig A. Bell^2,4

, Rosalind Jeffree⁵

, Stephen Rose³, Kristofer J. Thurecht^2,4, Andrew W. Boyd^1,‡ and Bryan W. Day^1,6,*,‡

¹ Department of Cell and Molecular Biology, QIMR Berghofer Medical Research Institute, Brisbane 4006, Australia

² Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane 4072, Australia

³ Commonwealth Scientific and Industrial Research Organisation (CSIRO), Brisbane 4006, Australia

⁴ Centre for Advanced Imaging, The University of Queensland, Brisbane 4072, Australia

⁵ Kenneth G. Jamieson Department of Neurosurgery, Royal Brisbane and Women’s Hospital, Brisbane 4029, Australia

⁶ School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane 4059, Australia

^† These authors contributed equally to the manuscript.

^‡ Co-Senior authors.

Cancers 2018, 10(12), 519; https://doi.org/10.3390/cancers10120519 - 17 Dec 2018

Cited by 32 | Viewed by 7235

Abstract

The EphA3 receptor has recently emerged as a functional tumour-specific therapeutic target in glioblastoma (GBM). EphA3 is significantly elevated in recurrent disease, is most highly expressed on glioma stem cells (GSCs), and has a functional role in maintaining self-renewal and tumourigenesis. An unlabelled [...] Read more.

The EphA3 receptor has recently emerged as a functional tumour-specific therapeutic target in glioblastoma (GBM). EphA3 is significantly elevated in recurrent disease, is most highly expressed on glioma stem cells (GSCs), and has a functional role in maintaining self-renewal and tumourigenesis. An unlabelled EphA3-targeting therapeutic antibody is currently under clinical assessment in recurrent GBM patients. In this study, we assessed the efficacy of EphA3 antibody drug conjugate (ADC) and radioimmunotherapy (RIT) approaches using orthotopic animal xenograft models. Brain uptake studies, using positron emission tomography/computed tomography (PET/CT) imaging, show EphA3 antibodies are effectively delivered across the blood-tumour barrier and accumulate at the tumour site with no observed normal brain reactivity. A robust anti-tumour response, with no toxicity, was observed using EphA3, ADC, and RIT approaches, leading to a significant increase in overall survival. Our current research provides evidence that GBM patients may benefit from pay-loaded EphA3 antibody therapies. Full article

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

▼ Show Figures

Figure 1

15 pages, 2379 KiB

Open AccessArticle

RNA-Sequencing Analysis of Adrenocortical Carcinoma, Pheochromocytoma and Paraganglioma from a Pan-Cancer Perspective

by Joakim Crona^1,2,*

, Samuel Backman³, Staffan Welin¹, David Taïeb⁴, Per Hellman³, Peter Stålberg³, Britt Skogseid¹ and Karel Pacak²

¹ Department of Medical Sciences, Uppsala University, Akademiska Sjukhuset ing 78, 75185 Uppsala, Sweden

² Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 10 Center Drive, Building 10, Room 1E-3140, Bethesda, MD 20892, USA

³ Department of Surgical Sciences, Uppsala University, Akademiska Sjukhuset ing 70, 75185 Uppsala, Sweden

⁴ Department of Nuclear Medicine, La Timone University Hospital, European Center for Research in Medical Imaging, Aix Marseille Université, 13385 Marseille, France

Cancers 2018, 10(12), 518; https://doi.org/10.3390/cancers10120518 - 15 Dec 2018

Cited by 9 | Viewed by 5890

Abstract

Adrenocortical carcinoma (ACC) and pheochromocytoma and paraganglioma (PPGL) are defined by clinicopathological criteria and can be further sub-divided based on different molecular features. Whether differences between these molecular subgroups are significant enough to re-challenge their current clinicopathological classification is currently unknown. It is [...] Read more.

Adrenocortical carcinoma (ACC) and pheochromocytoma and paraganglioma (PPGL) are defined by clinicopathological criteria and can be further sub-divided based on different molecular features. Whether differences between these molecular subgroups are significant enough to re-challenge their current clinicopathological classification is currently unknown. It is also not fully understood to which other cancers ACC and PPGL show similarity to. To address these questions, we included recent RNA-Seq data from the Cancer Genome Atlas (TCGA) and Therapeutically Applicable Research to Generate Effective Treatments (TARGET) datasets. Two bioinformatics pipelines were used for unsupervised clustering and principal components analysis. Results were validated using consensus clustering model and interpreted according to previous pan-cancer experiments. Two datasets consisting of 3319 tumors from 35 disease categories were studied. Consistent with the current classification, ACCs clustered as a homogenous group in a pan-cancer context. It also clustered close to neural crest derived tumors, including gliomas, neuroblastomas, pancreatic neuroendocrine tumors, and PPGLs. Contrary, some PPGLs mixed with pancreatic neuroendocrine tumors or neuroblastomas. Thus, our unbiased gene-expression analysis of PPGL did not overlap with their current clinicopathological classification. These results emphasize some importances of the shared embryological origin of these tumors, all either related or close to neural crest tumors, and opens for investigation of a complementary categorization based on gene-expression features. Full article

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

▼ Show Figures

Figure 1

15 pages, 10738 KiB

Open AccessArticle

In Silico Approach for Immunohistochemical Evaluation of a Cytoplasmic Marker in Breast Cancer

by Claudia Mazo^1,2,3,*,†

, Estibaliz Orue-Etxebarria^4,‡, Ignacio Zabalza^5,‡, Maria d. M. Vivanco^4,‡, Robert M. Kypta^4,6,‡

and Andoni Beristain^1,‡

¹ Vicomtech, eHealth and Biomedical Applications, 20009 San Sebastian-Donostia, Spain

² School of Computer Science, University College Dublin, D14 YH57 Dublin, Ireland

³ CeADAR: Centre for Applied Data Analytics Research, D04 V1 W8 Dublin, Ireland

⁴ CIC bioGUNE, Center for Cooperative Research in Biosciences, 48160 Bilbao, Spain

⁵ Department of Pathology, Galdakao-Usansolo Hospital, 48960 Galdakao, Spain

⁶ Imperial College London, Department of Surgery and Cancer, London SW7 2AZ, UK

^† Current address: Affiliation 2 and 3.

^‡ Authors with unequally contribution to this work.

Cancers 2018, 10(12), 517; https://doi.org/10.3390/cancers10120517 - 15 Dec 2018

Cited by 4 | Viewed by 5464

Abstract

Breast cancer is the most frequently diagnosed cancer in women and the second most common cancer overall, with nearly

1.7

million new cases worldwide every year. Breast cancer patients need accurate tools for early diagnosis and to improve treatment. Biomarkers are increasingly used [...] Read more.

Breast cancer is the most frequently diagnosed cancer in women and the second most common cancer overall, with nearly

1.7

million new cases worldwide every year. Breast cancer patients need accurate tools for early diagnosis and to improve treatment. Biomarkers are increasingly used to describe and evaluate tumours for prognosis, to facilitate and predict response to therapy and to evaluate residual tumor, post-treatment. Here, we evaluate different methods to separate Diaminobenzidine (DAB) from Hematoxylin and Eosin (H&E) staining for Wnt-1, a potential cytoplasmic breast cancer biomarker. A method comprising clustering and Color deconvolution allowed us to recognize and quantify Wnt-1 levels accurately at pixel levels. Experimental validation was conducted using a set of 12,288 blocks of

m \times n

pixels without overlap, extracted from a Tissue Microarray (TMA) composed of 192 tissue cores. Intraclass Correlations (ICC) among evaluators of the data of

0.634

,

0.791

,

0.551

and

0.63

for each Allred class and an average ICC of

0.752

among evaluators and automatic classification were obtained. Furthermore, this method received an average rating of

4.26

out of 5 in the Wnt-1 segmentation process from the evaluators. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

▼ Show Figures

Figure 1

12 pages, 1051 KiB

Open AccessArticle

Combination Therapy after TACE for Hepatocellular Carcinoma with Macroscopic Vascular Invasion: Stereotactic Body Radiotherapy versus Sorafenib

by Lujun Shen^1,2,†

, Mian Xi^2,3,†, Lei Zhao^2,3

, Xuhui Zhang^2,3, Xiuchen Wang^1,2, Zhimei Huang^1,2, Qifeng Chen^1,2

, Tianqi Zhang^1,2, Jingxian Shen^2,4, Mengzhong Liu^2,3 and Jinhua Huang^1,2,*

¹ Department of Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, China

² State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, China

³ Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China

⁴ Department of Radiology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China

^† These authors contributed equally to this work.

Cancers 2018, 10(12), 516; https://doi.org/10.3390/cancers10120516 - 14 Dec 2018

Cited by 30 | Viewed by 4632

Abstract

Stereotactic body radiotherapy (SBRT) has shown promising results in the control of macroscopic vascular invasion in patients with hepatocellular carcinoma (HCC); however, its efficacy in comparison to sorafenib when combined with transarterial chemoembolization (TACE) remains to be determined. Between 2009 and 2017, 77 [...] Read more.

Stereotactic body radiotherapy (SBRT) has shown promising results in the control of macroscopic vascular invasion in patients with hepatocellular carcinoma (HCC); however, its efficacy in comparison to sorafenib when combined with transarterial chemoembolization (TACE) remains to be determined. Between 2009 and 2017, 77 HCC patients with macroscopic vascular invasion receiving TACE–SBRT or TACE–sorafenib combination therapies were enrolled. The best treatment responses, overall survival (OS), and progression-free survival (PFS) of the two treatment arms were compared. Of the patients enrolled, 26 patients (33.8%) received TACE–SBRT treatment, and 51 (66.2%) received TACE–sorafenib treatment. The patients in the TACE–SBRT group were more frequently classified as elder in age (p = 0.012), having recurrent disease (p = 0.026), and showing lower rates of multiple hepatic lesions (p = 0.005) than patients in TACE–sorafenib group. After propensity score matching (PSM), 26 pairs of well-matched HCC patients were selected; patients in the TACE–SBRT group showed better overall response rates in trend compared to those in the TACE–sorafenib group. The hazard ratio (HR) of OS to PFS for the TACE–SBRT approach and the TACE–sorafenib approach was 0.36 (95% CI, 0.17–0.75; p = 0.007) and 0.35 (95% CI, 0.20–0.62; p < 0.001), respectively. For HCC patients with macrovascular invasion, TACE plus SBRT could provide improved OS and PFS compared to TACE–sorafenib therapy. Full article

▼ Show Figures

Figure 1

24 pages, 716 KiB

Open AccessReview

Radiotherapy as a New Player in Immuno-Oncology

by Shang-Jui Wang and Bruce Haffty^*

Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, 195 Little Albany St., New Brunswick, NJ 08901, USA

Cancers 2018, 10(12), 515; https://doi.org/10.3390/cancers10120515 - 14 Dec 2018

Cited by 22 | Viewed by 5253

Abstract

Recent development in radiation biology has revealed potent immunogenic properties of radiotherapy in cancer treatments. However, antitumor immune effects of radiotherapy are limited by the concomitant induction of radiation-dependent immunosuppressive effects. In the growing era of immunotherapy, combining radiotherapy with immunomodulating agents has [...] Read more.

Recent development in radiation biology has revealed potent immunogenic properties of radiotherapy in cancer treatments. However, antitumor immune effects of radiotherapy are limited by the concomitant induction of radiation-dependent immunosuppressive effects. In the growing era of immunotherapy, combining radiotherapy with immunomodulating agents has demonstrated enhancement of radiation-induced antitumor immune activation that correlated with improved treatment outcomes. Yet, how to optimally deliver combination therapy regarding dose-fractionation and timing of radiotherapy is largely unknown. Future prospective testing to fine-tune this promising combination of radiotherapy and immunotherapy is warranted. Full article

(This article belongs to the Special Issue New Developments in Radiotherapy)

▼ Show Figures

Figure 1

19 pages, 1766 KiB

Open AccessReview

Racial Disparity and Triple-Negative Breast Cancer in African-American Women: A Multifaceted Affair between Obesity, Biology, and Socioeconomic Determinants

by Sumit Siddharth^* and Dipali Sharma^*

Department of Oncology, Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA

Cancers 2018, 10(12), 514; https://doi.org/10.3390/cancers10120514 - 14 Dec 2018

Cited by 147 | Viewed by 14475

Abstract

Triple negative breast cancer (TNBC) is a molecularly heterogeneous disease whose incidence is disproportionately higher in African American (AA) women compared to European American (EA) women. Earlier onset, more advanced stage at diagnosis, and aggressive tumor phenotype are some of the characteristic features [...] Read more.

Triple negative breast cancer (TNBC) is a molecularly heterogeneous disease whose incidence is disproportionately higher in African American (AA) women compared to European American (EA) women. Earlier onset, more advanced stage at diagnosis, and aggressive tumor phenotype are some of the characteristic features of TNBC in women with African ethnicity in comparison to EA women, denoting one of the most significant examples of racial disparity in oncology. It is still contentious whether health disparities result in aggressive behavior of TNBC in AA women or it is indeed a molecularly distinct disease. Given the “gaps-in-knowledge” surrounding racial disparity in TNBC, this review discusses various socioeconomic factors and the genetic predispositions contributing to poor prognosis of TNBC in AA women. While socioeconomic factors may contribute to poorer survival, multiple preclinical and clinical studies suggest inherent genetic risk factors and aberrant activation of oncogenic pathways in AA TNBC. Additionally, AA women are more likely to be obese and obesity is known to drive a molecular circuitry resulting in aggressive tumor progression indicating a potential obesity-TNBC axis at work in AA women. Given the multifactorial nature of AA TNBC, a transdisciplinary approach may help bridge the disparity that exists between AA and EA TNBC. Full article

▼ Show Figures

Figure 1

16 pages, 980 KiB

Open AccessReview

BRCA1-Dependent Transcriptional Regulation: Implication in Tissue-Specific Tumor Suppression

by Xiaowen Zhang^*

and Rong Li^*

Department of Biochemistry & Molecular Medicine, School of Medicine & Health Sciences, The George Washington University, Washington, DC 20037, USA

Cancers 2018, 10(12), 513; https://doi.org/10.3390/cancers10120513 - 14 Dec 2018

Cited by 17 | Viewed by 6136

Abstract

Germ-line mutations in breast cancer susceptibility gene 1 (BRCA1) predominantly predispose women to breast and ovarian cancers. BRCA1 is best known for its functions in maintenance of genomic integrity including repairing DNA double-strand breaks through homologous recombination and suppressing DNA replication [...] Read more.

Germ-line mutations in breast cancer susceptibility gene 1 (BRCA1) predominantly predispose women to breast and ovarian cancers. BRCA1 is best known for its functions in maintenance of genomic integrity including repairing DNA double-strand breaks through homologous recombination and suppressing DNA replication stress. However, whether these universally important BRCA1 functions in maintenance of genomic stability are sufficient to account for its tissue-specific tumor-suppressing function remains unclear. Accumulating evidence indicates that there are previously underappreciated roles of BRCA1 in transcriptional regulation and chromatin remodeling. In this review, we discuss the functional significance of interactions between BRCA1 and various transcription factors, its role in epigenetic regulation and chromatin dynamics, and BRCA1-dependent crosstalk between the machineries of transcription and genome integrity. Furthermore, we propose a model of how transcriptional regulation could contribute to tissue-dependent tumor-suppressing function of BRCA1. Full article

(This article belongs to the Special Issue BRCA Mutations and Cancer)

▼ Show Figures

Figure 1

17 pages, 2057 KiB

Open AccessArticle

The STAT3/Slug Axis Enhances Radiation-Induced Tumor Invasion and Cancer Stem-like Properties in Radioresistant Glioblastoma

by Jang-Chun Lin^1,2,3, Jo-Ting Tsai^2,3, Tsu-Yi Chao^1,4, Hsin-I Ma^5,6 and Wei-Hsiu Liu^5,6,*

¹ Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11042, Taiwan

² Department of Radiation Oncology, Shuang Ho Hospital, Taipei Medical University, Taipei 23561, Taiwan

³ Department of Radiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11042, Taiwan

⁴ Division of Hematology/Oncology, Shuang-Ho Hospital, Taipei Medical University, Taipei 23561, Taiwan

⁵ Department of Neurological Surgery, Tri-Service General Hospital and National Defense Medical Center, No. 325, Sec. 2, Cheng-Kung Road, Taipei 11490, Taiwan

⁶ Department of Surgery, School of Medicine, National Defense Medical Center, Taipei 11490, Taiwan

Cancers 2018, 10(12), 512; https://doi.org/10.3390/cancers10120512 - 13 Dec 2018

Cited by 57 | Viewed by 4887

Abstract

Glioblastoma multiforme (GBM) requires radiotherapy (RT) as a part of definitive management strategy. RT is highly effective, destroying cancer cells that may exist around the surgical tumor bed. However, GBM still has a poor prognosis and a high local recurrence rate after RT. [...] Read more.

Glioblastoma multiforme (GBM) requires radiotherapy (RT) as a part of definitive management strategy. RT is highly effective, destroying cancer cells that may exist around the surgical tumor bed. However, GBM still has a poor prognosis and a high local recurrence rate after RT. Accumulating research indicates that GBM contains cancer stem-like cells (CSCs), which are radioresistant and result in therapeutic failure. Additionally, GBM cells can aggressively invade normal brain tissue, inducing therapeutic failure. Using clinical observations, we evaluated the effect of radiation on tumor control. We also explored the biomolecular pathways that connect radioresistance and CSC- and epithelial-mesenchymal transition (EMT)-associated phenotypes in patient-derived GBM cells. Transwell and microarray assay demonstrated that radioresistant GBM cells (GBM-R2I2) exhibit increased invasion and self-renewal abilities compared with parental GBM cells. Finally, to identify potential mechanisms underlying these observations, we used a PCR array to search for molecular markers of cell motility. Signal transducer and activator of transcription 3 (STAT3) directly bound to the Slug promoter in a chromatin immunoprecipitation assay. Reduced STAT3 decreased Slug expression and suppressed cell invasion in GBM-R2I2 cells while increasing Slug reversed these effects. In addition, STAT3 knockdown significantly inhibited CSC properties, synergistically increased the radiotherapeutic effect, and effectively increased the survival rate in vivo. We deciphered a new pathway of GBM radioresistance, invasion, and recurrence via the STAT3/Slug axis that could be a new target of GBM therapy. Full article

▼ Show Figures

Figure 1

26 pages, 2094 KiB

Open AccessArticle

Use of Germline Genetic Variability for Prediction of Chemoresistance and Prognosis of Breast Cancer Patients

by Viktor Hlavac^1,†

, Maria Kovacova^2,†, Katerina Elsnerova^1,2, Veronika Brynychova¹, Renata Kozevnikovova³, Karel Raus⁴, Katerina Kopeckova⁵, Sona Mestakova⁶, David Vrana⁷

, Jiri Gatek⁸, Pavel Ostasov⁹

, Radka Vaclavikova¹ and Pavel Soucek^1,*

¹ Laboratory of Pharmacogenomics, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, 323 00 Pilsen, Czech Republic

² Third Faculty of Medicine, Charles University, 100 00 Prague, Czech Republic

³ Department of Oncosurgery, Medicon, 140 00 Prague, Czech Republic

⁴ Department of Breast Services, Institute for the Care for Mother and Child, 147 00 Prague, Czech Republic

⁵ Department of Oncology, Second Faculty of Medicine, Charles University and Motol University Hospital, 150 06 Prague, Czech Republic

⁶ Department of Surgery, Second Faculty of Medicine, Charles University and Motol University Hospital, 150 06 Prague, Czech Republic

⁷ Department of Oncology, Palacky University Medical School and Teaching Hospital, 771 47 Olomouc, Czech Republic

⁸ Department of Surgery, EUC Hospital and University of Tomas Bata in Zlin, 760 01 Zlin, Czech Republic

⁹ Laboratory of Tumor Biology, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, 323 00 Pilsen, Czech Republic

^† These authors contributed equally to this work.

Cancers 2018, 10(12), 511; https://doi.org/10.3390/cancers10120511 - 12 Dec 2018

Cited by 16 | Viewed by 4966

Abstract

The aim of our study was to set up a panel for targeted sequencing of chemoresistance genes and the main transcription factors driving their expression and to evaluate their predictive and prognostic value in breast cancer patients. Coding and regulatory regions of 509 [...] Read more.

The aim of our study was to set up a panel for targeted sequencing of chemoresistance genes and the main transcription factors driving their expression and to evaluate their predictive and prognostic value in breast cancer patients. Coding and regulatory regions of 509 genes, selected from PharmGKB and Phenopedia, were sequenced using massive parallel sequencing in blood DNA from 105 breast cancer patients in the testing phase. In total, 18,245 variants were identified of which 2565 were novel variants (without rs number in dbSNP build 150) in the testing phase. Variants with major allele frequency over 0.05 were further prioritized for validation phase based on a newly developed decision tree. Using emerging in silico tools and pharmacogenomic databases for functional predictions and associations with response to cytotoxic therapy or disease-free survival of patients, 55 putative variants were identified and used for validation in 805 patients with clinical follow up using KASP^TM technology. In conclusion, associations of rs2227291, rs2293194, and rs4376673 (located in ATP7A, KCNAB1, and DFFB genes, respectively) with response to neoadjuvant cytotoxic therapy and rs1801160 in DPYD with disease-free survival of patients treated with cytotoxic drugs were validated and should be further functionally characterized. Full article

(This article belongs to the Special Issue Cancer Chemoresistance)

▼ Show Figures

Figure 1

14 pages, 248 KiB

Open AccessReview

Management of Typical and Atypical Pulmonary Carcinoids Based on Different Established Guidelines

by Rohit Gosain¹, Sarbajit Mukherjee^1,2, Sai S. Yendamuri³ and Renuka Iyer^1,*

¹ Division of Hematology & Oncology, Roswell Park Comprehensive Cancer Center, University at Buffalo School of Medicine, Buffalo, NY 14203, USA

² Division of Hematology & Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA

³ Depart of Thoracic Surgery Oncology, Roswell Park Comprehensive Cancer Center, University at Buffalo School of Medicine, Buffalo, NY 14203, USA

Cancers 2018, 10(12), 510; https://doi.org/10.3390/cancers10120510 - 12 Dec 2018

Cited by 57 | Viewed by 5940

Abstract

Neuroendocrine tumors (NETs) are a group of malignancies that originated from neuroendocrine cells, with the most common sites being lungs and the gastrointestinal tract. Lung NETs comprise 25% of all lung malignancies. Small cell lung cancer is the most common form of lung [...] Read more.

Neuroendocrine tumors (NETs) are a group of malignancies that originated from neuroendocrine cells, with the most common sites being lungs and the gastrointestinal tract. Lung NETs comprise 25% of all lung malignancies. Small cell lung cancer is the most common form of lung NETs, and other rare forms include well-differentiated typical carcinoids (TCs) and poorly differentiated atypical carcinoids (ACs). Given the paucity of randomized studies, rational treatment is challenging. Therefore, it is recommended that these decisions be made using a multidisciplinary collaborative approach. Surgery remains the mainstay of treatment, when feasible. Following surgery, various guidelines offer different recommendations in the adjuvant setting. In this paper, we describe the adjuvant management of lung NETs, as recommended by different guidelines, and highlight their differences. In addition to that, we also discuss the management of metastatic lung NETS, including the use of peptide receptor radionucleotide therapy. Full article

16 pages, 2125 KiB

Open AccessArticle

Mitochondrial Hyperactivation and Enhanced ROS Production are Involved in Toxicity Induced by Oncogenic Kinases Over-Signaling

by Monica Ceccon^1,*

, Mario Mauri¹

, Luca Massimino²

, Giovanni Giudici³, Rocco Piazza¹, Carlo Gambacorti-Passerini¹ and Luca Mologni¹

¹ Department of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy

² Division of Neuroscience, San Raffaele Scientific Institute, 20132 Milano, Italy

³ Tettamanti Research Centre, Pediatric Clinic, c/o Nuovo Osp.San Gerardo, 20900 Monza, Italy

Cancers 2018, 10(12), 509; https://doi.org/10.3390/cancers10120509 - 12 Dec 2018

Cited by 4 | Viewed by 3495

Abstract

Targeted therapy is an effective, rational, and safe approach to solid and hematological tumors treatment. Unfortunately, a significant fraction of patients treated with tyrosine kinase inhibitors (TKI) relapses mainly because of gene amplification, mutations, or other bypass mechanisms. Recently a growing number of [...] Read more.

Targeted therapy is an effective, rational, and safe approach to solid and hematological tumors treatment. Unfortunately, a significant fraction of patients treated with tyrosine kinase inhibitors (TKI) relapses mainly because of gene amplification, mutations, or other bypass mechanisms. Recently a growing number of papers showed how, in some cases, resistance due to oncogene overexpression may be associated with drug addiction: cells able to proliferate in the presence of high TKI doses become also TKI dependent, undergoing cellular stress, and apoptosis/death upon drug withdrawal. Notably, if a sub-cellular population survives TKI discontinuation it is also partially re-sensitized to the same drug. Thus, it is possible that a subset of patients relapsing upon TKI treatment may benefit from a discontinuous therapeutic schedule. We focused on two different hematologic malignancies, chronic myeloid leukemia (CML) and anaplastic large cell lymphoma (ALCL), both successfully treatable with TKIs. The two models utilized (LAMA and SUP-M2) differed in having oncogene overexpression as the sole cause of drug resistance (CML), or additionally carrying kinase domain mutations (ALCL). In both cases drug withdrawal caused a sudden overload of oncogenic signal, enhanced mitochondria activity, induced the release of a high amount of reactive oxygen species (ROS), and caused genotoxic stress and massive cell death. In LAMA cells (CML) we could rescue the cells from death by partially blocking downstream oncogenic signaling or lowering ROS detrimental effect by adding reduced glutathione. Full article

▼ Show Figures

Figure 1

1 pages, 156 KiB

Open AccessErratum

Erratum: Shibata S.; et al. Proton Beam Therapy without Fiducial Markers Using Four-Dimensional CT Planning for Large Hepatocellular Carcinomas. Cancers 2018, 10, 71

by Satoshi Shibata^1,2,*, Shigeyuki Takamatsu^1,2

, Kazutaka Yamamoto¹, Miu Mizuhata¹, Sayuri Bou¹, Yoshitaka Sato¹, Mariko Kawamura³, Satoko Asahi⁴, Yuji Tameshige¹, Yoshikazu Maeda¹, Makoto Sasaki¹, Tomoyasu Kumano², Satoshi Kobayashi⁵

, Hiroyasu Tamamura¹ and Toshifumi Gabata⁵

¹ Proton Therapy Center, Fukui Prefectural Hospital, Fukui 910-8526, Japan

² Department of Radiotherapy, Kanazawa University Hospital, Kanazawa, Ishikawa 920-8641, Japan

³ Department of Radiology, Nagoya University Hospital, Nagoya, Aichi 466-8560, Japan

⁴ Department of Radiology, University of Fukui Hospital, Eiheiji, Fukui 910-1193, Japan

⁵ Department of Radiology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa 920-8641, Japan

Cancers 2018, 10(12), 508; https://doi.org/10.3390/cancers10120508 - 11 Dec 2018

Cited by 2 | Viewed by 2390

Abstract

The authors wish to make the following corrections to this paper [...] Full article

20 pages, 4835 KiB

Open AccessArticle

The Role of Arrestin Domain-Containing 3 in Regulating Endocytic Recycling and Extracellular Vesicle Sorting of Integrin β4 in Breast Cancer

by Young Hwa Soung, Shane Ford, Cecilia Yan and Jun Chung^*

Department of Pathology, Stony Brook Medicine, Stony Brook, New York, NY 11794, USA

Cancers 2018, 10(12), 507; https://doi.org/10.3390/cancers10120507 - 11 Dec 2018

Cited by 16 | Viewed by 4349

Abstract

Despite the established role of integrin β4 (ITG β4) in breast cancer progression, the importance of endocytic recycling of ITG β4 and its regulatory mechanism are poorly understood. Here, we found that a sub-population of ITG β4 is sorted into early endosomes, recycled [...] Read more.

Despite the established role of integrin β4 (ITG β4) in breast cancer progression, the importance of endocytic recycling of ITG β4 and its regulatory mechanism are poorly understood. Here, we found that a sub-population of ITG β4 is sorted into early endosomes, recycled back to the plasma membrane, and secreted in the form of extracellular vesicles (EVs) upon EGF treatment in triple negative breast cancer (TNBC) cells. A metastasis suppressor, ARRDC3 (arrestin domain-containing 3) prevents EGF-driven endocytic recycling of ITG β4 by inducing NEDD4-dependent ubiquitination of ITG β4 and targeting endosomal ITG β4 into lysosomes. Endocytic recycling of ITG β4 is linked to sorting of ITG β4 into EVs (ITG β4+ EVs). ITG β4+ EVs are mainly detectable from supernatants of TNBC cells and their production is inhibited by ARRDC3 expression. ARRDC3 reduces the metastatic potentials of breast cancer cell-derived EVs by reducing ITG β4 levels in EVs. Overall, current studies provide novel mechanistic insights on the regulatory mechanism of ITG β4 recycling, and its importance in invasive potentials of TNBC EVs, thus providing the basis for therapeutic targeting of the ARRDC3/ITG β4 pathway in TNBC. Full article

▼ Show Figures

Figure 1

22 pages, 643 KiB

Open AccessFeature PaperReview

Targeting BRCA Deficiency in Breast Cancer: What are the Clinical Evidences and the Next Perspectives?

by Emanuel Nicolas¹, François Bertucci^1,2, Renaud Sabatier^1,2

and Anthony Gonçalves^1,2,*

¹ Department of Medical Oncology, Institut Paoli-Calmettes, 13009 Marseille, France

² CRCM-Predictive Oncology laboratory, Institut Paoli-Calmettes, Inserm U1068, CNRS UMR7258, Aix-Marseille Univ, 13009 Marseille, France

Cancers 2018, 10(12), 506; https://doi.org/10.3390/cancers10120506 - 11 Dec 2018

Cited by 38 | Viewed by 5106

Abstract

Breast cancers (BC) associated with germline mutations of BRCA1/2 represent 3–5% of cases. BRCA1/2-associated BC have biological features leading to genomic instability and potential sensitivity to DNA damaging agents, including poly(ADP-ribose) polymerase (PARP) and platinum agents. In this review, we will summarize [...] Read more.

Breast cancers (BC) associated with germline mutations of BRCA1/2 represent 3–5% of cases. BRCA1/2-associated BC have biological features leading to genomic instability and potential sensitivity to DNA damaging agents, including poly(ADP-ribose) polymerase (PARP) and platinum agents. In this review, we will summarize clinical trials of chemotherapy and PARP inhibitors (PARPi), alone or in combination, at the early or late stage of BRCA1/2-associated BC. We will also present the mechanisms of resistance to PARPi as well as the new therapeutic strategies of association with PARPi. Finally, we will discuss under which conditions the use of DNA damaging agents can be extended to the BRCA1/2-wild type population, the BRCAness concept. Full article

(This article belongs to the Special Issue BRCA Mutations and Cancer)

▼ Show Figures

Figure 1

17 pages, 2931 KiB

Open AccessArticle

Intracellular Iron Chelation by a Novel Compound, C7, Reactivates Epstein–Barr Virus (EBV) Lytic Cycle via the ERK-Autophagy Axis in EBV-Positive Epithelial Cancers

by Stephanie Pei Tung Yiu^1,2,†

, Kwai Fung Hui^1,2,†, Chung King Choi^1,2,†, Richard Yi Tsun Kao³, Chi Wang Ma⁴, Dan Yang⁴ and Alan Kwok Shing Chiang^1,2,*

¹ Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong SAR, China

² Center for Nasopharyngeal Carcinoma Research, The University of Hong Kong, Hong Kong SAR, China

³ Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China

⁴ Department of Chemistry, The University of Hong Kong, Hong Kong SAR, China

^† These authors contributed equally to this work.

Cancers 2018, 10(12), 505; https://doi.org/10.3390/cancers10120505 - 11 Dec 2018

Cited by 23 | Viewed by 4679

Abstract

Pharmaceutical reactivation of lytic cycle of Epstein–Barr virus (EBV) represents a potential therapeutic strategy against EBV-associated epithelial malignancies, e.g., gastric carcinoma (GC) and nasopharyngeal carcinoma (NPC). A novel lytic-inducing compound, C7, which exhibits structural similarity to Di-2-Pyridyl Ketone 4, 4-Dimethyl-3-Thiosemicarbazone (Dp44mT), a known [...] Read more.

Pharmaceutical reactivation of lytic cycle of Epstein–Barr virus (EBV) represents a potential therapeutic strategy against EBV-associated epithelial malignancies, e.g., gastric carcinoma (GC) and nasopharyngeal carcinoma (NPC). A novel lytic-inducing compound, C7, which exhibits structural similarity to Di-2-Pyridyl Ketone 4, 4-Dimethyl-3-Thiosemicarbazone (Dp44mT), a known chelator of intracellular iron, is found to reactivate EBV lytic cycle in GC and NPC. This study aims to investigate the role of intracellular iron chelation by C7 and other iron chelators in lytic reactivation of EBV in GC and NPC. Testing of six structural analogs of C7 revealed only those which have high affinity towards transition metals could induce EBV lytic cycle. Precomplexing C7 and iron chelators to iron prior to treatment of the cells abolished EBV lytic reactivation. Though hypoxia signaling pathway was activated, it was not the only pathway associated with EBV reactivation. Specifically, C7 and iron chelators initiated autophagy by activating extracellular signal-regulated kinase (ERK1/2) to reactivate EBV lytic cycle since autophagy and EBV lytic reactivation were abolished in cells treated with ERK1/2 blockers whilst inhibition of autophagy by 3-Methyladenine (3-MA) and atg5 knockdown significantly abolished EBV lytic reactivation. In summary, we discovered a novel mechanism of reactivation of the EBV lytic cycle through intracellular iron chelation and induction of ERK-autophagy axis in EBV-positive epithelial malignancies, raising the question whether clinically available iron chelators can be incorporated into existing therapeutic regimens to treat these cancers. Full article

▼ Show Figures

Figure 1

13 pages, 391 KiB

Open AccessArticle

Pathological and Molecular Characteristics of Colorectal Cancer with Brain Metastases

by Pauline Roussille^1,2,3, Gaelle Tachon^2,3,4, Claire Villalva⁴, Serge Milin⁵, Eric Frouin^3,5, Julie Godet⁵, Antoine Berger¹, Sheik Emambux^2,3,4,6, Christos Petropoulos^2,3,4, Michel Wager^2,3,7, Lucie Karayan-Tapon^2,3,4,† and David Tougeron^3,6,8,*,†

¹ Department of Radiation Oncology, University Hospital of Poitiers, 86021 Poitiers, France

² INSERM 1084, Experimental and Clinical Neurosciences Laboratory, University of Poitiers, 86073 Poitiers, France

³ Faculty of Medicine, University of Poitiers, 86021 Poitiers, France

⁴ Cancer Biology Department, University Hospital of Poitiers, 86021 Poitiers, France

⁵ Pathology Department, University Hospital of Poitiers, 86021 Poitiers, France

⁶ Medical Oncology Department, University Hospital of Poitiers, 86021 Poitiers, France

⁷ Department of Neurosurgery, University Hospital of Poitiers, 86021 Poitiers, France

⁸ Department of Gastroenterology, University Hospital of Poitiers, 86021 Poitiers, France

^† These authors have contributed equally to this article.

Cancers 2018, 10(12), 504; https://doi.org/10.3390/cancers10120504 - 10 Dec 2018

Cited by 23 | Viewed by 4174

Abstract

Background: Colorectal cancers (CRC) with brain metastases (BM) are scarcely described. The main objective of this study was to determine the molecular profile of CRC with BM. Methods: We included 82 CRC patients with BM. KRAS, NRAS, BRAF and mismatch repair [...] Read more.

Background: Colorectal cancers (CRC) with brain metastases (BM) are scarcely described. The main objective of this study was to determine the molecular profile of CRC with BM. Methods: We included 82 CRC patients with BM. KRAS, NRAS, BRAF and mismatch repair (MMR) status were investigated on primary tumors (n = 82) and BM (n = 38). ALK, ROS1, cMET, HER-2, PD-1, PD-L1, CD3 and CD8 status were evaluated by immunohistochemistry, and when recommended, by fluorescence in situ hybridization. Results: In primary tumors, KRAS, NRAS and BRAF mutations were observed in 56%, 6%, and 6% of cases, respectively. No ROS1, ALK and cMET rearrangement was detected. Only one tumor presented HER-2 amplification. Molecular profiles were mostly concordant between BM and paired primary tumors, except for 9% of discordances for RAS mutation. CD3, CD8, PD-1 and PD-L1 expressions presented some discordance between primary tumors and BM. In multivariate analysis, multiple BM, lung metastases and PD-L1+ tumor were predictive of poor overall survival. Conclusions: CRCs with BM are associated with high frequency of RAS mutations and significant discordance for RAS mutational status between BM and paired primary tumors. Multiple BM, lung metastases and PD-L1+ have been identified as prognostic factors and can guide therapeutic decisions for CRC patients with BM. Full article

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

▼ Show Figures

Figure 1

27 pages, 1247 KiB

Open AccessFeature PaperReview

Transporter and Lysosomal Mediated (Multi)drug Resistance to Tyrosine Kinase Inhibitors and Potential Strategies to Overcome Resistance

by Daniel J. De Klerk¹

, Richard J. Honeywell¹

, Gerrit Jansen² and Godefridus J. Peters^1,*

¹ Laboratory Medical Oncology, Amsterdam UMC, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands

² Rheumatology and Immunology Center—Location VUmc, Amsterdam UMC, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands

Cancers 2018, 10(12), 503; https://doi.org/10.3390/cancers10120503 - 10 Dec 2018

Cited by 48 | Viewed by 8080

Abstract

Tyrosine kinase inhibitors are a class of chemotherapeutic drugs that target specific protein kinases. These tyrosine kinase inhibitors constitute a relatively new class of drugs which target for instance Bcr-Abl, Epidermal Growth Factor Receptor (EGFR) and Vascular Endothelial Growth Factor Receptor (VEGFR). Despite [...] Read more.

Tyrosine kinase inhibitors are a class of chemotherapeutic drugs that target specific protein kinases. These tyrosine kinase inhibitors constitute a relatively new class of drugs which target for instance Bcr-Abl, Epidermal Growth Factor Receptor (EGFR) and Vascular Endothelial Growth Factor Receptor (VEGFR). Despite some initial successes, the overall therapeutic benefit of tyrosine kinase inhibitors in the clinic has been mixed. Next to mutations in the target, multidrug resistance is a major obstacle for which still no clinically effective strategies have been developed. Major mechanisms of multidrug resistance are mediated by drug efflux transporter proteins. Moreover, there is accumulating evidence that multidrug resistance can also be caused by lysosomal sequestration of drugs, effectively trapping tyrosine kinase inhibitors and preventing them from reaching their target. Lysosomal drug sequestration seems to work together with ATP-binding cassette transporters, increasing the capacity of lysosomes to mediate sequestration. Both membrane efflux transporter proteins and lysosomes present potential therapeutic targets that could reverse multidrug resistance and increase drug efficacy in combination therapy. This review describes both mechanisms and discusses a number of proposed strategies to circumvent or reverse tyrosine kinase inhibitor-related multidrug resistance. Full article

(This article belongs to the Special Issue Cancer Chemoresistance)

▼ Show Figures

Figure 1

12 pages, 920 KiB

Open AccessReview

Treatment of Pain in Cancer: Towards Personalised Medicine

by Marieke H. J. Van den Beuken-van Everdingen^1,*

, Sander M. J. Van Kuijk², Daisy J. A. Janssen^1,3

and Elbert A. J. Joosten^4,5

¹ Centre of Expertise for Palliative Care, Maastricht University Medical Centre (MUMC+), 6229HX Maastricht, The Netherlands

² Department of Clinical Epidemiology and Medical Technology Assessment, Maastricht University Medical Centre (MUMC+), 6229HX Maastricht, The Netherlands

³ Centre of Expertise for Chronic Organ Failure (CIRO), 6085NM Horn, The Netherlands

⁴ Department of Anesthesiology and Pain Management, Maastricht University Medical Centre (MUMC+), University Pain Centre Maastricht (UPCM), 6229HX Maastricht, The Netherlands

⁵ Department of Translational Neuroscience, School of Mental Health and Neuroscience, Maastricht University, 6211LK Maastricht The Netherlands

Cancers 2018, 10(12), 502; https://doi.org/10.3390/cancers10120502 - 10 Dec 2018

Cited by 46 | Viewed by 7532

Abstract

Despite increased attention to cancer pain, pain prevalence in patients with cancer has not improved over the last decade and one third of cancer patients on anticancer therapy and half of patients with advanced disease still suffer from moderate to severe pain. In [...] Read more.

Despite increased attention to cancer pain, pain prevalence in patients with cancer has not improved over the last decade and one third of cancer patients on anticancer therapy and half of patients with advanced disease still suffer from moderate to severe pain. In this review, we explore the possible reasons for the ongoing high prevalence of cancer pain and discuss possible future directions for improvement in personalised pain management. Among possible reasons for the lack of improvement are: Barriers for patients to discuss pain with clinicians spontaneously; pain measurement instruments are not routinely used in daily practice; limited knowledge concerning the assessment of undertreatment; changes in patients’ characteristics, including the ageing of the population; lack of significant improvement in the treatment of neuropathic pain; limitations of pharmacological treatment and lack of evidence-based nonpharmacological treatment strategies. In order to improve cancer pain treatment, we recommend: (1) Physicians proactively ask about pain and measure pain using assessment instruments; (2) the development of an optimal tool measuring undertreatment; (3) educational interventions to improve health care workers’ skills in pain management; (4) the development of more effective and personalised pharmacological and nonpharmacological pain treatment. Full article

(This article belongs to the Special Issue Cancer Pains)

▼ Show Figures

Figure 1

16 pages, 3357 KiB

Open AccessArticle

Venous Thromboembolism in Asian Patients with Pancreatic Cancer Following Palliative Chemotherapy: Low Incidence but a Negative Prognosticator for Those with Early Onset

by Jen-Shi Chen¹

, Chia-Yen Hung^1,2

, Hung Chang¹, Chien-Ting Liu³

, Yen-Yang Chen³, Chang-Hsien Lu⁴, Pei-Hung Chang⁵

, Yu-Shin Hung¹ and Wen-Chi Chou^1,*

¹ Departments of Hematology-Oncology, Chang Gung Memorial Hospital at Linkou and Chang Gung University College of Medicine, Taoyaun 333, Taiwan

² Division of Hematology-Oncology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei 104, Taiwan

³ Department of Hematology-Oncology, Chang Gung Memorial Hospital at Kaohsiung, Kaohsiung 833, Taiwan

⁴ Departments of Hematology-Oncology, Chang Gung Memorial Hospital at Chiayi, Chiayi 612, Taiwan

⁵ Department of Hematology-Oncology, Chang Gung Memorial Hospital at Keelung, Keelung 204, Taiwan

Cancers 2018, 10(12), 501; https://doi.org/10.3390/cancers10120501 - 10 Dec 2018

Cited by 22 | Viewed by 3666

Abstract

Background: Few studies have reported the epidemiology and clinical outcome of venous thromboembolism (VTE) in Asian patients with pancreatic cancer. This study investigated the incidence, risk factors, and clinical outcome of VTE in patients with pancreatic cancer following palliative chemotherapy. Methods: The medical [...] Read more.

Background: Few studies have reported the epidemiology and clinical outcome of venous thromboembolism (VTE) in Asian patients with pancreatic cancer. This study investigated the incidence, risk factors, and clinical outcome of VTE in patients with pancreatic cancer following palliative chemotherapy. Methods: The medical records of 838 patients with newly diagnosed locally advanced or metastatic pancreatic cancer who underwent palliative chemotherapy between 2010 and 2016 at four institutes in Taiwan were retrospectively reviewed. The clinical characteristics of all patients were analyzed to identify independent predictors of VTE and their effects on survival outcome. Results: During the median follow-up period of 7.7 months (range, 0.6–55.6), VTE occurred in 67 (8.0%) of the 838 patients. Leukocyte count > 11,000/μL and presence of liver metastases were the independent predictors of VTE. Patients with VTE did not show significantly poorer survival outcomes than those without VTE. However, early-onset VTE that occurred within 1.5 months after chemotherapy initiation was an independent negative prognosticator for overall survival. Conclusion: VTE incidence was found to be lower in Asian patients with pancreatic cancer than in their Western counterparts. Early-onset VTE, but not late-onset VTE, is a negative prognosticator for survival outcomes. Full article

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

▼ Show Figures

Figure 1

26 pages, 2994 KiB

Open AccessArticle

Mitochondrial RNA Expression and Single Nucleotide Variants in Association with Clinical Parameters in Primary Breast Cancers

by Marjolein J. A. Weerts^*, Marcel Smid, John A. Foekens, Stefan Sleijfer and John W. M. Martens

Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015 CE Rotterdam, The Netherlands

Cancers 2018, 10(12), 500; https://doi.org/10.3390/cancers10120500 - 9 Dec 2018

Cited by 8 | Viewed by 3730

Abstract

The human mitochondrial DNA (mtDNA) encodes 37 genes, including thirteen proteins essential for the respiratory chain, and RNAs functioning in the mitochondrial translation apparatus. The total number of mtDNA molecules per cell (mtDNA content) is variable between tissue types and also between tumors [...] Read more.

The human mitochondrial DNA (mtDNA) encodes 37 genes, including thirteen proteins essential for the respiratory chain, and RNAs functioning in the mitochondrial translation apparatus. The total number of mtDNA molecules per cell (mtDNA content) is variable between tissue types and also between tumors and their normal counterparts. For breast cancer, tumors tend to be depleted in their mtDNA content compared to adjacent normal mammary tissue. Various studies have shown that primary breast tumors harbor somatic mtDNA variants. A decrease in mtDNA content or the presence of somatic variants could indicate a reduced mitochondrial function within breast cancer. In this explorative study we aimed to further understand genomic changes and expression of the mitochondrial genome within breast cancer, by analyzing RNA sequencing data of primary breast tumor specimens of 344 cases. We demonstrate that somatic variants detected at the mtRNA level are representative for somatic variants in the mtDNA. Also, the number of somatic variants within the mitochondrial transcriptome is not associated with mutational processes impacting the nuclear genome, but is positively associated with age at diagnosis. Finally, we observe that mitochondrial expression is related to ER status. We conclude that there is a large heterogeneity in somatic mutations of the mitochondrial genome within primary breast tumors, and differences in mitochondrial expression among breast cancer subtypes. The exact impact on metabolic differences and clinical relevance deserves further study. Full article

▼ Show Figures

Figure 1

26 pages, 8363 KiB

Open AccessArticle

Mitochondrial VDAC1 Silencing Leads to Metabolic Rewiring and the Reprogramming of Tumour Cells into Advanced Differentiated States

by Tasleem Arif^†,‡

, Avijit Paul^†, Yakov Krelin, Anna Shteinfer-Kuzmine and Varda Shoshan-Barmatz^*

¹ Department of Life Sciences, The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel

^† Contributed equal to these authors.

^‡ Present address: Department of Cell, Developmental & Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA

Cancers 2018, 10(12), 499; https://doi.org/10.3390/cancers10120499 - 8 Dec 2018

Cited by 46 | Viewed by 6379

Abstract

Oncogenic properties, along with the metabolic reprogramming necessary for tumour growth and motility, are acquired by cancer cells. Thus, tumour metabolism is becoming a target for cancer therapy. Here, cancer cell metabolism was tackled by silencing the expression of voltage-dependent anion channel 1 [...] Read more.

Oncogenic properties, along with the metabolic reprogramming necessary for tumour growth and motility, are acquired by cancer cells. Thus, tumour metabolism is becoming a target for cancer therapy. Here, cancer cell metabolism was tackled by silencing the expression of voltage-dependent anion channel 1 (VDAC1), a mitochondrial protein that controls cell energy, as well as metabolic and survival pathways and that is often over-expressed in many cancers. We demonstrated that silencing VDAC1 expression using human-specific siRNA (si-hVDAC1) inhibited cancer cell growth, both in vitro and in mouse xenograft models of human glioblastoma (U-87MG), lung cancer (A549), and triple negative breast cancer (MDA-MB-231). Importantly, treatment with si-hVDAC1 induced metabolic rewiring of the cancer cells, reversing their oncogenic properties and diverting them towards differentiated-like cells. The si-hVDAC1-treated residual “tumour” showed reprogrammed metabolism, decreased proliferation, inhibited stemness and altered expression of genes and proteins, leading to cell differentiation toward less malignant lineages. These VDAC1 depletion-mediated effects involved alterations in master transcription factors associated with cancer hallmarks, such as highly increased expression of p53 and decreased expression of HIF-1a and c-Myc that regulate signalling pathways (e.g., AMPK, mTOR). High expression of p53 and the pro-apoptotic proteins cytochrome c and caspases without induction of apoptosis points to functions for these proteins in promoting cell differentiation. These results clearly show that VDAC1 depletion similarly leads to a rewiring of cancer cell metabolism in breast and lung cancer and glioblastoma, regardless of origin or mutational status. This metabolic reprogramming results in cell growth arrest and inhibited tumour growth while encouraging cell differentiation, thus generating cells with decreased proliferation capacity. These results further suggest VDAC1 to be an innovative and markedly potent therapeutic target. Full article

(This article belongs to the Special Issue Molecular Stress Response Dysregulation in Cancer: Therapeutic Targets and Opportunities)

▼ Show Figures

Figure 1

19 pages, 7030 KiB

Open AccessArticle

IL-12 Gene Electrotransfer Triggers a Change in Immune Response within Mouse Tumors

by Guilan Shi¹, Chelsea Edelblute¹, Sezgi Arpag¹, Cathryn Lundberg¹ and Richard Heller^1,2,*

¹ Frank Reidy Research Center for Bioelectrics, Old Dominion Unviersity, Norfolk, VA 23508, USA

² School of Medical Diagnostics and Translational Science, Old Dominion University, Norfolk, VA 23508, USA

Cancers 2018, 10(12), 498; https://doi.org/10.3390/cancers10120498 - 8 Dec 2018

Cited by 32 | Viewed by 5396

Abstract

Metastatic melanoma is an aggressive skin cancer with a relatively low survival rate. Immune-based therapies have shown promise in the treatment of melanoma, but overall complete response rates are still low. Previous studies have demonstrated the potential of plasmid IL-12 (pIL-12) delivered by [...] Read more.

Metastatic melanoma is an aggressive skin cancer with a relatively low survival rate. Immune-based therapies have shown promise in the treatment of melanoma, but overall complete response rates are still low. Previous studies have demonstrated the potential of plasmid IL-12 (pIL-12) delivered by gene electrotransfer (GET) to be an effective immunotherapy for melanoma. However, events occurring in the tumor microenvironment following delivery have not been delineated. Therefore, utilizing a B16F10 mouse melanoma model, we evaluated changes in the tumor microenvironment following delivery of pIL-12 using different GET parameters or injection of plasmid alone. The results revealed a unique immune cell composition after intratumoral injection of pIL-12 GET. The number of immune memory cells was markedly increased in pIL-12 GET melanoma groups compared to control group. This was validated using flow cytometry to analyze peripheral blood mononuclear cells as well as delineating immune cell content using immunohistochemistry. Significant differences in multiple cell types were observed, including CD8⁺ T cells, regulatory T cells and myeloid cells, which were induced to mount a CD8⁺PD1⁻ T cells immune response. Taken together, these findings suggest a basic understanding of the sequence of immune activity following pIL-12 GET and also illuminates that adjuvant immunotherapy can have a positive influence on the host immune response to cancer. Full article

▼ Show Figures

Figure 1

Journal Menu

Journal Browser

Cancers, Volume 10, Issue 12 (December 2018) – 65 articles

Further Information

Guidelines

MDPI Initiatives

Follow MDPI