Showing papers in "Oncotarget in 2016"

Cross-validation of survival associated biomarkers in gastric cancer using transcriptomic data of 1,065 patients

Abstract: // A. Marcell Szasz 1, 2 , Andras Lanczky 1 , Adam Nagy 1 , Susann Forster 3 , Kim Hark 4 , Jeffrey E. Green 4 , Alex Boussioutas 5, 6, 7 , Rita Busuttil 5, 6, 7 , Andras Szabo 8 , Balazs Győrffy 1, 8 1 MTA-TTK Lendulet Cancer Biomarker Research Group, Budapest, Hungary 2 2nd Department of Pathology, Semmelweis University, Budapest, Hungary 3 Max Delbruck Center for Molecular Medicine, Berlin, Germany 4 Transgenic Oncogenesis and Genomics Section, Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, Maryland, USA 5 Cancer Genetics and Genomics Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Australia 6 Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Australia 7 Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Melbourne, Australia 8 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary Correspondence to: Balazs Győrffy, email: gyorffy.balazs@ttk.mta.hu Keywords: gastric cancer, survival, meta-analysis Received: April 07, 2016 Accepted: June 13, 2016 Published: June 30, 2016 ABSTRACT Introduction: Multiple gene expression based prognostic biomarkers have been repeatedly identified in gastric carcinoma. However, without confirmation in an independent validation study, their clinical utility is limited. Our goal was to establish a robust database enabling the swift validation of previous and future gastric cancer survival biomarker candidates. Results: The entire database incorporates 1,065 gastric carcinoma samples, gene expression data. Out of 29 established markers, higher expression of BECN1 (HR = 0.68, p = 1.5E-05), CASP3 (HR = 0.5, p = 6E-14), COX2 (HR = 0.72, p = 0.0013), CTGF (HR = 0.72, p = 0.00051), CTNNB1 (HR = 0.47, p = 4.3E-15), MET (HR = 0.63, p = 1.3E-05), and SIRT1 (HR = 0.64, p = 2.2E-07) correlated to longer OS. Higher expression of BIRC5 (HR = 1.45, p = 1E-04), CNTN1 (HR = 1.44, p = 3.5E- 05), EGFR (HR = 1.86, p = 8.5E-11), ERCC1 (HR = 1.36, p = 0.0012), HER2 (HR = 1.41, p = 0.00011), MMP2 (HR = 1.78, p = 2.6E-09), PFKB4 (HR = 1.56, p = 3.2E-07), SPHK1 (HR = 1.61, p = 3.1E-06), SP1 (HR = 1.45, p = 1.6E-05), TIMP1 (HR = 1.92, p = 2.2E- 10) and VEGF (HR = 1.53, p = 5.7E-06) were predictive for poor OS. Materials and Methods: We integrated samples of three major cancer research centers (Berlin, Bethesda and Melbourne datasets) and publicly available datasets with available follow-up data to form a single integrated database. Subsequently, we performed a literature search for prognostic markers in gastric carcinomas (PubMed, 2012–2015) and re-validated their findings predicting first progression (FP) and overall survival (OS) using uni- and multivariate Cox proportional hazards regression analysis. Conclusions: The major advantage of our analysis is that we evaluated all genes in the same set of patients thereby making direct comparison of the markers feasible. The best performing genes include BIRC5, CASP3, CTNNB1, TIMP-1, MMP-2, SIRT, and VEGF.

Association and prognostic significance of BRCA1/2-mutation status with neoantigen load, number of tumor-infiltrating lymphocytes and expression of PD-1/PD-L1 in high grade serous ovarian cancer.

Abstract: // Kyle C. Strickland 1 , Brooke E. Howitt 1 , Sachet A. Shukla 2, 4 , Scott Rodig 1 , Lauren L. Ritterhouse 1 , Joyce F. Liu 3 , Judy E. Garber 4 , Dipanjan Chowdhury 5 , Catherine J. Wu 2, 4 , Alan D. D’Andrea 5 , Ursula A. Matulonis 3 , Panagiotis A. Konstantinopoulos 3 1 Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA 2 The Broad Institute of Harvard and MIT, Cambridge, MA, USA 3 Medical Gynecologic Oncology Program, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA 4 Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA 5 Division of Genomic Stability and DNA Repair, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA Correspondence to: Panagiotis A. Konstantinopoulos, e-mail: panagiotis_konstantinopoulos@dfci.harvard.edu Keywords: high grade serous ovarian cancer, BRCA1 and BRCA2 mutations, homologous recombination DNA repair, immunogenicity, PD-1 and PD-L1 Received: October 12, 2015 Accepted: January 24, 2016 Published: February 09, 2016 ABSTRACT Immune checkpoint inhibitors (e.g., anti-PD-1 and anti-PD-L1 antibodies) have demonstrated remarkable efficacy against hypermutated cancers such as melanomas and lung carcinomas. One explanation for this effect is that hypermutated lesions harbor more tumor-specific neoantigens that stimulate recruitment of an increased number of tumor-infiltrating lymphocytes (TILs), which is counterbalanced by overexpression of immune checkpoints such as PD-1 or PD-L1. Given that BRCA1/2-mutated high grade serous ovarian cancers (HGSOCs) exhibit a higher mutational load and a unique mutational signature with an elevated number of larger indels up to 50 bp, we hypothesized that they may also harbor more tumor-specific neoantigens, and, therefore, exhibit increased TILs and PD-1/PD-L1 expression. Here, we report significantly higher predicted neoantigens in BRCA1/2-mutated tumors compared to tumors without alterations in homologous recombination (HR) genes (HR-proficient tumors). Tumors with higher neoantigen load were associated with improved overall survival and higher expression of immune genes associated with tumor cytotoxicity such as genes of the TCR, the IFN-gamma and the TNFR pathways. Furthermore, immunohistochemistry studies demonstrated that BRCA1/2-mutated tumors exhibited significantly increased CD3+ and CD8+ TILs, as well as elevated expression of PD-1 and PD-L1 in tumor-associated immune cells compared to HR-proficient tumors. Survival analysis showed that both BRCA1/2-mutation status and number of TILs were independently associated with outcome. Of note, two distinct groups of HGSOCs, one with very poor prognosis (HR proficient with low number of TILs) and one with very good prognosis (BRCA1/2-mutated tumors with high number of TILs) were defined. These findings support a link between BRCA1/2-mutation status, immunogenicity and survival, and suggesting that BRCA1/2-mutated HGSOCs may be more sensitive to PD-1/PD-L1 inhibitors compared to HR-proficient HGSOCs.

The prevalence of EGFR mutation in patients with non-small cell lung cancer: a systematic review and meta-analysis

Abstract: // Yue-Lun Zhang 1, 2 , Jin-Qiu Yuan 1, 2 , Kai-Feng Wang 3 , Xiao-Hong Fu 1, 2 , Xiao-Ran Han 1, 2 , Diane Threapleton 1 , Zu-Yao Yang 1, 2 , Chen Mao 1, 2 , Jin-Ling Tang 1, 2 1 Division of Epidemiology, The Jockey Club School of Public Health and Primary Care, The Chinese University of Hong Kong, Hong Kong, China 2 Shenzhen Municipal Key Laboratory for Health Risk Analysis, Shenzhen Research Institute of The Chinese University of Hong Kong, Shenzhen, Guangdong Province, China 3 Division of Epidemiology, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, Guangdong Province, China Correspondence to: Chen Mao, email: maochen@cuhk.edu.hk Jin-Ling Tang, email: jltang@cuhk.edu.hk Keywords: non-small cell lung cancer, epidermal growth factor receptor, prevalence, systematic review, meta-analysis Received: May 17, 2016 Accepted: September 25, 2016 Published: October 12, 2016 ABSTRACT Objectives: Estimate the epidermal growth factor receptor ( EGFR ) mutation prevalence in all non-small cell lung cancer (NSCLC) patients and patient subgroups. Results: A total of 456 studies were included, reporting 30,466 patients with EGFR mutation among 115,815 NSCLC patients. The overall pooled prevalence for EGFR mutations was 32.3% (95% CI 30.9% to 33.7%), ranging from 38.4% (95% CI: 36.5% to 40.3%) in China to 14.1% (95% CI: 12.7% to 15.5%) in Europe. The pooled prevalence of EGFR mutation was higher in females (females vs. males: 43.7% vs. 24.0%; OR: 2.7, 95% CI: 2.5 to 2.9), non-smokers (non-smokers vs. past or current smokers: 49.3% vs. 21.5%; OR: 3.7, 95% CI: 3.4 to 4.0), and patients with adenocarcinoma (adenocarcinoma vs. non-adenocarcinoma: 38.0% vs. 11.7%; OR: 4.1, 95% CI: 3.6 to 4.8). Materials and Methods: PubMed, EMBASE, and the Cochrane Library were searched to June 2013. Eligible studies reported EGFR mutation prevalence and the association with at least one of the following factors: gender, smoking status and histology. Random-effects models were used to pool EGFR mutation prevalence data. Conclusion: This study provides the exact prevalence of EGFR mutations in different countries and NSCLC patient subgroups.

Aldehyde dehydrogenase 1A1 in stem cells and cancer

Abstract: The human genome contains 19 putatively functional aldehyde dehydrogenase (ALDH) genes, which encode enzymes critical for detoxification of endogenous and exogenous aldehyde substrates through NAD(P)+-dependent oxidation. ALDH1 has three main isotypes, ALDH1A1, ALDH1A2, and ALDH1A3, and is a marker of normal tissue stem cells (SC) and cancer stem cells (CSC), where it is involved in self-renewal, differentiation and self-protection. Experiments with murine and human cells indicate that ALDH1 activity, predominantly attributed to isotype ALDH1A1, is tissue- and cancer-specific. High ALDH1 activity and ALDH1A1 overexpression are associated with poor cancer prognosis, though high ALDH1 and ALDH1A1 levels do not always correlate with highly malignant phenotypes and poor clinical outcome. In cancer therapy, ALDH1A1 provides a useful therapeutic CSC target in tissue types that normally do not express high levels of ALDH1A1, including breast, lung, esophagus, colon and stomach. Here we review the functions and mechanisms of ALDH1A1, the key ALDH isozyme linked to SC populations and an important contributor to CSC function in cancers, and we outline its potential in future anticancer strategies.

PI3K/Akt/mTOR signaling pathway and targeted therapy for glioblastoma

Abstract: // Xiaoman Li 1,* , Changjing Wu 1,* , Nianci Chen 2 , Huadi Gu 3 , Allen Yen 4 , Liu Cao 1 , Enhua Wang 3,5 and Liang Wang 3,5 1 Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, China 2 Class 9 of the 97th Clinical Medicine of Seven-Year Program, China Medical University, Shenyang, China 3 Department of Pathology, The College of Basic Medical Sciences, China Medical University, Shenyang, China 4 School of Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas, United States of America 5 Department of Pathology, The First Affiliated Hospital of China Medical University, Shenyang, China * These authors have contributed equally to this work Correspondence to: Liang Wang, email: // Keywords : glioblastoma, EGFR, PI3K/Akt/mTOR pathway, targeted therapy Received : December 05, 2015 Accepted : February 24, 2016 Published : March 07, 2016 Abstract Glioblastoma multiform (GBM) is the most common malignant glioma of all the brain tumors and currently effective treatment options are still lacking. GBM is frequently accompanied with overexpression and/or mutation of epidermal growth factor receptor (EGFR), which subsequently leads to activation of many downstream signal pathways such as phosphatidylinositol 3-kinase (PI3K)/Akt/rapamycin-sensitive mTOR-complex (mTOR) pathway. Here we explored the reason why inhibition of the pathway may serve as a compelling therapeutic target for the disease, and provided an update data of EFGR and PI3K/Akt/mTOR inhibitors in clinical trials.

Emerging roles of circRNA_001569 targeting miR-145 in the proliferation and invasion of colorectal cancer.

Abstract: // Huijun Xie 1, 2, 3, * , Xiaoli Ren 1, 2, 3, * , Sainan Xin 1, 2, 3, * , Xiaoliang Lan 4 , Guifeng Lu 1, 2, 3 , Yuan Lin 1, 2, 3 , Shaoshan Yang 1, 2, 3 , Zhicheng Zeng 1, 2, 3 , Wenting Liao 1, 2, 3 , Yan-Qing Ding 1, 2, 3 , Li Liang 1, 2, 3 1 Department of Pathology, Nanfang Hospital, Guangzhou, Guangdong, China 2 Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China 3 Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China 4 Department of General Surgery, Nanfang Hospital, Guangzhou, Guangdong, China * These authors contributed equally to this work Correspondence to: Li Liang, email: redsnow007@hotmail.com Yan-Qing Ding, email: dyq@fimmu.com Keywords: hsa_circ_001569, miR-145, colorectal cancer, FMNL2, BAG4 Received: December 08, 2015 Accepted: March 07, 2016 Published: April 05, 2016 ABSTRACT Circular RNAs (circRNAs), a large class of RNAs, have recently shown huge capabilities as gene regulators in mammals. Some of them bind with microRNAs (miRNAs) and act as natural miRNA sponges to inhibit related miRNAs’ activities. Here we showed that hsa_circ_001569 acted as a positive regulator in cell proliferation and invasion of colorectal cancer (CRC). Moreover, hsa_circ_001569 was identified as a sponge of miR-145 and up-regulated miR-145 functional targets E2F5, BAG4 and FMNL2. In CRC tissues, circ_001569 negatively correlated with miR-145, and miR-145 correlated negatively with E2F5, BAG4 and FMNL2 expressions. Our study reveals a novel regulatory mechanism of circ_001569 in cell proliferation and invasion in CRC, provides a comprehensive landscape of circ_001569 that will facilitate further biomarker discoveries in the progression of CRC.

Targeting the CCL2-CCR2 signaling axis in cancer metastasis.

Abstract: The CCL2-CCR2 signaling axis has generated increasing interest in recent years due to its association with the progression of cancer. Although first described as a chemotactic molecule with physiological roles in regulating inflammation, recent studies have revealed a pro-tumorigenic function for CCL2 in favoring cancer development and subsequent metastasis. CCL2 binds the cognate receptor CCR2, and together this signaling pair has been shown to have multiple pro-tumorigenic roles, from mediating tumor growth and angiogenesis to recruiting and usurping host stromal cells to support tumor progression. The importance of CCL2-CCR2 signaling has been further championed by the establishment of clinical trials targeting this signaling pair in solid and metastatic cancers. Here we review the roles of CCL2-CCR2 signaling in the development and progression of cancer metastasis. We further evaluate the outcome of several clinical trials targeting either CCL2 or CCR2, and discuss the prospects and challenges of manipulating CCL2-CCR2 interaction as a potential approach for combating metastatic disease.

Mitochondrial dysfunction and oxidative stress in aging and cancer

Abstract: // Anna V. Kudryavtseva 1,2 , George S. Krasnov 1 , Alexey A. Dmitriev 1 , Boris Y. Alekseev 2 , Olga L. Kardymon 1 , Asiya F. Sadritdinova 1,2 , Maria S. Fedorova 1 , Anatoly V. Pokrovsky 3 , Nataliya V. Melnikova 1 , Andrey D. Kaprin 2 , Alexey A. Moskalev 1,4 and Anastasiya V. Snezhkina 1 1 Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia 2 National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Moscow, Russia 3 A.V. Vishnevsky Institute of Surgery, Moscow, Russia 4 Moscow Institute of Physics and Technology, Dolgoprudny, Russia Correspondence to: Anna V. Kudryavtseva, email: // Keywords : oxidative stress, mitochondrial dysfunction, ROS, aging, cancer, Gerotarget Received : November 23, 2015 Accepted : May 28, 2016 Published : June 05, 2016 Abstract Aging and cancer are the most important issues to research. The population in the world is growing older, and the incidence of cancer increases with age. There is no doubt about the linkage between aging and cancer. However, the molecular mechanisms underlying this association are still unknown. Several lines of evidence suggest that the oxidative stress as a cause and/or consequence of the mitochondrial dysfunction is one of the main drivers of these processes. Increasing ROS levels and products of the oxidative stress, which occur in aging and age-related disorders, were also found in cancer. This review focuses on the similarities between ageing-associated and cancer-associated oxidative stress and mitochondrial dysfunction as their common phenotype.

Stability of the hybrid epithelial/mesenchymal phenotype

Abstract: // Mohit Kumar Jolly 1,2 , Satyendra C. Tripathi 8,* , Dongya Jia 1,5,* , Steven M. Mooney 7 , Muge Celiktas 8 , Samir M. Hanash 8,10 , Sendurai A. Mani 9,11 , Kenneth J. Pienta 12 , Eshel Ben-Jacob 1,5,6,** and Herbert Levine 1,2,3,4 1 Center for Theoretical Biological Physics, Rice University, Houston, TX, USA 2 Department of Bioengineering, Rice University, Houston, TX, USA 3 Department of Physics and Astronomy, Rice University, Houston, TX, USA 4 Department of Biosciences, Rice University, Houston, TX, USA 5 Graduate Program in Systems, Synthetic and Physical Biology, Rice University, Houston, TX, USA 6 School of Physics and Astronomy and The Sagol School of Neuroscience, Tel-Aviv University, Tel-Aviv, Israel 7 Department of Biology, University of Waterloo, Waterloo, ON, Canada 8 Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, TX, USA 9 Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA 10 Red and Charline McCombs Institute for the Early Detection and Treatment of Cancer, University of Texas MD Anderson Cancer Center, Houston, TX, USA 11 Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX, USA 12 The James Brady Urological Institute, and Departments of Urology, Oncology, Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA * These authors have contributed equally to this work ** Deceased on June 5, 2015 Correspondence to: Herbert Levine, email: // Keywords : partial EMT, epithelial-mesenchymal transition, cancer stem cells, multistability, cell-fate decisions Received : January 08, 2016 Accepted : March 07, 2016 Published : March 17, 2016 Abstract Epithelial-to-Mesenchymal Transition (EMT) and its reverse – Mesenchymal to Epithelial Transition (MET) – are hallmarks of cellular plasticity during embryonic development and cancer metastasis. During EMT, epithelial cells lose cell-cell adhesion and gain migratory and invasive traits either partially or completely, leading to a hybrid epithelial/mesenchymal (hybrid E/M) or a mesenchymal phenotype respectively. Mesenchymal cells move individually, but hybrid E/M cells migrate collectively as observed during gastrulation, wound healing, and the formation of tumor clusters detected as Circulating Tumor Cells (CTCs). Typically, the hybrid E/M phenotype has largely been tacitly assumed to be transient and ‘metastable’. Here, we identify certain ‘phenotypic stability factors’ (PSFs) such as GRHL2 that couple to the core EMT decision-making circuit (miR-200/ZEB) and stabilize hybrid E/M phenotype. Further, we show that H1975 lung cancer cells can display a stable hybrid E/M phenotype and migrate collectively, a behavior that is impaired by knockdown of GRHL2 and another previously identified PSF - OVOL. In addition, our computational model predicts that GRHL2 can also associate hybrid E/M phenotype with high tumor-initiating potential, a prediction strengthened by the observation that the higher levels of these PSFs may be predictive of poor patient outcome. Finally, based on these specific examples, we deduce certain network motifs that can stabilize the hybrid E/M phenotype. Our results suggest that partial EMT, i.e. a hybrid E/M phenotype, need not be ‘metastable’, and strengthen the emerging notion that partial EMT, but not necessarily a complete EMT, is associated with aggressive tumor progression.

iACP: a sequence-based tool for identifying anticancer peptides

Abstract: // Wei Chen 1, 4 , Hui Ding 2 , Pengmian Feng 3 , Hao Lin 2, 4 , Kuo-Chen Chou 4, 5 1 Department of Physics, School of Sciences, Center for Genomics and Computational Biology, North China University of Science and Technology, Tangshan, China 2 Key Laboratory for Neuro-Information of Ministry of Education, Center of Bioinformatics, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China 3 School of Public Health, North China University of Science and Technology, Tangshan, China 4 Gordon Life Science Institute, Belmont, Massachusetts, United States of America 5 Center of Excellence in Genomic Medicine Research (CEGMR), King Abdulaziz University, Jeddah, Saudi Arabia Correspondence to: Wei Chen, e-mail: wchen@gordonlifescience.org , chenweiimu@gmail.com Hao Lin, e-mail: hlin@uestc.edu.cn Kuo-Chen Chou, e-mail: kcchou@gordonlifescience.org Keywords: anticancer peptides, PseAAC, g-gap dipeptide mode, incremental feature selection, iACP webserver Received: January 06, 2016 Accepted: February 11, 2016 Published: March 01, 2016 ABSTRACT Cancer remains a major killer worldwide. Traditional methods of cancer treatment are expensive and have some deleterious side effects on normal cells. Fortunately, the discovery of anticancer peptides (ACPs) has paved a new way for cancer treatment. With the explosive growth of peptide sequences generated in the post genomic age, it is highly desired to develop computational methods for rapidly and effectively identifying ACPs, so as to speed up their application in treating cancer. Here we report a sequence-based predictor called iACP developed by the approach of optimizing the g-gap dipeptide components. It was demonstrated by rigorous cross-validations that the new predictor remarkably outperformed the existing predictors for the same purpose in both overall accuracy and stability. For the convenience of most experimental scientists, a publicly accessible web-server for iACP has been established at http://lin.uestc.edu.cn/server/iACP , by which users can easily obtain their desired results.

Hallmarks of glycosylation in cancer

Abstract: // Jennifer Munkley 1 and David J. Elliott 1 1 Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, NE1 3BZ, UK Correspondence to: Jennifer Munkley, email: // Keywords : cancer, glycosylation, hallmarks, glycans, aberrant Received : January 28, 2016 Accepted : March 02, 2016 Published : March 17, 2016 Abstract Aberrant glycosylation plays a fundamental role in key pathological steps of tumour development and progression. Glycans have roles in cancer cell signalling, tumour cell dissociation and invasion, cell-matrix interactions, angiogenesis, metastasis and immune modulation. Aberrant glycosylation is often cited as a ‘hallmark of cancer’ but is notably absent from both the original hallmarks of cancer and from the next generation of emerging hallmarks. This review discusses how glycosylation is clearly an enabling characteristic that is causally associated with the acquisition of all the hallmark capabilities. Rather than aberrant glycosylation being itself a hallmark of cancer, another perspective is that glycans play a role in every recognised cancer hallmark.

TGF-β induces M2-like macrophage polarization via SNAIL-mediated suppression of a pro-inflammatory phenotype

Abstract: // Fan Zhang 1, 2 , Hongsheng Wang 2 , Xianfeng Wang 3 , Guanmin Jiang 4 , Hao Liu 5 , Ge Zhang 2 , Hao Wang 2 , Rui Fang 2 , Xianzhang Bu 2 , Shaohui Cai 6 , Jun Du 2 1 Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan 430060, PR China 2 Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China 3 Shijiazhuang City Center for Disease Control and Prevention, Shijiazhuang 050000, PR China 4 Department of Clinical Laboratory, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, PR China 5 Cancer Hospital and Cancer Research Institute, Guangzhou Medical University, Guangzhou 510095, PR China 6 Department of Pharmacology, College of Pharmacy, Jinan University, Guangzhou 510632, PR China Correspondence to: Jun Du, email: dujun@mail.sysu.edu.cn Shaohui Cai, email: caish5689@sina.com Keywords: SNAIL, TGF-β, macrophage polarization, tumor-associated macrophage, immunotherapy Received: September 24, 2015 Accepted: June 29, 2016 Published: July 13, 2016 ABSTRACT Tumor-associated macrophages (TAMs) are a major component of leukocytic infiltrate in tumors, which facilitates tumor progression and promotes inflammation. TGF-β promotes the differentiation of non-activated macrophages into a TAM-like (M2-like) phenotype; however, the underlying mechanisms are not clear. In this study, we found that TGF-β induces a M2-like phenotype characterized by up-regulation of the anti-inflammatory cytokine IL-10, and down-regulation of the pro-inflammatory cytokines TNF-α and IL-12. In human THP-1 macrophages, overexpression of SNAIL caused M2-like differentiation by inhibiting pro-inflammatory cytokine release and promoting the expression of M2-specific markers. By contrast, SNAIL knockdown promoted M1 polarization through up-regulation of pro-inflammatory cytokines and abolished TGF-β-mediated M2-polarization of THP-1 macrophages. The SMAD2/3 and PI3K/AKT signaling pathways were crucial for TGF-β-induced SNAIL overexpression in THP-1 cells. These findings suggest that TGF-β skews macrophage polarization towards a M2-like phenotype via SNAIL up-regulation, and blockade of TGF-β/SNAIL signaling restores the production of pro-inflammatory cytokines. This study provides new understanding of the role of SNAIL in M2 polarization of macrophages, and suggests a potential therapeutic target for antitumor immunity.

Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate cancer

Abstract: // Julie N. Graff 1,2 , Joshi J. Alumkal 1 , Charles G. Drake 3 , George V. Thomas 4 , William L. Redmond 5 , Mohammad Farhad 5,6 , Jeremy P. Cetnar 1 , Frederick S. Ey 1 , Raymond C. Bergan 1 , Rachel Slottke 1 and Tomasz M. Beer 1 1 Division of Hematology/Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA 2 VA Portland Health Care System, Portland, OR, USA 3 Sidney Kimmel Comprehensive Cancer Center and the Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA 4 Pathology and Laboratory Medicine, Oregon Health and Science University, Portland, OR, USA 5 Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, OR, USA 6 Cell, Developmental, and Cancer Biology Department, Oregon Health and Science University, Portland, OR, USA Correspondence to: Julie N. Graff, email: // Keywords : prostate cancer, PD-1, immunotherapy, enzalutamide, Immunology and Microbiology Section, Immune response, Immunity Received : May 31, 2016 Accepted : June 17, 2016 Published : July 12, 2016 Abstract While programmed cell death 1 (PD-1) inhibitors have shown clear anti-tumor efficacy in several solid tumors, prior results in men with metastatic castration resistant prostate cancer (mCRPC) showed no evidence of activity. Here we report unexpected antitumor activity seen in mCRPC patients treated with the anti-PD-1 antibody pembrolizumab. Patients with evidence of progression on enzalutamide were treated with pembrolizumab 200 mg IV every 3 weeks for 4 doses; pembrolizumab was added to standard dose enzalutamide. Three of the first ten patients enrolled in this ongoing phase II trial experienced rapid prostate specific antigen (PSA) reductions to ≤ 0.2 ng/ml. Two of these three patients had measurable disease upon study entry; both achieved a partial response. There were three patients with significant immune-related adverse events. One had grade 2 myositis, one had grade 3 hypothyroidism, and one had grade 2 hypothyroidism. None of these patients had a response. Two of the three responders had a baseline tumor biopsy. Immunohistochemistry from those biopsies showed the presence of CD3 + , CD8 + , and CD163 + leukocyte infiltrates and PD-L1 expression. Genetic analysis of the two responders revealed markers of microsatellite instability in one. The surprising and robust responses seen in this study should lead to re-examination of PD-1 inhibition in prostate cancer.

Mutational landscape of MCPyV-positive and MCPyV-negative Merkel cell carcinomas with implications for immunotherapy.

Abstract: Merkel cell carcinoma (MCC) is a rare but highly aggressive cutaneous neuroendocrine carcinoma, associated with the Merkel cell polyomavirus (MCPyV) in 80% of cases. To define the genetic basis of MCCs, we performed exome sequencing of 49 MCCs. We show that MCPyV-negative MCCs have a high mutation burden (median of 1121 somatic single nucleotide variants (SSNVs) per-exome with frequent mutations in RB1 and TP53 and additional damaging mutations in genes in the chromatin modification (ASXL1, MLL2, and MLL3), JNK (MAP3K1 and TRAF7), and DNA-damage pathways (ATM, MSH2, and BRCA1). In contrast, MCPyV-positive MCCs harbor few SSNVs (median of 12.5 SSNVs/tumor) with none in the genes listed above. In both subgroups, there are rare cancer-promoting mutations predicted to activate the PI3K pathway (HRAS, KRAS, PIK3CA, PTEN, and TSC1) and to inactivate the Notch pathway (Notch1 and Notch2). TP53 mutations appear to be clinically relevant in virus-negative MCCs as 37% of these tumors harbor potentially targetable gain-of-function mutations in TP53 at p.R248 and p.P278. Moreover, TP53 mutational status predicts death in early stage MCC (5-year survival in TP53 mutant vs wild-type stage I and II MCCs is 20% vs. 92%, respectively; P = 0.0036). Lastly, we identified the tumor neoantigens in MCPyV-negative and MCPyV-positive MCCs. We found that virus-negative MCCs harbor more tumor neoantigens than melanomas or non-small cell lung cancers (median of 173, 65, and 111 neoantigens/sample, respectively), two cancers for which immune checkpoint blockade can produce durable clinical responses. Collectively, these data support the use of immunotherapies for virus-negative MCCs.

Targeting folate receptor alpha for cancer treatment

Abstract: Promising targeted treatments and immunotherapy strategies in oncology and advancements in our understanding of molecular pathways that underpin cancer development have reignited interest in the tumor-associated antigen Folate Receptor alpha (FRα). FRα is a glycosylphosphatidylinositol (GPI)-anchored membrane protein. Its overexpression in tumors such as ovarian, breast and lung cancers, low and restricted distribution in normal tissues, alongside emerging insights into tumor-promoting functions and association of expression with patient prognosis, together render FRα an attractive therapeutic target. In this review, we summarize the role of FRα in cancer development, we consider FRα as a potential diagnostic and prognostic tool, and we discuss different targeted treatment approaches with a specific focus on monoclonal antibodies. Renewed attention to FRα may point to novel individualized treatment approaches to improve the clinical management of patient groups that do not adequately benefit from current conventional therapies.

Dietary phytochemicals and cancer chemoprevention: a review of the clinical evidence.

Abstract: // Ritesh Kotecha 1 , Akiyoshi Takami 2 and J. Luis Espinoza 3 1 Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, United States of America 2 Department of Internal Medicine, Division of Hematology, Aichi Medical University, School of Medicine, Nagakute, Aichi, Japan 3 Department of Hematology Oncology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan Correspondence to: J. Luis Espinoza, email: // Keywords : cancer chemoprevention, phytochemicals, resveratrol, curcumin, antioxidants Received : December 30, 2015 Accepted : May 12, 2016 Published : May 25, 2016 Abstract Cancer chemoprevention involves the use of different natural or biologic agents to inhibit or reverse tumor growth. Epidemiological and pre-clinical data suggest that various natural phytochemicals and dietary compounds possess chemopreventive properties, and in-vitro and animal studies support that these compounds may modulate signaling pathways involved in cell proliferation and apoptosis in transformed cells, enhance the host immune system and sensitize malignant cells to cytotoxic agents. Despite promising results from experimental studies, only a limited number of these compounds have been tested in clinical trials and have shown variable results. In this review, we summarize the data regarding select phytochemicals including curcumin, resveratrol, lycopene, folates and tea polyphenols with emphasis on the clinical evidence supporting the efficacy of these compounds in high-risk populations.

OASIS 2: online application for survival analysis 2 with features for the analysis of maximal lifespan and healthspan in aging research

Abstract: Online application for survival analysis (OASIS) has served as a popular and convenient platform for the statistical analysis of various survival data, particularly in the field of aging research. With the recent advances in the fields of aging research that deal with complex survival data, we noticed a need for updates to the current version of OASIS. Here, we report OASIS 2 (http://sbi.postech.ac.kr/oasis2), which provides extended statistical tools for survival data and an enhanced user interface. In particular, OASIS 2 enables the statistical comparison of maximal lifespans, which is potentially useful for determining key factors that limit the lifespan of a population. Furthermore, OASIS 2 provides statistical and graphical tools that compare values in different conditions and times. That feature is useful for comparing age-associated changes in physiological activities, which can be used as indicators of "healthspan." We believe that OASIS 2 will serve as a standard platform for survival analysis with advanced and user-friendly statistical tools for experimental biologists in the field of aging research.

Long non-coding RNA NEAT1 promotes non-small cell lung cancer progression through regulation of miR-377-3p-E2F3 pathway

Abstract: // Chengcao Sun 1 , Shujun Li 1, 2 , Feng Zhang 1 , Yongyong Xi 1 , Liang Wang 1 , Yongyi Bi 1 , Dejia Li 1 1 Department of Occupational and Environmental Health, School of Public Health, Wuhan University, Wuhan, P. R. China 2 Wuhan Hospital for the Prevention and Treatment of Occupational Diseases, Wuhan, P. R. China Correspondence to: Dejia Li, email: lodjlwhu@sina.com Keywords: long non-coding RNA NEAT1 (lncRNA NEAT1), hsa-miRNA-377-3p (miR-377-3p), E2F3 , non-small cell lung cancer (NSCLC), tumorigenesis Received: February 16, 2016 Accepted: May 05, 2016 Published: June 16, 2016 ABSTRACT Recently, the long non-coding RNA (lncRNA) NEAT1 has been identified as an oncogenic gene in multiple cancer types and elevated expression of NEAT1 was tightly linked to tumorigenesis and cancer progression. However, the molecular basis for this observation has not been characterized in progression of non-small cell lung cancer (NSCLC). In our studies, we identified NEAT1 was highly expressed in patients with NSCLC and was a novel regulator of NSCLC progression. Patients whose tumors had high NEAT1 expression had a shorter overall survival than patients whose tumors had low NEAT1 expression. Further, NEAT1 significantly accelerates NSCLC cell growth and metastasis in vitro and tumor growth in vivo. Additionally, by using bioinformatics study and RNA pull down combined with luciferase reporter assays, we demonstrated that NEAT1 functioned as a competing endogenous RNA (ceRNA) for hsa-miR-377-3p, antagonized its functions and led to the de-repression of its endogenous targets E2F3, which was a core oncogene in promoting NSCLC progression. Taken together, these observations imply that the NEAT1 modulated the expression of E2F3 gene by acting as a ceRNA, which may build up the missing link between the regulatory miRNA network and NSCLC progression.

Epithelial ovarian cancer-secreted exosomal miR-222-3p induces polarization of tumor-associated macrophages.

Abstract: Cancer secreted exosomal miRNAs are emerging as mediators between tumor-stoma crosstalk. Here, we show epithelial ovarian cancer (EOC)-derived exosomes activated macrophages to a tumor-associated macrophage (TAM)-like phenotype with SOCS3/STAT3 pathway involvement, which could facilitate the progression of cancer. MiR-222-3p was enrichment in exosomes released from EOC cells and it could be transferred to macrophages. Overexpression of miR-222-3p in macrophages induced polarization of the M2 phenotype. Luciferase assay verified miR-222-3p targeted SOCS3 genes and expression of SOCS3 was decreased after transfection with a miR-222-3p mimic. Down-regulation of SOCS3 correlated with an increased expression of STAT3 activation. MiR-222-3p could be detected in the exosomes from serum and its levels were related to EOC. These observations propose tumor-derived exosomal miR-222-3p is an effective regulator in the polarization of tumor-promoting M2 macrophages and may be a biomarker of EOC.

Chimeric antigen receptor T cells secreting anti-PD-L1 antibodies more effectively regress renal cell carcinoma in a humanized mouse model.

Abstract: Advances in the treatment of metastatic clear cell renal cell carcinoma (ccRCC) have led to improved progression-free survival of many patients; however the therapies are toxic, rarely achieve durable long-term complete responses and are not curative. Herein we used a single bicistronic lentiviral vector to develop a new combination immunotherapy that consists of human anti-carbonic anhydrase IX (CAIX)-targeted chimeric antigen receptor (CAR) T cells engineered to secrete human anti-programmed death ligand 1 (PD-L1) antibodies at the tumor site. The local antibody delivery led to marked immune checkpoint blockade. Tumor growth diminished 5 times and tumor weight reduced 50-80% when compared with the anti-CAIX CAR T cells alone in a humanized mice model of ccRCC. The expression of PD-L1 and Ki67 in the tumors decreased and an increase in granzyme B levels was found in CAR T cells. The anti-PD-L1 IgG1 isotype, which is capable of mediating ADCC, was also able to recruit human NK cells to the tumor site in vivo. These armed second-generation CAR T cells empowered to secrete human anti-PD-L1 antibodies in the ccRCC milieu to combat T cell exhaustion is an innovation in this field that should provide renewed potential for CAR T cell immunotherapy of solid tumors where limited efficacy is currently seen.

Molecular mechanisms of long noncoding RNAs on gastric cancer

Abstract: Long noncoding RNAs (lncRNAs) are non-protein coding transcripts longer than 200 nucleotides. Aberrant expression of lncRNAs has been found associated with gastric cancer, one of the most malignant tumors. By complementary base pairing with mRNAs or forming complexes with RNA binding proteins (RBPs), some lncRNAs including GHET1, MALAT1, and TINCR may mediate mRNA stability and splicing. Other lncRNAs, such as BC032469, GAPLINC, and HOTAIR, participate in the competing endogenous RNA (ceRNA) network. Under certain circumstances, ANRIL, GACAT3, H19, MEG3, and TUSC7 exhibit their biological roles by associating with microRNAs (miRNAs). By recruiting histone-modifying complexes, ANRIL, FENDRR, H19, HOTAIR, MALAT1, and PVT1 may inhibit the transcription of target genes in cis or trans. Through these mechanisms, lncRNAs form RNA-dsDNA triplex. CCAT1, GAPLINC, GAS5, H19, MEG3, and TUSC7 play oncogenic or tumor suppressor roles by correlated with tumor suppressor P53 or onco-protein c-Myc, respectively. In conclusion, interaction with DNA, RNA and proteins is involved in lncRNAs' participation in gastric tumorigenesis and development.

Structural basis for small molecule targeting of the programmed death ligand 1 (PD-L1)

Abstract: Targeting the PD-1/PD-L1 immunologic checkpoint with monoclonal antibodies has provided unprecedented results in cancer treatment in the recent years. Development of chemical inhibitors for this pathway lags the antibody development because of insufficient structural information. The first nonpeptidic chemical inhibitors that target the PD-1/PD-L1 interaction have only been recently disclosed by Bristol-Myers Squibb. Here, we show that these small-molecule compounds bind directly to PD-L1 and that they potently block PD-1 binding. Structural studies reveal a dimeric protein complex with a single small molecule which stabilizes the dimer thus occluding the PD-1 interaction surface of PD-L1s. The small-molecule interaction "hot spots" on PD-L1 surfaces suggest approaches for the PD-1/PD-L1 antagonist drug discovery.

Repurposing metformin for cancer treatment: current clinical studies

Abstract: // Young Kwang Chae 1,2,3 , Ayush Arya 3 , Mary-Kate Malecek 3 , Daniel Sanghoon Shin 4 , Benedito Carneiro 1,2,3 , Sunandana Chandra 1,2,3 , Jason Kaplan 1,2,3 , Aparna Kalyan 1,2,3 , Jessica K. Altman 1,2,3 , Leonidas Platanias 1,2,3,5 and Francis Giles 1,2,3 1 Northwestern Medicine Developmental Therapeutics Institute, Chicago, IL, USA 2 Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA 3 Northwestern University Feinberg School of Medicine, Chicago, IL, USA 4 David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA 5 Division of Hematology-Oncology, Department of Medicine, Jesse Brown VA Medical Center, Chicago, IL, USA Correspondence to: Young Kwang Chae, email: // Keywords : metformin, clinical trials, cancer Received : September 20, 2015 Accepted : March 06, 2016 Published : March 19, 2016 Abstract In recent years, several studies have presented evidence suggesting a potential role for metformin in anti-cancer therapy. Preclinical studies have demonstrated several anticancer molecular mechanisms of metformin including mTOR inhibition, cytotoxic effects, and immunomodulation. Epidemiologic data have demonstrated decreased cancer incidence and mortality in patients taking metformin. Several clinical trials, focused on evaluation of metformin as an anti-cancer agent are presently underway. Data published from a small number of completed trials has put forth intriguing results. Clinical trials in pre-surgical endometrial cancer patients exhibited a significant decrease in Ki67 with metformin monotherapy. Another interesting observation was made in patients with breast cancer, wherein a trend towards improvement in cancer proliferation markers was noted in patients without insulin resistance. Data on survival outcomes with the use of metformin as an anti-cancer agent is awaited. This manuscript will critically review the role of metformin as a potential cancer treatment.

CRISPR-dCas9 mediated TET1 targeting for selective DNA demethylation at BRCA1 promoter.

Abstract: // Samrat Roy Choudhury 1 , Yi Cui 1 , Katarzyna Lubecka 2 , Barbara Stefanska 2,3 , Joseph Irudayaraj 1,3 1 Department of Agricultural & Biological Engineering, Bindley Bioscience Centre, Purdue University, West Lafayette, IN 47907, USA 2 Department of Nutrition Science, Purdue University, West Lafayette, IN 47907, USA 3 Purdue Centre for Cancer Research, Purdue University, West Lafayette, IN 47907, USA Correspondence to: Barbara Stefanska, email: bstefanska@purdue.edu Joseph Irudayaraj, email: josephi@purdue.edu Keywords: CRISPR-dCas9, TET1, BRCA1, DNA demethylation, gene activation Received: March 10, 2016 Accepted: May 30, 2016 Published: June 23, 2016 ABSTRACT DNA hypermethylation at the promoter of tumour-suppressor genes is tightly correlated with their transcriptional repression and recognized as the hallmark of majority of cancers. Epigenetic silencing of tumour suppressor genes impairs their cellular functions and activates a cascade of events driving cell transformation and cancer progression. Here, we examine site-specific and spatiotemporal alteration in DNA methylation at a target region in BRCA1 gene promoter, a model tumour suppressor gene. We have developed a programmable CRISPR-Cas9 based demethylase tool containing the deactivated Cas9 (dCas9) fused to the catalytic domain (CD) of Ten-Eleven Translocation (TET) dioxygenase1 (TET1CD). The fusion protein selectively demethylates targeted regions within BRCA1 promoter as directed by the designed single-guide RNAs (sgRNA), leading to the transcriptional up-regulation of the gene. We also noticed the increment in 5-hydroxymethylation content (5-hmC) at the target DNA site undergoing the most profound demethylation. It confirms the catalytic activity of TET1 in TET1-dCas9 fusion proteins-mediated demethylation at these target sequences. The modular design of the fusion constructs presented here allows for the selective substitution of other chromatin or DNA modifying enzymes and for loci-specific targeting to uncover epigenetic regulatory pathways at gene promoters and other selected genomic regions.

Exosomal long noncoding RNA CRNDE-h as a novel serum-based biomarker for diagnosis and prognosis of colorectal cancer

Abstract: Cancer-secreted long non-coding RNAs (lncRNAs) are emerging mediators of cancer-host cross talk. The aim of our study was to illustrate the clinical significance of the lncRNA CRNDE-h in exosomes purified from the serum of patients with colorectal cancer (CRC). The study was divided into four parts: (1) The exosome isolated methods and lncRNA detected methods which accurately and reproducibly measure CRC-related exosomal CRNDE-h in serum were optimized in preliminary pilot stage; (2) The stability of exosomal CRNDE-h was evaluated systematically; (3) The origin of exosomal CRNDE-h was explorated in vitro and in vivo; (4) The diagnostic and prognostic value of exosomal CRNDE-h for CRC were validated in 468 patients. In pilot study, our results indicated that exosomal CRNDE-h was detectable and stable in serum of CRC patients, and derived from tumor cells. Then, the increased expression of exosomal CRNDE-h was successfully validated in 148 CRC patients when compared with colorectal benign disease patients and healthy donors. Exosomal CRNDE-h level significantly correlated with CRC regional lymph node metastasis (P = 0.019) and distant metastasis (P = 0.003). Moreover, at the cut-off value of 0.020 exosomal CRNDE-h level of serum, the area under ROC curve distinguishing CRC from colorectal benign disease patients and healthy donors was 0.892, with 70.3% sensitivity and 94.4% specificity, which was superior to carcinoembryogenic antigen. In addition, high exosomal CRNDE-h level has a lower overall survival rates than that for low groups (34.6% vs. 68.2%, P < 0.001). In conclusion, detection of lncRNA CRNDE-h in exosome shed a light on utilizing exosomal CRNDE-h as a noninvasive serum-based tumor marker for diagnosis and prognosis of CRC.

Metastatic spread in patients with gastric cancer.

Abstract: // Matias Riihimaki 1, 2 , Akseli Hemminki 3, 4 , Kristina Sundquist 2 , Jan Sundquist 2 , Kari Hemminki 1, 2 1 Division of Molecular Genetic Epidemiology, German Cancer Research Centre (DKFZ), Heidelberg, Germany 2 Center for Primary Health Care Research, Lund University, Malmo, Sweden 3 Cancer Gene Therapy Group, Faculty of Medicine, University of Helsinki, Finland 4 Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland Correspondence to: Matias Riihimaki, email: matias.riihimaki@gmail.com Keywords: gastric cancer, metastasis, epidemiology Received: December 22, 2015 Accepted: June 16, 2016 Published: July 20, 2016 ABSTRACT Background: The epidemiology of metastatic gastric cancer is unexplored because cancer registries seldom cover metastatic involvement apart from “present or not”. We used a novel approach by utilizing Swedish registers to assess metastatic spread in gastric cancer. To our knowledge, this is the first nationwide description of metastases in gastric cancer. Results: The most common sites of metastasis were liver (in 48% of metastatic cancer patients), peritoneum (32%), lung (15%), and bone (12%). Metastases to the lung, nervous system, and bone were more frequent in cardia cancer and men, whereas non-cardia cancer more frequently metastasized within the peritoneum. Signet ring adenocarcinomas more frequently metastasized within the peritoneum, bone and ovaries, and less frequently to the lungs and liver compared with generic adenocarcinoma. The liver and the peritoneum were commonly single metastases while lung metastases occurred frequently together with liver metastases. The median survival in metastatic gastric cancer was 3 months, worst among those with bone and liver metastases (2 months). Methods: A total of 7,559 patients with gastric cancer were identified. Metastatic patterns and survival depending on sex, age, stage, anatomical location (cardia and non-cardia), and histological type were assessed. Conclusions: The patterns of metastasis differ notably depending on histological type. Cardia cancer exhibits a completely different metastatic behavior than non-cardia cancer. Awareness of the differing patterns may guide in tailored diagnosis of metastases. Survivors from cardia cancer would benefit from increased surveillance of extraperitoneal metastases. Bone metastases should be considered in patients with signet ring adenocarcinoma if symptoms emerge.

PD-L1 is an independent prognostic predictor in gastric cancer of Western patients

Abstract: Targeting the PD-1/PD-L1 immune checkpoint signaling is a novel promising treatment strategy in several tumor entities, and it is suggested that PD-L1/PD-1 expression is predictive for a PD-1/PD-L1 checkpoint inhibitor treatment response. We investigated the expression of PD-L1 and PD-1 by immunohistochemistry in a large and well characterized gastric cancer (GC) cohort of Caucasian patients, consisting of 465 GC samples and 15 corresponding liver metastases. Staining results were correlated with clinico-pathological characteristics and survival. PD-L1 expression was found in tumor cells of 140 GCs (30.1%) and 9 liver metastases (60%) respectively in immune cells of 411 GCs (88.4%) and 11 liver metastases (73.3%). PD-1 was expressed in tumor infiltrating lymphocytes in 250 GCs (53.8%) and in 11 liver metastases (73.3%). PD-L1 expression was significantly more prevalent in men, GCs of the proximal stomach, unclassified, papillary, Her2/neu-positive, Epstein-Barr-virus-positive, microsatellite instable, and PIK3CA-mutated GCs. A high PD-L1/PD-1 expression was associated with a significantly better patient outcome, and PD-L1 turned out to be an independent survival prognosticator. The correlation of PD-L1/PD-1 expression with distinct clinico-pathological patient characteristics may serve as a surrogate marker of PD-L1-positive GCs and may direct the use of immune checkpoint treatment strategies.

PD-1 mediates functional exhaustion of activated NK cells in patients with Kaposi sarcoma.

Abstract: // Asma Beldi-Ferchiou 1, 2, 11 , Marion Lambert 1, 2 , Stephanie Dogniaux 3 , Frederic Vely 4, 5 , Eric Vivier 4, 5 , Daniel Olive 6 , Stephanie Dupuy 1 , Frank Levasseur 1 , David Zucman 7 , Celeste Lebbe 8 , Damien Sene 1, 2, 9 , Claire Hivroz 4 , Sophie Caillat-Zucman 1, 2, 10 1 Institut National de Recherche Medicale (INSERM) UMR1149, Centre de Recherche Sur l’Inflammation, Equipe Immunite Innee Chez l’enfant, Hopital Robert Debre, Paris, France 2 Universite Paris Diderot, Sorbonne Paris Cite, Paris, France 3 Institut Curie, Centre de Recherche, PSL Research University, INSERM U932 Immunite et Cancer, Paris, France 4 Centre d’Immunologie de Marseille-Luminy, Aix-Marseille Universite UM2, INSERM U1104, CNRS UMR7280, Marseille, France 5 Immunologie, Hopital de la Conception, Assistance Publique- Hopitaux de Marseille, Marseille, France 6 Centre de Cancerologie de Marseille, INSERM U1068, Equipe Immunite et Cancer, Institut Paoli-Calmettes, Aix-Marseille Universite, CNRS, UMR7258, Marseille, France 7 Hopital Foch, Service de Medecine Interne, Suresnes, France 8 Assistance Publique-Hopitaux de Paris (AP-HP), Hopital Saint-Louis, Departement de Dermatologie, INSERM U976, Universite Paris Diderot, Paris, France 9 Assistance Publique-Hopitaux de Paris (AP-HP), Hopital Lariboisiere, Departement de Medecine Interne, Paris, France 10 Assistance Publique-Hopitaux de Paris (AP-HP), Hopital Saint-Louis, Laboratoire d’Immunologie, Paris, France 11 Present address: Assistance Publique-Hopitaux de Paris (AP-HP), Hopital Henri Mondor, Laboratoire d’Immunologie, Creteil, France Correspondence to: Sophie Caillat-Zucman, email: sophie.caillat@inserm.fr Keywords: NK cells, Kaposi sarcoma, PD-1, immune checkpoint, tumor escape Received: March 31, 2016 Accepted: September 13, 2016 Published: September 20, 2016 ABSTRACT Programmed Death-1 (PD-1), an inhibitory receptor expressed by activated lymphocytes, is involved in regulating T- and B-cell responses. PD-1 and its ligands are exploited by a variety of cancers to facilitate tumor escape through PD-1-mediated functional exhaustion of effector T cells. Here, we report that PD-1 is upregulated on Natural Killer (NK) cells from patients with Kaposi sarcoma (KS). PD-1 was expressed in a sub-population of activated, mature CD56 dim CD16 pos NK cells with otherwise normal expression of NK surface receptors. PD-1 pos NK cells from KS patients were hyporesponsive ex vivo following direct triggering of NKp30, NKp46 or CD16 activating receptors, or short stimulation with NK cell targets. PD-1 pos NK cells failed to degranulate and release IFNγ, but exogenous IL-2 or IL-15 restored this defect. That PD-1 contributed to NK cell functional impairment and was not simply a marker of dysfunctional NK cells was confirmed in PD-1-transduced NKL cells. In vitro , PD-1 was induced at the surface of healthy control NK cells upon prolonged contact with cells expressing activating ligands, i.e. a condition mimicking persistent stimulation by tumor cells. Thus, PD-1 appears to plays a critical role in mediating NK cell exhaustion. The existence of this negative checkpoint fine-tuning NK activation highlights the possibility that manipulation of the PD-1 pathway may be a strategy for circumventing tumor escape not only from the T cell-, but also the NK-cell mediated immune surveillance.

LncRNA HULC enhances epithelial-mesenchymal transition to promote tumorigenesis and metastasis of hepatocellular carcinoma via the miR-200a-3p/ZEB1 signaling pathway.

Abstract: // Shi-Peng Li 1, * , Hai-Xu Xu 3, * , Yao Yu 1, * , Jin-Dan He 1, * , Zhen Wang 1 , Yan-Jie Xu 1 , Chang-Ying Wang 3 , Hai-Ming Zhang 1, 2 , Rong-Xin Zhang 4 , Jian-Jun Zhang 1, 2 , Zhi Yao 3 , Zhong-Yang Shen 1, 2 1 First Central Clinical College, Tianjin Medical University, Tianjin, P.R. China 2 Oriental Organ Transplant Center of Tianjin First Central Hospital, Key Laboratory of Organ Transplantation of Tianjin, Tianjin, P.R.China 3 Department of Immunology, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Immuno Microenvironment and Disease of the Educational Ministry, Tianjin Medical University, Tianjin, P.R.China 4 Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Basic Medical College, Tianjin Medical University, Tianjin, P.R.China * These authors have contributed equally to this work Correspondence to: Jian-Jun Zhang, email: zhangjianjun9999@yeah.net Zhong-Yang Shen, email: zhongyangshen@vip.sina.com Rong-Xin Zhang, email: rongxinz@yahoo.com Zhi Yao, email: yaozhi@tijmu.edu.cn Keywords: hepatocellular carcinoma, lncRNA HULC, epithelial-mesenchymal transition, miR-200a-3p, ZEB1 Received: November 29, 2015 Accepted: May 14, 2016 Published: June 7, 2016 ABSTRACT Highly upregulated in liver cancer (HULC), a lncRNA that is considered a key molecule in human liver cancer, has recently been revealed to be involved in hepatocellular carcinoma (HCC) development and progression [1, 2]. It has been reported that HULC can promote tumor invasion and metastasis of HCC, but its function and mechanism of action in HCC have not been elucidated. In this study, we found that HULC was aberrantly up-regulated in HCC tissues and associated with TNM stage, intrahepatic metastases, HCC recurrence, and postoperative survival. HULC depletion inhibited the growth and metastasis of HCC cell lines in vitro and in vivo . Moreover, HULC contributes to ZEB1-induced epithelial-mesenchymal transition (EMT), a requirement for tumor invasion and metastasis that plays a key role in cancer progression. This effect of ZEB1 was inhibited by HULC siRNA. We conclude that the HULC functioned as a competing endogenous RNA (ceRNA) to mediate EMT via up-regulating ZEB1. In this way, it sequesters the miR-200a-3p signaling pathway to facilitate HCC metastasis. HULC comes into play as an oncogene in HCC, acting mechanistically by inducing HCC cells to activate EMT. Such an effect promotes tumor progression and metastasis through the miR-200a-3p/ZEB1 signaling pathway. The identification of this novel pathway that links high expression levels of HULC with EMT in HCC cells may serve as the foundation for the development of novel anti-tumor therapeutics.

Abundant PD-L1 expression in Epstein-Barr Virus-infected gastric cancers.

Abstract: Gastric cancer (GC) is a deadly disease with limited treatment options. Recent studies with PD-1 inhibition have shown promising results in GC, but key questions remain regarding which GC subclass may respond best. In other cancers, expression of the PD-1 ligand PD-L1 has been shown to identify cancers with greater likelihood of response to PD-1 blockade. We here show with immunohistochemistry that Epstein-Barr Virus (EBV)+ GCs (n = 32) have robust PD-L1 expression not seen in other GCs. In EBV+ GC, we observed PD-L1 staining in tumor cells in 50% (16/32) and immune cells in 94% (30/32) of cases. Among EBV-negative GCs, PD-L1 expression within tumors cells was observed only in cases with microsatellite instability (MSI), although 35% of EBV-/MSS GCs possessed PD-L1 expression of inflammatory cells. Moreover, distinct classes of GC showed different patterns of PD-L1+ immune cell infiltrations. In both EBV+ and MSI tumors, PD-L1+ inflammatory cells were observed to infiltrate the tumor. By contrast, such cells remained at the tumor border of EBV-/MSS GCs. Consistent with these findings, we utilized gene expression profiling of GCs from The Cancer Genome Atlas study to demonstrate that an interferon-γ driven gene signature, an additional proposed marker of sensitivity to PD-1 therapy, were enriched in EBV+ and MSI GC. These data suggest that patients with EBV+ and MSI GC may have greater likelihood of response to PD-1 blockade and that EBV and MSI status should be evaluated as variables in clinical trials of these emerging inhibitors.