Showing papers in "Oncotarget in 2015"
TL;DR: Inflammation is a biological response of the immune system that can be triggered by a variety of factors, including pathogens, damaged cells and toxic compounds, potentially leading to tissue damage or disease.
Abstract: Inflammation is a biological response of the immune system that can be triggered by a variety of factors, including pathogens, damaged cells and toxic compounds. These factors may induce acute and/or chronic inflammatory responses in the heart, pancreas, liver, kidney, lung, brain, intestinal tract and reproductive system, potentially leading to tissue damage or disease. Both infectious and non-infectious agents and cell damage activate inflammatory cells and trigger inflammatory signaling pathways, most commonly the NF-κB, MAPK, and JAK-STAT pathways. Here, we review inflammatory responses within organs, focusing on the etiology of inflammation, inflammatory response mechanisms, resolution of inflammation, and organ-specific inflammatory responses.
2,197 citations
TL;DR: Results indicate that cir-ITCH may have an inhibitory effect on ESCC by regulating the Wnt pathway.
Abstract: // Fang Li 1,* , Liyuan Zhang 2,* , Wei Li 1 , Jieqiong Deng 1 , Jian Zheng 1 , Mingxing An 1 , Jiachun Lu 3 and Yifeng Zhou 1 1 Department of Genetics, Medical College of Soochow University, Suzhou, China 2 Department of Radiotherapy & Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China 3 The Institute for Chemical Carcinogenesis, The State Key Lab of Respiratory Disease, Guangzhou Medical University, Guangzhou, China * These authors contributed equally to this work Correspondence to: Yifeng Zhou, email: // Keywords : Cir-ITCH, ESCC, Wnt/β-catenin pathway Received : December 01, 2014 Accepted : January 20, 2015 Published : February 28, 2015 Abstract Circular RNAs with exonic sequences represent a special form of non-coding RNAs, discovered by analyzing a handful of transcribed genes. It has been observed that circular RNAs function as microRNA sponges. In the present study, we investigated whether the expression of circular RNAs is altered during the development of esophageal squamous cell carcinoma (ESCC). Using a TaqMan-based reverse transcriptase polymerase chain reaction assay, the relationship between cir-ITCH and ESCC was analyzed in a total of 684 ESCC and paired adjacent non-tumor tissue samples from eastern and southern China. We found that cir-ITCH expression was usually low in ESCC compared to the peritumoral tissue. The functional relevance of cir-ITCH was further examined by biochemical assays. As sponge of miR-7, miR-17, and miR-214, cir-ITCH might increase the level of ITCH . ITCH hyper expression promotes ubiquitination and degradation of phosphorylated Dvl2, thereby inhibiting the Wnt/β-catenin pathway. These results indicate that cir-ITCH may have an inhibitory effect on ESCC by regulating the Wnt pathway.
605 citations
TL;DR: It is implied that the lncRNA H19 modulated the expression of multiple genes involved in EMT by acting as a competing endogenous RNA, which may build up the missing link between the regulatory miRNA network and EMT progression.
Abstract: Recently, the long non-coding RNA (lncRNA) H19 has been identified as an oncogenic gene in multiple cancer types and elevated expression of H19 was tightly linked to tumorigenesis and cancer progression. However, the molecular basis for this observation has not been characterized in colorectal cancer (CRC) especially during epithelial to mesenchymal transition (EMT) progression. In our studies, H19 was characterized as a novel regulator of EMT in CRC. We found that H19 was highly expressed in mesenchymal-like cancer cells and primary CRC tissues. Stable expression of H19 significantly promotes EMT progression and accelerates in vivo and in vitro tumor growth. Furthermore, by using bioinformatics study and RNA immunoprecipitation combined with luciferase reporter assays, we demonstrated that H19 functioned as a competing endogenous RNA (ceRNA) for miR-138 and miR-200a, antagonized their functions and led to the de-repression of their endogenous targets Vimentin, ZEB1, and ZEB2, all of which were core marker genes for mesenchymal cells. Taken together, these observations imply that the lncRNA H19 modulated the expression of multiple genes involved in EMT by acting as a competing endogenous RNA, which may build up the missing link between the regulatory miRNA network and EMT progression.
511 citations
TL;DR: PDL1 upregulation, more frequent in basal breast cancers, was associated with increased T-cell cytotoxic immune response and better survival and response to chemotherapy, and reactivation of dormant tumor-infiltrating lymphocytes by PDL1-inhibitors could represent promising strategy.
Abstract: // Renaud Sabatier 1,2,3 , Pascal Finetti 1 , Emilie Mamessier 1 , Jose Adelaide 1 , Max Chaffanet 1 , Hamid Raza Ali 4,5 , Patrice Viens 1,2,3 , Carlos Caldas 5 , Daniel Birnbaum 1 and Francois Bertucci 1,2,3 1 Departement d’Oncologie Moleculaire, “Equipe labellisee Ligue Contre le Cancer”, Centre de Recherche en Cancerologie de Marseille (CRCM), Institut Paoli-Calmettes, INSERM UMR1068, CNRS UMR725, Marseille, France 2 Departement d’Oncologie Medicale, CRCM, Institut Paoli-Calmettes, Marseille, France 3 Faculte de Medecine, Aix-Marseille Universite, Marseille, France 4 Department of Pathology, University of Cambridge, Cambridge, United Kingdom 5 Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom Correspondence: Francois Bertucci, email: // Keywords : breast cancer, chemotherapy, immune response, PDL1, survival Received : November 17, 2014 Accepted : December 26, 2014 Published : December 31, 2014 Abstract Expression of programmed cell death receptor ligand 1 (PDL1) has been scarcely studied in breast cancer. Recently PD1/PDL1-inhibitors have shown promising results in different carcinomas with correlation between PDL1 tumor expression and responses. We retrospectively analyzed PDL1 mRNA expression in 45 breast cancer cell lines and 5,454 breast cancers profiled using DNA microarrays. Compared to normal breast samples, PDL1 expression was upregulated in 20% of clinical samples and 38% of basal tumors. High expression was associated with poor-prognosis features (large tumor size, high grade, ER-negative, PR-negative, ERBB2- positive status, high proliferation, basal and ERBB2 -enriched subtypes). PDL1 upregulation was associated with biological signs of strong cytotoxic local immune response. PDL1 upregulation was not associated with survival in the whole population, but was associated with better metastasis-free and overall specific survivals in basal tumors, independently of clinicopathological features. Pathological complete response after neoadjuvant chemotherapy was higher in case of PDL1 upregulation (50% versus 21%). In conclusion, PDL1 upregulation, more frequent in basal breast cancers, was associated with increased T-cell cytotoxic immune response. In this aggressive subtype, upregulation was associated with better survival and response to chemotherapy. Reactivation of dormant tumor-infiltrating lymphocytes by PDL1-inhibitors could represent promising strategy in PDL1-upregulated basal breast cancer.
415 citations
TL;DR: The association of the EMT program with CTCs and CSCs is extensively discussed to characterize a subpopulation of patients prone to relapses and to facilitate the development of new or enhanced personalized therapeutic regimens.
Abstract: Tumor relapse and metastasis are the primary causes of poor survival rates in patients with advanced cancer despite successful resection or chemotherapeutic treatment. A primary cause of relapse and metastasis is the persistence of cancer stem cells (CSCs), which are highly resistant to chemotherapy. Although highly efficacious drugs suppressing several subpopulations of CSCs in various tissue-specific cancers are available, recurrence is still common in patients. To find more suitable therapy for relapse, the mechanisms underlying metastasis and drug-resistance associated with relapse-initiating CSCs need to be identified. Recent studies in circulating tumor cells (CTCs) of some cancer patients manifest phenotypes of both CSCs and epithelial-mesenchymal transition (EMT). These patients are unresponsive to standard chemotherapies and have low progression free survival, suggesting that EMT-positive CTCs are related to co-occur with or transform into relapse-initiating CSCs. Furthermore, EMT programming in cancer cells enables in the remodeling of extracellular matrix to break the dormancy of relapse-initiating CSCs. In this review, we extensively discuss the association of the EMT program with CTCs and CSCs to characterize a subpopulation of patients prone to relapses. Identifying the mechanisms by which EMT-transformed CTCs and CSCs initiate relapse could facilitate the development of new or enhanced personalized therapeutic regimens.
400 citations
TL;DR: It is demonstrated that vimentin serves as a regulator to maintain intracellular mechanical homeostasis by mediating cytoskeleton architecture and the balance of cell force generation in EMT cancer cells.
Abstract: Modulations of cytoskeletal organization and focal adhesion turnover correlate to tumorigenesis and epithelial-mesenchymal transition (EMT), the latter process accompanied by the loss of epithelial markers and the gain of mesenchymal markers (e.g., vimentin). Clinical microarray results demonstrated that increased levels of vimentin mRNA after chemotherapy correlated to a poor prognosis of breast cancer patients. We hypothesized that vimentin mediated the reorganization of cytoskeletons to maintain the mechanical integrity in EMT cancer cells. By using knockdown strategy, the results showed reduced cell proliferation, impaired wound healing, loss of directional migration, and increased large membrane extension in MDA-MB 231 cells. Vimentin depletion also induced reorganization of cytoskeletons and reduced focal adhesions, which resulted in impaired mechanical strength because of reduced cell stiffness and contractile force. In addition, overexpressing vimentin in MCF7 cells increased cell stiffness, elevated cell motility and directional migration, reoriented microtubule polarity, and increased EMT phenotypes due to the increased β1-integrin and the loss of junction protein E-cadherin. The EMT-related transcription factor slug was also mediated by vimentin. The current study demonstrated that vimentin serves as a regulator to maintain intracellular mechanical homeostasis by mediating cytoskeleton architecture and the balance of cell force generation in EMT cancer cells.
386 citations
TL;DR: It is demonstrated that CSF exosomal RNA molecules are reliable biomarkers with fair robustness in regard to specificity and sensitivity in differentiating PD from healthy and diseased (AD) controls.
Abstract: The differential diagnosis of Parkinson's diseases (PD) is challenging, especially in the early stages of the disease. We developed a microRNA profiling strategy for exosomal miRNAs isolated from cerebrospinal fluid (CSF) in PD and AD. Sixteen exosomal miRNAs were up regulated and 11 miRNAs were under regulated significantly in PD CSF when compared with those in healthy controls (relative fold > 2, p < 0.05). MiR-1 and miR-19b-3p were validated and significantly reduced in independent samples. While miR-153, miR-409-3p, miR-10a-5p, and let-7g-3p were significantly over expressed in PD CSF exosome. Bioinformatic analysis by DIANA-mirPath demonstrated that Neurotrophin signaling, mTOR signaling, Ubiquitin mediated proteolysis, Dopaminergic synapse, and Glutamatergic synapse were the most prominent pathways enriched in quantiles with PD miRNA patterns. Messenger RNA (mRNA) transcripts [amyloid precursor protein (APP), α-synuclein (α-syn), Tau, neurofilament light gene (NF-L), DJ-1/PARK7, Fractalkine and Neurosin] and long non-coding RNAs (RP11-462G22.1 and PCA3) were differentially expressed in CSF exosomes in PD and AD patients. These data demonstrated that CSF exosomal RNA molecules are reliable biomarkers with fair robustness in regard to specificity and sensitivity in differentiating PD from healthy and diseased (AD) controls.
381 citations
TL;DR: Hemin and CO-releasing molecules (CORM) promote Erastin-induced ferroptotic cell death, not by biliverdin and bilirubin, but by hemin and CORM accelerate the HO-1 expression in the presence of Erastsin and increase membranous lipid peroxidation.
Abstract: The oncogenic RAS-selective lethal small molecule Erastin triggers a unique iron-dependent form of nonapoptotic cell death termed ferroptosis. Ferroptosis is dependent upon the production of intracellular iron-dependent reactive oxygen species (ROS), but not other metals. However, key regulators remain unknown. The heme oxygenase (HO) is a major intracellular source of iron. In this study, the role of heme oxygenase in Erastin-triggered ferroptotic cancer cell death has been investigated. Zinc protoporphyrin IX (ZnPP), a HO-1 inhibitor, prevented Erastin-triggered ferroptotic cancer cell death. Furthermore, Erastin induced the protein and mRNA levels of HO-1 in HT-1080 fibrosarcoma cells. HO-1+/+ and HO-1-/- fibroblast, HO-1 overexpression, and chycloheximide-treated experiments revealed that the expression of HO-1 has a decisive effects in Erastin-triggered cell death. Hemin and CO-releasing molecules (CORM) promote Erastin-induced ferroptotic cell death, not by biliverdin and bilirubin. In addition, hemin and CORM accelerate the HO-1 expression in the presence of Erastin and increase membranous lipid peroxidation. Thus, HO-1 is an essential enzyme for iron-dependent lipid peroxidation during ferroptotic cell death.
376 citations
TL;DR: It is proposed to treat cancer like an infectious disease, by repurposing FDA-approved antibiotics for anti-cancer therapy, across multiple tumor types, and these drug classes should also be considered for prevention studies, specifically focused on the prevention of tumor recurrence and distant metastasis.
Abstract: Here, we propose a new strategy for the treatment of early cancerous lesions and advanced metastatic disease, via the selective targeting of cancer stem cells (CSCs), a.k.a., tumor-initiating cells (TICs). We searched for a global phenotypic characteristic that was highly conserved among cancer stem cells, across multiple tumor types, to provide a mutation-independent approach to cancer therapy. This would allow us to target cancer stem cells, effectively treating cancer as a single disease of "stemness", independently of the tumor tissue type. Using this approach, we identified a conserved phenotypic weak point - a strict dependence on mitochondrial biogenesis for the clonal expansion and survival of cancer stem cells. Interestingly, several classes of FDA-approved antibiotics inhibit mitochondrial biogenesis as a known "side-effect", which could be harnessed instead as a "therapeutic effect". Based on this analysis, we now show that 4-to-5 different classes of FDA-approved drugs can be used to eradicate cancer stem cells, in 12 different cancer cell lines, across 8 different tumor types (breast, DCIS, ovarian, prostate, lung, pancreatic, melanoma, and glioblastoma (brain)). These five classes of mitochondrially-targeted antibiotics include: the erythromycins, the tetracyclines, the glycylcyclines, an anti-parasitic drug, and chloramphenicol. Functional data are presented for one antibiotic in each drug class: azithromycin, doxycycline, tigecycline, pyrvinium pamoate, as well as chloramphenicol, as proof-of-concept. Importantly, many of these drugs are non-toxic for normal cells, likely reducing the side effects of anti-cancer therapy. Thus, we now propose to treat cancer like an infectious disease, by repurposing FDA-approved antibiotics for anti-cancer therapy, across multiple tumor types. These drug classes should also be considered for prevention studies, specifically focused on the prevention of tumor recurrence and distant metastasis. Finally, recent clinical trials with doxycycline and azithromycin (intended to target cancer-associated infections, but not cancer cells) have already shown positive therapeutic effects in cancer patients, although their ability to eradicate cancer stem cells was not yet appreciated.
371 citations
TL;DR: It is found that UCA1 was aberrantly upregulated in HCC tissues and associated with TNM stage, metastasis and postoperative survival, and a novel lncRNA- miRNA-mRNA regulatory network that is U CA1-miR-216b-FGFR1-ERK signaling pathway in H CC is elucidated, which may help to lead a better understanding of the pathogenesis of HCC.
Abstract: // Feng Wang 1, * , Hou-Qun Ying 2, * , Bang-Shun He 1 , Yu-Qin Pan 1 , Qi-Wen Deng 1 , Hui-Ling Sun 3 , Jie Chen 3 , Xian Liu 1 , Shu-Kui Wang 1 1 Central Laboratory, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China 2 Medical college, Southeast University, Nanjing, Jiangsu, China 3 Department of Life Sciences, Nanjing Normal University, Nanjing, Jiangsu, China * These authors have contributed equally to this work Correspondence to: Shu-Kui Wang, e-mail: shukwangnj@163.com Keywords: hepatocellular carcinoma, lncRNA, UCA1, miR-216b, FGFR1 Received: November 17, 2014 Accepted: January 26, 2015 Published: February 11, 2015 ABSTRACT The long non-coding RNA (lncRNA) urothelial carcinoma-associated 1 (UCA1) has been recently shown to be dysregulated, which plays an important role in the progression of several cancers. However, the biological role and clinical significance of UCA1 in the carcinogenesis of hepatocellular carcinoma (HCC) remain unclear. Herein, we found that UCA1 was aberrantly upregulated in HCC tissues and associated with TNM stage, metastasis and postoperative survival. UCA1 depletion inhibited the growth and metastasis of HCC cell lines in vitro and in vivo . Furthermore, UCA1 could act as an endogenous sponge by directly binding to miR-216b and downregulation miR-216b expression. In addition, UCA1 could reverse the inhibitory effect of miR-216b on the growth and metastasis of HCC cells, which might be involved in the derepression of fibroblast growth factor receptor 1 (FGFR1) expression, a target gene of miR-216b, and the activation of ERK signaling pathway. Taken together, our data highlights the pivotal role of UCA1 in the tumorigenesis of HCC. Moreover, the present study elucidates a novel lncRNA-miRNA-mRNA regulatory network that is UCA1-miR-216b-FGFR1-ERK signaling pathway in HCC, which may help to lead a better understanding the pathogenesis of HCC and probe the feasibility of lncRNA-directed diagnosis and therapy for this deadly disease.
324 citations
TL;DR: An overview of the next-generation artificial intelligence and blockchain technologies is provided and innovative solutions that may be used to accelerate the biomedical research and enable patients with new tools to control and profit from their personal data as well with the incentives to undergo constant health monitoring are presented.
Abstract: The increased availability of data and recent advancements in artificial intelligence present the unprecedented opportunities in healthcare and major challenges for the patients, developers, providers and regulators. The novel deep learning and transfer learning techniques are turning any data about the person into medical data transforming simple facial pictures and videos into powerful sources of data for predictive analytics. Presently, the patients do not have control over the access privileges to their medical records and remain unaware of the true value of the data they have. In this paper, we provide an overview of the next-generation artificial intelligence and blockchain technologies and present innovative solutions that may be used to accelerate the biomedical research and enable patients with new tools to control and profit from their personal data as well with the incentives to undergo constant health monitoring. We introduce new concepts to appraise and evaluate personal records, including the combination-, time- and relationship-value of the data. We also present a roadmap for a blockchain-enabled decentralized personal health data ecosystem to enable novel approaches for drug discovery, biomarker development, and preventative healthcare. A secure and transparent distributed personal data marketplace utilizing blockchain and deep learning technologies may be able to resolve the challenges faced by the regulators and return the control over personal data including medical records back to the individuals.
TL;DR: This work summarizes how miRNAs regulate apoptotic, autophagic and necroptotic pathways and cancer progression and discusses how mi RNAs link different types of cell death.
Abstract: MicroRNAs (miRNAs) are endogenous 22 nt non-coding RNAs that target mRNAs for cleavage or translational repression. Numerous miRNAs regulate programmed cell death including apoptosis, autophagy and necroptosis. We summarize how miRNAs regulate apoptotic, autophagic and necroptotic pathways and cancer progression. We also discuss how miRNAs link different types of cell death.
TL;DR: It is concluded that miR-200 family may serve as novel targets for the therapy of multiple types of cancer.
Abstract: // Brock Humphries 1, 2 , Chengfeng Yang 1, 2, 3 1 Department of Physiology, Michigan State University, East Lansing, MI 48824, USA 2 Cellular and Molecular Biology Graduate Program, Michigan State University, East Lansing, MI 48824, USA 3 Center for Integrative Toxicology, Michigan State University, East Lansing, MI 48824, USA Correspondence to: Chengfeng Yang, e-mail: yangcf@msu.edu Keywords: microRNA, miR-200, cancer initiation, cancer metastasis, cancer therapeutic target Received: November 14, 2014 Accepted: January 06, 2015 Published: January 30, 2015 ABSTRACT MicroRNAs (miRNAs) are a large family of small non-coding RNAs that negatively regulate protein-coding gene expression post-transcriptionally via base pairing between the 5′ seed region of a miRNA and the 3′ untranslated region (3′UTR) of a messenger RNA (mRNA). Recent evidence has supported the critical role that miRNAs play in many diseases including cancer. The miR-200 family consisting of 5 members (miR-200a, -200b, -200c, -141, -429) is an emerging miRNA family that has been shown to play crucial roles in cancer initiation and metastasis, and potentially be important for the diagnosis and treatment of cancer. While miR-200s were found to be critically involved in the metastatic colonization to the lungs in mouse mammary xenograft tumor models, a large number of studies demonstrated their strong suppressive effects on cell transformation, cancer cell proliferation, migration, invasion, tumor growth and metastasis. This review aims to discuss research findings about the role of the miR-200 family in cancer initiation, each step of cancer metastatic cascade, cancer diagnosis and treatment. A comprehensive summary of currently validated miR-200 targets is also presented. It is concluded that miR-200 family may serve as novel targets for the therapy of multiple types of cancer.
TL;DR: Observations indicate that LO represent a discrete EV type that may play a distinct role in tumor progression and that may be a source of cancer-specific markers.
Abstract: // Valentina R. Minciacchi 1 , Sungyong You 1 , Cristiana Spinelli 1 , Samantha Morley 2 , Mandana Zandian 1 , Paul-Joseph Aspuria 3 , Lorenzo Cavallini 1,4 , Chiara Ciardiello 1,5 , Mariana Reis Sobreiro 1 , Matteo Morello 1 , Geetanjali Kharmate 6 , Su Chul Jang 7 , Dae-Kyum Kim 7 , Elham Hosseini-Beheshti 6 , Emma Tomlinson Guns 6 , Martin Gleave 6 , Yong Song Gho 7 , Suresh Mathivanan 8 , Wei Yang 1 , Michael R. Freeman 1,2 and Dolores Di Vizio 1,2 1 Division of Cancer Biology and Therapeutics, Departments of Surgery, Biomedical Sciences and Pathology and Laboratory Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA 2 The Urological Diseases Research Center, Boston Children’s Hospital, Boston, MA, Department of Surgery, Harvard Medical School, Boston, MA, USA 3 Women’s Cancer Program, Cedars-Sinai Medical Center, Los Angeles, CA, USA 4 Department of Experimental and Clinical Biomedical Science, University of Florence, Florence, Italy 5 Experimental Pharmacology Unit, Department of Research, IRCCS-Istituto Nazionale Tumori G. Pascale, Naples, Italy 6 Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, BC, Canada 7 Department of Life Sciences, Pohang University of Science and Technology, Pohang, Republic of Korea 8 Department of Biochemistry, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Australia Correspondence to: Dolores Di Vizio, email: // Keywords : Extracellular Vesicles, SILAC Proteomics, Cancer metabolism, Tumor progression, Amoeboid blebbing Received : January 05, 2015 Accepted : February 22, 2015 Published : March 14, 2015 Abstract Large oncosomes (LO) are atypically large (1-10µm diameter) cancer-derived extracellular vesicles (EVs), originating from the shedding of membrane blebs and associated with advanced disease. We report that 25% of the proteins, identified by a quantitative proteomics analysis, are differentially represented in large and nano-sized EVs from prostate cancer cells. Proteins enriched in large EVs included enzymes involved in glucose, glutamine and amino acid metabolism, all metabolic processes relevant to cancer. Glutamine metabolism was altered in cancer cells exposed to large EVs, an effect that was not observed upon treatment with exosomes. Large EVs exhibited discrete buoyant densities in iodixanol (OptiPrep TM ) gradients. Fluorescent microscopy of large EVs revealed an appearance consistent with LO morphology, indicating that these structures can be categorized as LO. Among the proteins enriched in LO, cytokeratin 18 (CK18) was one of the most abundant (within the top 5 th percentile) and was used to develop an assay to detect LO in the circulation and tissues of mice and patients with prostate cancer. These observations indicate that LO represent a discrete EV type that may play a distinct role in tumor progression and that may be a source of cancer-specific markers.
TL;DR: The role of AMPK in regulating inflammation, metabolism, and other regulatory processes with an emphasis on cancer is reviewed and the potential for targeting AMPK to treat various types of cancer is discussed.
Abstract: // Weidong Li 1,3,* , Shakir M. Saud 2,3,* , Matthew R. Young 3 , Guohong Chen 4 , Baojin Hua 1 1 Department of Oncology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China 2 Nutritional Science Research Group, Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Rockville, Maryland, USA 3 Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland, USA 4 Department of Urinary Surgery, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China * These authors have contributed equally to this work Correspondence to: Baojin Hua, email: // Guohong Chen, email: // Keywords : AMP activated kinase, cancer, prevention, treatment Received : February 02, 2015 Accepted : February 26, 2015 Published : March 20, 2015 Abstract AMP-activated protein kinase (AMPK) is an important mediator in maintaining cellular energy homeostasis. AMPK is activated in response to a shortage of energy. Once activated, AMPK can promote ATP production and regulate metabolic energy. AMPK is a known target for treating metabolic syndrome and type-2 diabetes; however, recently AMPK is emerging as a possible metabolic tumor suppressor and target for cancer prevention and treatment. Recent epidemiological studies indicate that treatment with metformin, an AMPK activator reduces the incidence of cancer. In this article we review the role of AMPK in regulating inflammation, metabolism, and other regulatory processes with an emphasis on cancer, as well as, discuss the potential for targeting AMPK to treat various types of cancer. Activation of AMPK has been found to oppose tumor progression in several cancer types and offers a promising cancer therapy. This review evaluates the evidence linking AMPK with tumor suppressor function and analyzes the molecular mechanisms involved. AMPK activity opposes tumor development and progression in part by regulating inflammation and metabolism.
TL;DR: The data demonstrate that ctDNA is a useful biomarker of response to kinase inhibitor therapy and can be used to monitor tumor evolution and detect the early appearance of resistance effectors.
Abstract: // Elin S. Gray 1 , Helen Rizos 2,8 , Anna L. Reid 1 , Suzanah C. Boyd 2,8 , Michelle R. Pereira 1 , Johnny Lo 3 , Varsha Tembe 4 , James Freeman 1 , Jenny H.J. Lee 4,5 , Richard A. Scolyer 6,8 , Kelvin Siew 9 , Chris Lomma 9 , Adam Cooper 5 , Muhammad A. Khattak 10,11 , Tarek M. Meniawy 9,11 , Georgina V. Long 7,8 , Matteo S. Carlino 5,8 , Michael Millward 9,11 and Melanie Ziman 1,12 1 School of Medical Sciences, Edith Cowan University, Joondalup, Western Australia, Australia 2 Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia 3 School of Engineering, Edith Cowan University, Joondalup, Western Australia, Australia 4 Centre for Cancer Research, The University of Sydney at Westmead Millennium Institute, Westmead Hospital, Westmead, New South Wales, Australia 5 Department of Medical Oncology, Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, New South Wales, Australia 6 Disciplines of Pathology, The University of Sydney, Sydney, New South Wales, Australia 7 Medicine, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia 8 Melanoma Institute Australia, Sydney, New South Wales, Australia 9 Department of Medical Oncology, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia 10 Department of Medical Oncology, Fiona Stanley Hospital, Murdoch, Western Australia, Australia 11 School of Medicine and Pharmacology, The University of Western Australia, Crawley, Western Australia, Australia 12 School of Pathology and Laboratory Medicine, The University of Western Australia, Crawley, Western Australia, Australia Correspondence to: Elin Gray, email: // Keywords : melanoma, ctDNA, acquired resistance, MAPK inhibition, immunotherapy Received : August 03, 2015 Accepted : August 31, 2015 Published : September 22, 2015 Abstract Repeat tumor biopsies to study genomic changes during therapy are difficult, invasive and data are confounded by tumoral heterogeneity. The analysis of circulating tumor DNA (ctDNA) can provide a non-invasive approach to assess prognosis and the genetic evolution of tumors in response to therapy. Mutation-specific droplet digital PCR was used to measure plasma concentrations of oncogenic BRAF and NRAS variants in 48 patients with advanced metastatic melanoma prior to treatment with targeted therapies (vemurafenib, dabrafenib or dabrafenib/trametinib combination) or immunotherapies (ipilimumab, nivolumab or pembrolizumab). Baseline ctDNA levels were evaluated relative to treatment response and progression-free survival (PFS). Tumor-associated ctDNA was detected in the plasma of 35/48 (73%) patients prior to treatment and lower ctDNA levels at this time point were significantly associated with response to treatment and prolonged PFS, irrespective of therapy type. Levels of ctDNA decreased significantly in patients treated with MAPK inhibitors ( p < 0.001) in accordance with response to therapy, but this was not apparent in patients receiving immunotherapies. We show that circulating NRAS mutations, known to confer resistance to BRAF inhibitors, were detected in 3 of 7 (43%) patients progressing on kinase inhibitor therapy. Significantly, ctDNA rebound and circulating mutant NRAS preceded radiological detection of progressive disease. Our data demonstrate that ctDNA is a useful biomarker of response to kinase inhibitor therapy and can be used to monitor tumor evolution and detect the early appearance of resistance effectors.
TL;DR: Findings suggest that lncRNA-ATB, a mediator of TGF-β signaling, could predispose breast cancer patients to EMT and trastuzumab resistance.
Abstract: // Sheng-Jia Shi 1, * , Li-Juan Wang 2, * , Bo Yu 1 , Yun-Hui Li 1 , Yong Jin 1 , Xiao-Zhong Bai 1 1 Department of Administration and Department of Aristogenesis, No. 202 Hospital of PLA, No. 5, Shenyang, 110003, Liaoning Province, P.R. China 2 Department of Oncology, the First Affiliated Hospital of Medical College of Xi’an Jiaotong University, Xi’an, 710061, Shaanxi Province, P.R. China * These authors have contributed equally to this work Correspondence to: Xiao-Zhong Bai, e-mail: baixz2015@163.com Keywords: lnc-ATB, trastuzumab resistance, EMT, TGF-β, breast cancer Received: February 05, 2015 Accepted: February 25, 2015 Published: March 23, 2015 ABSTRACT Trastuzumab resistance is leading cause of mortality in HER2-positive breast cancers, and the role of TGF-β-induced epithelial-mesenchymal transition (EMT) in trastuzumab resistance is well established, but the involvement of lncRNAs in trastuzumab resistance is still unknown. Here, we generated trastuzumab-resistant breast cancer cells with increased invasiveness compared with parental cells, and observed robust epithelial–mesenchymal transition (EMT) and consistently elevated TGF-β signaling in these cells. We identified long noncoding RNA activated by TGF-β (lnc-ATB) was the most remarkably upregulated lncRNA in TR SKBR-3 cells and the tissues of TR breast cancer patients. We found that lnc-ATB could promote trastuzumab resistance and invasion-metastasis cascade in breast cancer by competitively biding miR-200c, up-regulating ZEB1 and ZNF-217, and then inducing EMT. In addition, we also found that the high level of lnc-ATB was correlated with trastuzumab resistance of breast cancer patients. Thus, these findings suggest that lncRNA-ATB, a mediator of TGF-β signaling, could predispose breast cancer patients to EMT and trastuzumab resistance.
TL;DR: This ADC, carrying a moderately-toxic drug targeting Trop-2 represents a novel cancer therapeutic that is showing promising activity in patients with several metastatic cancer types, including triple-negative breast cancer, non-small-cell and small-cell lung cancers.
Abstract: // David M. Goldenberg 1 , Thomas M. Cardillo 1 , Serengulam V. Govindan 1 , Edmund A. Rossi 1 , Robert M. Sharkey 1 1 Immunomedics, Inc., Morris Plains, NJ, USA * Presented in part as a lecture by DMG, “Challenging the Dogmas: Clinical Efficacy of SN-38-conjugated Antibodies in Solid Tumors,” at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapy, Barcelona, Spain, November 20, 2014. Correspondence to: David M. Goldenberg, e-mail: dmg.gscancer@att.net Keywords: antibody-drug conjugate, Trop-2, SN-38, solid cancers, triple-negative breast cancer Received: April 28, 2015 Accepted: June 05, 2015 Published: June 18, 2015 ABSTRACT Trop-2 is a novel target for ADC therapy because of its high expression by many solid cancers. The rational development of IMMU-132 represents a paradigm shift as an ADC that binds a well-known moderately-cytotoxic drug, SN-38, to the anti-Trop-2 antibody. In vitro and in vivo studies show enhanced efficacy, while there is a gradual release of SN-38 that contributes to the overall effect. IMMU-132 is most efficacious at a high drug:antibody ratio (DAR) of 7.6:1, which does not affect binding and pharmacokinetics. It targets up to 136-fold more SN-38 to a human cancer xenograft than irinotecan, SN-38′s prodrug. IMMU-132 delivers SN-38 in its most active, non-glucuronidated form, which may explain the lower frequency of severe diarrhea than with irinotecan. Thus, this ADC, carrying a moderately-toxic drug targeting Trop-2 represents a novel cancer therapeutic that is showing promising activity in patients with several metastatic cancer types, including triple-negative breast cancer, non-small-cell and small-cell lung cancers.
TL;DR: Evidence is provided that many cancer/testis antigens, in fact, have oncogenic functions, including support of growth, survival and metastasis, which has the potential to deliver more effective cancer vaccines.
Abstract: // Morten F. Gjerstorff 1 , Mads H. Andersen 2 and Henrik J. Ditzel 1,3 1 Department of Cancer and Inflammation Research, University of Southern Denmark, Odense, Denmark 2 Department of Haematology, Center for Cancer Immune Therapy (CCIT), Copenhagen University Hospital, Herlev, Denmark 3 Department of Oncology, Odense University Hospital, Odense, Denmark Correspondence to: Morten Gjerstorff, email: // Keywords : cancer/testis antigen, oncogenesis, immunotherapy Received : May 19, 2015 Accepted : June 21, 2015 Published : June 30, 2015 Abstract Recent developments have set the stage for immunotherapy as a supplement to conventional cancer treatment. Consequently, a significant effort is required to further improve efficacy and specificity, particularly the identification of optimal therapeutic targets for clinical testing. Cancer/testis antigens are immunogenic, highly cancer-specific, and frequently expressed in various types of cancer, which make them promising candidate targets for cancer immunotherapy, including cancer vaccination and adoptive T-cell transfer with chimeric T-cell receptors. Our current understanding of tumor immunology and immune escape suggests that targeting oncogenic antigens may be beneficial, meaning that identification of cancer/testis antigens with oncogenic properties is of high priority. Recent work from our lab and others provide evidence that many cancer/testis antigens, in fact, have oncogenic functions, including support of growth, survival and metastasis. This novel insight into the function of cancer/testis antigens has the potential to deliver more effective cancer vaccines. Moreover, immune targeting of oncogenic cancer/testis antigens in combination with conventional cytotoxic therapies or novel immunotherapies such as checkpoint blockade or adoptive transfer, represents a highly synergistic approach with the potential to improve patient survival.
TL;DR: This is the first comprehensive -omics based study that characterized the complex cargo of extracellular vesicles secreted by hMSCs and their role in supporting breast cancers.
Abstract: Human mesenchymal stem/stromal cells (hMSCs) have been shown to support breast cancer cell proliferation and metastasis, partly through their secretome. hMSCs have a remarkable ability to survive for long periods under stress, and their secretome is tumor supportive. In this study, we have characterized the cargo of extracellular vesicular (EV) fraction (that is in the size range of 40-150nm) of serum deprived hMSCs (SD-MSCs). Next Generation Sequencing assays were used to identify small RNA secreted in the EVs, which indicated presence of tumor supportive miRNA. Further assays demonstrated the role of miRNA-21 and 34a as tumor supportive miRNAs. Next, proteomic assays revealed the presence of ≈150 different proteins, most of which are known tumor supportive factors such as PDGFR-β, TIMP-1, and TIMP-2. Lipidomic assays verified presence of bioactive lipids such as sphingomyelin. Furthermore, metabolite assays identified the presence of lactic acid and glutamic acid in EVs. The co-injection xenograft assays using MCF-7 breast cancer cells demonstrated the tumor supportive function of these EVs. To our knowledge this is the first comprehensive -omics based study that characterized the complex cargo of extracellular vesicles secreted by hMSCs and their role in supporting breast cancers.
TL;DR: Tumor Fusobacterium species status is independently associated with a worse prognosis of pancreatic cancer, suggesting that FusOBacterium Species may be a prognostic biomarker of pancreatIC cancer.
Abstract: Recently, bacterial infection causing periodontal disease has attracted considerable attention as a risk factor for pancreatic cancer. Fusobacterium species is an oral bacterial group of the human microbiome. Some evidence suggests that Fusobacterium species promote colorectal cancer development; however, no previous studies have reported the association between Fusobacterium species and pancreatic cancer. Therefore, we examined whether Fusobacterium species exist in pancreatic cancer tissue. Using a database of 283 patients with pancreatic ductal adenocarcinoma (PDAC), we tested cancer tissue specimens for Fusobacterium species. We also tested the specimens for KRAS, NRAS, BRAF and PIK3CA mutations and measured microRNA-21 and microRNA-31. In addition, we assessed epigenetic alterations, including CpG island methylator phenotype (CIMP). Our data showed an 8.8% detection rate of Fusobacterium species in pancreatic cancers; however, tumor Fusobacterium status was not associated with any clinical and molecular features. In contrast, in multivariate Cox regression analysis, compared with the Fusobacterium species-negative group, we observed significantly higher cancer-specific mortality rates in the positive group (p = 0.023). In conclusion, Fusobacterium species were detected in pancreatic cancer tissue. Tumor Fusobacterium species status is independently associated with a worse prognosis of pancreatic cancer, suggesting that Fusobacterium species may be a prognostic biomarker of pancreatic cancer.
TL;DR: It is reported that chronic bacterial infection promotes OSCC, and that augmented signaling along the IL-6-STAT3 axis underlies this effect, the first demonstration of a mechanistic role for oral bacteria in chemically induced OSCC tumorigenesis.
Abstract: // Adi Binder Gallimidi 1, 2 , Stuart Fischman 2 , Brurya Revach 1 , Raanan Bulvik 1 , Alina Maliutina 2 , Ariel M. Rubinstein 1 , Gabriel Nussbaum 2, * , Michael Elkin 1, * 1 Sharett Oncology Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel 2 Institute of Dental Sciences, Hebrew University-Hadassah Faculty of Dental Medicine, Jerusalem, Israel * These authors have contributed equally to this work Correspondence to: Michael Elkin, e-mail: melkin@hadassah.org.il Gabriel Nussbaum, e-mail: gabrieln@ekmd.huji.ac.il Keywords: oral cancer, TLR2, STAT3, IL-6, periodontitis Received: April 16, 2015 Accepted: May 26, 2015 Published: June 08, 2015 ABSTRACT Oral squamous cell carcinoma (OSCC) is a lethal disease whose incidence is increasing. Epidemiologic studies demonstrate an association between periodontitis and oral cancer, and periodontal pathogens are implicated in the pathogenesis of numerous disorders, including rheumatoid arthritis, cardiovascular diseases, diabetes and gastrointestinal malignancies. Nevertheless, a causal role for periodontal pathogens in OSCC has not been shown, partly due to the lack of an appropriate animal model. Here, utilizing a newly-established murine model of periodontitis-associated oral tumorigenesis, we report that chronic bacterial infection promotes OSCC, and that augmented signaling along the IL-6-STAT3 axis underlies this effect. Our results indicate that periodontal pathogens P. gingivalis and F. nucleatum stimulate tumorigenesis via direct interaction with oral epithelial cells through Toll-like receptors. Furthermore, oral pathogens stimulate human OSCC proliferation and induce expression of key molecules implicated in tumorigenesis. To the best of our knowledge, these findings represent the first demonstration of a mechanistic role for oral bacteria in chemically induced OSCC tumorigenesis. These results are highly relevant for the design of effective prevention and treatment strategies for OSCC.
TL;DR: The ramification of a diagnosis of oligometastasis is a change in treatment paradigm, i.e. if the primary cancer site is controlled, or resected, and the metastatic sites are ablated, a prolonged disease-free interval, and perhaps even cure, may be achieved.
Abstract: Clinical reports of limited and treatable cancer metastases, a disease state that exists in a transitional zone between localized and widespread systemic disease, were noted on occasion historically and are now termed oligometastasis. The ramification of a diagnosis of oligometastasis is a change in treatment paradigm, i.e. if the primary cancer site (if still present) is controlled, or resected, and the metastatic sites are ablated (surgically or with radiation), a prolonged disease-free interval, and perhaps even cure, may be achieved. Contemporary molecular diagnostics are edging closer to being able to determine where an individual metastatic deposit is within the continuum of malignancy. Preclinical models are on the outset of laying the groundwork for understanding the oligometastatic state. Meanwhile, in the clinic, patients are increasingly being designated as having oligometastatic disease and being treated owing to improved diagnostic imaging, novel treatment options with the potential to provide either direct or bridging therapy, and progressively broad definitions of oligometastasis.
TL;DR: This study identifies for the first time a fraction of vesicles from lemon juice obtained as a result of different ultracentrifugation, and shows that isolated nanovesicles inhibit cancer cell proliferation in different tumor cell lines, by activating a TRAIL-mediated apoptotic cell death.
Abstract: // Stefania Raimondo 1 , Flores Naselli 1 , Simona Fontana 1 , Francesca Monteleone 1 , Alessia Lo Dico 1 , Laura Saieva 1 , Giovanni Zito 2 , Anna Flugy 1 , Mauro Manno 3 , Maria Antonietta Di Bella 1 , Giacomo De Leo 1 , Riccardo Alessandro 1 1 Dipartimento di Biopatologia e Biotecnologie Mediche, Universita degli Studi di Palermo, sezione di Biologia e Genetica, Palermo, Italy 2 Laboratorio di Ingegneria Tissutale – Piattaforme Innovative per l’Ingegneria Tissutale (PON01–00829), Istituto Ortopedico Rizzoli, Palermo, Italy 3 Istituto di Biofisica, Consiglio Nazionale delle Ricerche, Palermo, Italy Correspondence to: Riccardo Alessandro, e-mail: riccardo.alessandro@unipa.it Keywords: cancer, exosome-like nanovesicles, Citrus limon L., TRAIL-mediated cell death Received: April 03, 2015 Accepted: May 08, 2015 Published: May 18, 2015 ABSTRACT Nanosized vesicles are considered key players in cell to cell communication, thus influencing physiological and pathological processes, including cancer. Nanovesicles have also been found in edible-plants and have shown therapeutic activity in inflammatory bowel diseases; however information on their role in affecting cancer progression is missing. Our study identify for the first time a fraction of vesicles from lemon juice ( Citrus limon L.), obtained as a result of different ultracentrifugation, with density ranging from 1,15 to 1,19 g/ml and specific proteomic profile. By using an in vitro approach, we show that isolated nanovesicles inhibit cancer cell proliferation in different tumor cell lines, by activating a TRAIL-mediated apoptotic cell death. Furthermore, we demonstrate that lemon nanovesicles suppress CML tumor growth in vivo by specifically reaching tumor site and by activating TRAIL-mediated apoptotic cell processes. Overall, this study suggests the possible use of plant-edible nanovesicles as a feasible approach in cancer treatment.
TL;DR: The combination of siG12D-LODER™ and chemotherapy is well tolerated, safe and demonstrated a potential efficacy in patients with LAPC.
Abstract: // Talia Golan 1 , Elina Zorde Khvalevsky 2 , Ayala Hubert 3 , Rachel Malka Gabai 2 , Naama Hen 2 , Amiel Segal 4 , Abraham Domb 5 , Gil Harari 6 , Eliel Ben David 7 , Stephen Raskin 1 , Yuri Goldes 1 , Eran Goldin 8 , Rami Eliakim 1 , Maor Lahav 1 , Yael Kopleman 9 , Alain Dancour 8 , Amotz Shemi 2 and Eithan Galun 10 1 The Sackler School of Medicine, The Chaim Sheba Medical Center, Tel Aviv University, Tel Aviv, Israel 2 Silenseed Ltd., Jerusalem, Israel 3 Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel 4 The Gastroenterology Institute, Shaare Zedek Medical Centre, Jerusalem, Israel 5 Institute of Drug Research, School of Pharmacy-Faculty of Medicine, Center for Nanoscience and Nanotechnology and The Alex Grass Centre for Drug Design and Synthesis, The Hebrew University of Jerusalem, Jerusalem, Israel 6 MediStat Ltd., Jerusalem, Israel 7 Hadassah-Hebrew University Medical Centre, Jerusalem, Israel 8 The Gastroenterology Institute, Shaare Zedek Medical Center, Jerusalem, Israel 9 Gastroenterology Institute, Hadassah Hebrew University Medical Center, Jerusalem, Israel 10 The Goldyne Savad Institute for Gene Therapy, Hadassah Hebrew University Medical Center, Jerusalem, Israel Correspondence to: Talia Golan, email: // Keywords : Pancreatic cancer, KRAS, overall survival, siRNA, polymer implant Received : March 04, 2015 Accepted : May 02, 2015 Published : May 19, 2015 Abstract Purpose: The miniature biodegradable implant siG12D-LODER™ was inserted into a tumor and released a siRNA drug against KRAS(G12D) along four months. This novel siRNA based drug was studied, in combination with chemotherapy, as targeted therapy for Locally Advanced Pancreatic Cancer (LAPC). Methods: An open-label Phase 1/2a study in the first-line setting of patients with non-operable LAPC was initiated. In this study patients were assigned to receive a single dose of siG12D-LODERs , in three escalating dose cohorts (0.025mg, 0.75mg and 3.0mg). Gemcitabine was given on a weekly basis, following the siG12D-LODER TM insertion, until disease progression. The recommended dose was further examined with modified FOLFIRINOX. The follow up period was eight weeks and survival until death. Results: Fifteen patients with LAPC were enrolled. Among the 15 treated patients, the most frequent adverse events observed were grade 1or 2 in severity (89%); five patients experienced serious adverse events (SAEs). In 12 patients analyzed by CT scans, none showed tumor progression, the majority (10/12) demonstrated stable disease and two showed partial response. Decrease in tumor marker CA19-9 was observed in 70% (7/10) of patients. Median overall survival was 15.12 months; 18 month survival was 38.5%. Conclusions: The combination of siG12D-LODER™ and chemotherapy is well tolerated, safe and demonstrated a potential efficacy in patients with LAPC. NCT01188785
TL;DR: The results suggest that ENZ resistance is associated with the strong expression of anti-PD-1 therapy targets in circulating immune cells both in patients and in a pre-clinical model that is non-AR driven.
Abstract: Efficacy of Enzalutamide (ENZ) in castration resistant prostate cancer (CRPC) patients is short-lived. Immunotherapy like T cell checkpoint blockade may improve patient survival. However, when and where checkpoint molecules are expressed in CRPC and whether immune evasion is a mechanism of ENZ resistance remains unclear. Thus, we investigated whether clinically relevant immunotherapy targets, specifically PD-L1/2 , PD-1 and CTLA-4, are upregulated in ENZ resistant (ENZR) patients and in a pre-clinical model of ENZ resistance. We show for the first time that patients progressing on ENZ had significantly increased PD-L1/2+ dendritic cells (DC) in blood compared to those naive or responding to treatment, and a high frequency of PD-1+T cells. These data supported our pre-clinical results, in which we found significantly increased circulating PD-L1/2+ DCs in mice bearing ENZR tumors compared to CRPC, and ENZR tumors expressed significantly increased levels of tumor-intrinsic PD-L1. Importantly, the expression of PD-L1 on ENZR cells, or the ability to modulate PD-L1/2+ DC frequency, was unique to ENZR cell lines and xenografts that did not show classical activation of the androgen receptor. Overall, our results suggest that ENZ resistance is associated with the strong expression of anti-PD-1 therapy targets in circulating immune cells both in patients and in a pre-clinical model that is non-AR driven. Further evaluation of the contribution of tumor vs. immune cell PD-L1 expression in progression of CRPC to anti-androgen resistance and the utility of monitoring circulating cell PD-L1 pathway activity in CRPC patients to predict responsiveness to checkpoint immunotherapy, is warranted.
TL;DR: It is concluded that PC-related miRNAs can be transferred to dendritic cells via exosome and inhibit target mRNA expression and more importantly, PC-derived exosomes inhibit RFXAP expression via miR-212-3p, which decrease MHC II expression and induce immune tolerance of d endritic cells.
Abstract: // Guoping Ding 1 , Liangjing Zhou 1 , Yingming Qian 1 , Mingnian Fu 1 , Jian Chen 1 , Jionghuang Chen 1 , Jianyang Xiang 1 , Zhengrong Wu 1 , Guixing Jiang 1 , Liping Cao 1 1 Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China Correspondence to: Liping Cao, e-mail: caolipingzju@126.com Keywords: pancreatic cancer, exosomes, RFXAP, MHC II, miR-212-3p Received: April 05, 2015 Accepted: August 03, 2015 Published: August 14, 2015 ABSTRACT It has been reported tumor-derived exosomes can transfer miRNAs to recipient cells in the tumor microenvironment, promoting tumor invasion and metastasis. The present research aimed to explore how pancreatic cancer (PC) derived exosomal miRNAs inhibited mRNA expression of dendritic cells and induced immune tolerance. Our study revealed that 9 PC-related miRNAs were increased and 208 mRNAs were inhibited in exosome-stimulated dendritic cells (exo-iDCs) compared to immature dendritic cells (iDCs). A target prediction between the 9 miRNAs and 208 mRNAs was performed by bioinformatics database analysis. From the target prediction, it was predicted and validated that regulatory factor X-associated protein (RFXAP), an important transcription factor for MHC II, was inhibited by miR-212-3p transferred from PC-secreted exosomes, resulting in decreased MHC II expression. Moreover, a clinical study showed a negative correlation between miR-212-3p and RFXAP in PC tissue. From these data, we concluded that PC-related miRNAs can be transferred to dendritic cells via exosome and inhibit target mRNA expression. More importantly, PC-derived exosomes inhibit RFXAP expression via miR-212-3p, which decrease MHC II expression and induce immune tolerance of dendritic cells. RFXAP deficiency has never been reported in solid tumors. The functions and mechanisms of RFXAP in tumors deserve future explorations.
TL;DR: Prostate cancer exosomes dominantly dictate a programme of MSC differentiation generating myofibroblasts with functional properties consistent with disease promotion, which had pro-angiogenic functions and enhanced tumour proliferation and invasivity assessed in a 3D co-culture model.
Abstract: Stromal fibroblasts become altered in response to solid cancers, to exhibit myofibroblastic characteristics, with disease promoting influence. Infiltrating mesenchymal stem cells (MSC) may contribute towards these changes, but the factors secreted by cancer cells that impact MSC differentiation are poorly understood.
We investigated the role of nano-metre sized vesicles (exosomes), secreted by prostate cancer cells, on the differentiation of bone-marrow MSC (BM-MSC), and the subsequent functional consequences of such changes. Purified exosomes impaired classical adipogenic differentiation, skewing differentiation towards alpha-smooth muscle actin (αSMA) positive myofibroblastic cells. A single exosomes treatment generated myofibroblasts secreting high levels of VEGF-A, HGF and matrix regulating factors (MMP-1, −3 and −13). Differentiated MSC had pro-angiogenic functions and enhanced tumour proliferation and invasivity assessed in a 3D co-culture model. Differentiation was dependent on exosomal-TGFβ, but soluble TGFβ at matched dose could not generate the same phenotype. Exosomes present in the cancer cell secretome were the principal factors driving this phenotype.
Prostate cancer exosomes dominantly dictate a programme of MSC differentiation generating myofibroblasts with functional properties consistent with disease promotion.
TL;DR: It is shown that LAG3 and PD1 are co-expressed on both OVA-specific and non-specific T cells infiltrating murine ovarian tumors, and the association of L AG3 with PD1 contributes to their rapid trafficking to the immunological synapse, leading to a synergistic inhibitory effect on T cell signaling.
Abstract: The immune co-inhibitory receptors lymphocyte activation gene-3 (LAG3) and programmed cell death 1 (PD1) synergistically contribute to autoimmunity and tumor evasion. Here we demonstrate how they collaborate and interact to regulate T cell function. We first show that LAG3 and PD1 are co-expressed on both OVA-specific and non-specific T cells infiltrating murine ovarian tumors. Dual antibody blockade or genetic knockout of LAG3 and PD1 significantly enhanced T effector function and delayed tumor growth. LAG3 and PD1 co-localized in activated CD8+ T cells in vitro at the trans-Golgi vesicles, early/recycling endosomal compartments, lysosomes, and microtubule organizing center. Importantly, LAG3 and PD1 cluster with pLck at the immunological synapse. Reciprocal immunoprecipitation of T cell extracts revealed physical interaction between LAG3 and PD1. Mutational analyses indicate that the cytoplasmic domain of LAG3 is not absolutely required for its association with PD1, while the ITIM and ITSM of PD1 are necessary for its association with LAG3. Finally, LAG3 protein also associates with the Src-homology-2 domain-containing phosphatases (SHP1/2) which are known to be recruited by PD1 during T cell signaling. Our data indicate that the association of LAG3 with PD1 contributes to their rapid trafficking to the immunological synapse, leading to a synergistic inhibitory effect on T cell signaling.
TL;DR: It is ascertained that cancer cells facilitate oncogenesis by the secretion of mutant and oncoproteins into the tumor microenvironment via exosomes and ectosomes.
Abstract: // Shivakumar Keerthikumar 1,* , Lahiru Gangoda 1,* , Michael Liem 1 , Pamali Fonseka 1 , Ishara Atukorala 1 , Cemil Ozcitti 1 , Adam Mechler 2 , Christopher G. Adda 1 , Ching-Seng Ang 3 and Suresh Mathivanan 1 1 Department of Biochemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, Australia 2 Department of Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, Australia 3 Bio21 Institute, University of Melbourne, Victoria, Australia * These authors have contributed equally to this work Correspondence to: Suresh Mathivanan, email: // Keywords : exosomes, ectosomes, proteogenomics, extracellular vesicles, integrated OMICs analysis Received : January 27, 2015 Accepted : March 18, 2015 Published : April 12, 2015 Abstract Extracellular vesicles (EVs) include the exosomes (30-100 nm) that are produced through the endocytic pathway via the multivesicular bodies and the ectosomes (100-1000 nm) that are released through the budding of the plasma membrane. Despite the differences in the mode of biogenesis and size, reliable markers that can distinguish between exosomes and ectosomes are non-existent. Moreover, the precise functional differences between exosomes and ectosomes remains poorly characterised. Here, using label-free quantitative proteomics, we highlight proteins that could be exploited as markers to discriminate between exosomes and ectosomes. For the first time, a global proteogenomics analysis unveiled the secretion of mutant proteins that are implicated in cancer progression through tumor-derived EVs. Follow up integrated bioinformatics analysis highlighted the enrichment of oncogenic cargo in exosomes and ectosomes. Interestingly, exosomes induced significant cell proliferation and migration in recipient cells compared to ectosomes confirming the oncogenic nature of exosomes. These findings ascertain that cancer cells facilitate oncogenesis by the secretion of mutant and oncoproteins into the tumor microenvironment via exosomes and ectosomes. The integrative proteogenomics approach utilized in this study has the potential to identify disease biomarker candidates which can be later assayed in liquid biopsies obtained from cancer patients.