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      Placental growth factor promotes tumour desmoplasia and treatment resistance in intrahepatic cholangiocarcinoma

      research-article
      1 , 2 , 1 , 2 , 1 , 3 , 4 , 1 , 5 , 1 , 1 , 1 , 6 , 1 , 7 , 8 , 1 , 1 , 9 , 1 , 10 , 1 , 1 , 11 , 1 , 12 , 1 , 12 , 1 , 1 , 1 , 13 , 14 , 3 , 15 , 16 , 16 , 17 , 1 , 8 , 4 , 18 , 1 , 17 , 19 , 1 ,
      Gut
      BMJ Publishing Group
      cholangiocarcinoma, hepatic fibrosis

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Objective

          Intrahepatic cholangiocarcinoma (ICC)—a rare liver malignancy with limited therapeutic options—is characterised by aggressive progression, desmoplasia and vascular abnormalities. The aim of this study was to determine the role of placental growth factor (PlGF) in ICC progression.

          Design

          We evaluated the expression of PlGF in specimens from ICC patients and assessed the therapeutic effect of genetic or pharmacologic inhibition of PlGF in orthotopically grafted ICC mouse models. We evaluated the impact of PlGF stimulation or blockade in ICC cells and cancer-associated fibroblasts (CAFs) using in vitro 3-D coculture systems.

          Results

          PlGF levels were elevated in human ICC stromal cells and circulating blood plasma and were associated with disease progression. Single-cell RNA sequencing showed that the major impact of PlGF blockade in mice was enrichment of quiescent CAFs, characterised by high gene transcription levels related to the Akt pathway, glycolysis and hypoxia signalling. PlGF blockade suppressed Akt phosphorylation and myofibroblast activation in ICC-derived CAFs. PlGF blockade also reduced desmoplasia and tissue stiffness, which resulted in reopening of collapsed tumour vessels and improved blood perfusion, while reducing ICC cell invasion. Moreover, PlGF blockade enhanced the efficacy of standard chemotherapy in mice-bearing ICC.

          Conclusion

          PlGF blockade leads to a reduction in intratumorous hypoxia and metastatic dissemination, enhanced chemotherapy sensitivity and increased survival in mice-bearing aggressive ICC.

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          Most cited references58

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          GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses

          Abstract Tremendous amount of RNA sequencing data have been produced by large consortium projects such as TCGA and GTEx, creating new opportunities for data mining and deeper understanding of gene functions. While certain existing web servers are valuable and widely used, many expression analysis functions needed by experimental biologists are still not adequately addressed by these tools. We introduce GEPIA (Gene Expression Profiling Interactive Analysis), a web-based tool to deliver fast and customizable functionalities based on TCGA and GTEx data. GEPIA provides key interactive and customizable functions including differential expression analysis, profiling plotting, correlation analysis, patient survival analysis, similar gene detection and dimensionality reduction analysis. The comprehensive expression analyses with simple clicking through GEPIA greatly facilitate data mining in wide research areas, scientific discussion and the therapeutic discovery process. GEPIA fills in the gap between cancer genomics big data and the delivery of integrated information to end users, thus helping unleash the value of the current data resources. GEPIA is available at http://gepia.cancer-pku.cn/.
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            Highly Parallel Genome-wide Expression Profiling of Individual Cells Using Nanoliter Droplets.

            Cells, the basic units of biological structure and function, vary broadly in type and state. Single-cell genomics can characterize cell identity and function, but limitations of ease and scale have prevented its broad application. Here we describe Drop-seq, a strategy for quickly profiling thousands of individual cells by separating them into nanoliter-sized aqueous droplets, associating a different barcode with each cell's RNAs, and sequencing them all together. Drop-seq analyzes mRNA transcripts from thousands of individual cells simultaneously while remembering transcripts' cell of origin. We analyzed transcriptomes from 44,808 mouse retinal cells and identified 39 transcriptionally distinct cell populations, creating a molecular atlas of gene expression for known retinal cell classes and novel candidate cell subtypes. Drop-seq will accelerate biological discovery by enabling routine transcriptional profiling at single-cell resolution. VIDEO ABSTRACT.
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              A framework for advancing our understanding of cancer-associated fibroblasts

              Cancer-associated fibroblasts (CAFs) are a key component of the tumour microenvironment with diverse functions, including matrix deposition and remodelling, extensive reciprocal signalling interactions with cancer cells and crosstalk with infiltrating leukocytes. As such, they are a potential target for optimizing therapeutic strategies against cancer. However, many challenges are present in ongoing attempts to modulate CAFs for therapeutic benefit. These include limitations in our understanding of the origin of CAFs and heterogeneity in CAF function, with it being desirable to retain some antitumorigenic functions. On the basis of a meeting of experts in the field of CAF biology, we summarize in this Consensus Statement our current knowledge and present a framework for advancing our understanding of this critical cell type within the tumour microenvironment.
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                Author and article information

                Journal
                Gut
                Gut
                gutjnl
                gut
                Gut
                BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                0017-5749
                1468-3288
                January 2022
                11 January 2021
                : 71
                : 1
                : 185-193
                Affiliations
                [1 ] departmentRadiation Oncology/Steele Laboratories for Tumor Biology , Massachusetts General Hospital , Boston, Massachusetts, USA
                [2 ] departmentSurgery , Tohoku University Graduate School of Medicine , Sendai, Miyagi, Japan
                [3 ] departmentPathology , University Hospital Cologne , Cologne, Nordrhein-Westfalen, Germany
                [4 ] departmentCenter for Computational and Integrative Biology , Massachusetts General Hospital , Boston, Massachusetts, USA
                [5 ] departmentGeneral Surgery , Zhejiang University , Hangzhou, Zhejiang, China
                [6 ] departmentAnatomy and Developmental Biology , Tokyo Women's Medical University , Shinjuku-ku, Tokyo, Japan
                [7 ] departmentThoracic Surgery , Saitama Medical University , Iruma-gun, Saitama, Japan
                [8 ] departmentOncology , Mayo Clinic Arizona , Scottsdale, Arizona, USA
                [9 ] departmentBioengineering , Boston University , Boston, Massachusetts, USA
                [10 ] departmentResearch , STIMIT Corporation , Cambridge, Massachusetts, USA
                [11 ] departmentMolecular Oncology , Cancer Research Center , Marseille, France
                [12 ] departmentSurgery , Keio University Hospital , Shinjuku-ku, Tokyo, Japan
                [13 ] departmentMedicine , University of Hong Kong , Hong Kong Special Administrative Region, China
                [14 ] departmentRadiation Oncology , Massachusetts General Hospital , Boston, Massachusetts, USA
                [15 ] departmentDepartment of General, Visceral and Cancer Surgery , University of Cologne , Koln, Nordrhein-Westfalen, Germany
                [16 ] departmentCenter of Digestive Diseases and Liver Transplantation , Clinical Institute Fundeni , Bucuresti, Romania
                [17 ] departmentMedicine , Massachusetts General Hospital , Boston, Massachusetts, USA
                [18 ] departmentOrthopedics , Massachusetts General Hospital , Boston, Massachusetts, USA
                [19 ] departmentJiahui International Cancer Center , Jiahui Health , Shanghai, China
                Author notes
                [Correspondence to ] Dr Dan G Duda, Radiation Oncology/Steele Laboratories for Tumor Biology, Massachusetts General Hospital, Boston, MA 02114-2696, USA; duda@ 123456steele.mgh.harvard.edu
                Author information
                http://orcid.org/0000-0003-1596-4200
                http://orcid.org/0000-0002-7114-0305
                http://orcid.org/0000-0001-7065-8797
                Article
                gutjnl-2020-322493
                10.1136/gutjnl-2020-322493
                8666816
                33431577
                773509b8-8ca6-472b-bd06-0c0760b743e8
                © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

                This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

                History
                : 09 July 2020
                : 21 December 2020
                : 27 December 2020
                Funding
                Funded by: Cholangiocarcinoma Research Foundation;
                Award ID: Postdoctoral Fellowship
                Funded by: Harvard Ludwig Cancer Center;
                Award ID: Grant
                Funded by: FundRef http://dx.doi.org/10.13039/100000005, U.S. Department of Defense;
                Award ID: W81XWH-19-1-0284
                Award ID: W81XWH-19-1-0482
                Funded by: Cancéropôle PACA;
                Award ID: Grant
                Funded by: Romanian Ministry of Research and Innovation, CCCDI–UEFISCDI;
                Award ID: PN-III-P1-1.2-PCCDI-2017-0797/66PCCDI
                Funded by: FundRef http://dx.doi.org/10.13039/100005156, Alexander von Humboldt-Stiftung;
                Award ID: Postdoctoral Fellowship
                Funded by: FundRef http://dx.doi.org/10.13039/100001927, Advanced Medical Research Foundation;
                Award ID: Grant
                Funded by: Jane’s Trust Foundation;
                Award ID: Grant
                Funded by: FundRef http://dx.doi.org/10.13039/100000054, National Cancer Institute;
                Award ID: P01-CA080124
                Award ID: Proton Beam/Federal Share Program
                Award ID: R01-CA208205
                Award ID: R35-CA197743
                Award ID: R41-CA213678
                Award ID: U01-CA224173
                Funded by: FundRef http://dx.doi.org/10.13039/100001767, National Foundation for Cancer Research;
                Award ID: Fellow
                Funded by: FundRef http://dx.doi.org/10.13039/501100007263, Astellas Foundation for Research on Metabolic Disorders;
                Award ID: Postdoctoral Fellowship
                Funded by: FundRef http://dx.doi.org/10.13039/100008732, Uehara Memorial Foundation;
                Award ID: Postdoctoral Fellowship
                Categories
                Hepatology
                1506
                2312
                Original research
                Custom metadata
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                Gastroenterology & Hepatology
                cholangiocarcinoma,hepatic fibrosis
                Gastroenterology & Hepatology
                cholangiocarcinoma, hepatic fibrosis

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