Evidence map›Paper›PMID 27059374›Full record

ArticleJournal of the National Cancer Institute2016

Co-option of Liver Vessels and Not Sprouting Angiogenesis Drives Acquired Sorafenib Resistance in Hepatocellular Carcinoma.

Elizabeth A Kuczynski, Melissa Yin, Avinoam Bar-Zion, Christina R Lee, Henriett Butz, Shan Man, Frances Daley, Peter B Vermeulen, George M Yousef, F Stuart Foster and 2 more

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Journal of the National Cancer Institute, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 99 papers, 3 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
99citing papers in PubMed, 3 pooled it
11.6field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

99 citing papers in PubMed, 3 syntheses or guidelines pooled it, 167 citations in OpenAlex.

  1. Pooled it
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  12. Integrins as Key Mediators of Metastasis.International journal of molecular sciences · 2025
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  20. Mechanisms of angiogenesis in tumour.Frontiers in oncology · 2024
    Review

39 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

12 authors at 5 institutions in 4 countries.

Elizabeth A KuczynskiAffiliations of authors: Department of Medical Biophysics, University of Toronto, Toronto, Canada (EAK, FSF, RSK); Physical Sciences Platform (MY, FSF) and Biological Sciences Platform (CRL, SM, RSK), Sunnybrook Research Institute, Toronto, Canada; Department of Biomedical Engineering, Technion - Israel Institute of Technology, Haifa, Israel (ABZ); Keenan Research Centre, St. Michael's Hospital, Toronto, Canada (HB, GMY); The Breast Cancer Now Toby Robins Research Centre, Mary-Jean Mitchell Green Building, The Institute of Cancer Research, London, UK (FD, PBV, ARR); Translational Cancer Research Unit, GZA Hospitals St. Augustinus, Antwerp, Belgium (PBV).
Melissa YinAffiliations of authors: Department of Medical Biophysics, University of Toronto, Toronto, Canada (EAK, FSF, RSK); Physical Sciences Platform (MY, FSF) and Biological Sciences Platform (CRL, SM, RSK), Sunnybrook Research Institute, Toronto, Canada; Department of Biomedical Engineering, Technion - Israel Institute of Technology, Haifa, Israel (ABZ); Keenan Research Centre, St. Michael's Hospital, Toronto, Canada (HB, GMY); The Breast Cancer Now Toby Robins Research Centre, Mary-Jean Mitchell Green Building, The Institute of Cancer Research, London, UK (FD, PBV, ARR); Translational Cancer Research Unit, GZA Hospitals St. Augustinus, Antwerp, Belgium (PBV).
Avinoam Bar-ZionAffiliations of authors: Department of Medical Biophysics, University of Toronto, Toronto, Canada (EAK, FSF, RSK); Physical Sciences Platform (MY, FSF) and Biological Sciences Platform (CRL, SM, RSK), Sunnybrook Research Institute, Toronto, Canada; Department of Biomedical Engineering, Technion - Israel Institute of Technology, Haifa, Israel (ABZ); Keenan Research Centre, St. Michael's Hospital, Toronto, Canada (HB, GMY); The Breast Cancer Now Toby Robins Research Centre, Mary-Jean Mitchell Green Building, The Institute of Cancer Research, London, UK (FD, PBV, ARR); Translational Cancer Research Unit, GZA Hospitals St. Augustinus, Antwerp, Belgium (PBV).
Christina R LeeAffiliations of authors: Department of Medical Biophysics, University of Toronto, Toronto, Canada (EAK, FSF, RSK); Physical Sciences Platform (MY, FSF) and Biological Sciences Platform (CRL, SM, RSK), Sunnybrook Research Institute, Toronto, Canada; Department of Biomedical Engineering, Technion - Israel Institute of Technology, Haifa, Israel (ABZ); Keenan Research Centre, St. Michael's Hospital, Toronto, Canada (HB, GMY); The Breast Cancer Now Toby Robins Research Centre, Mary-Jean Mitchell Green Building, The Institute of Cancer Research, London, UK (FD, PBV, ARR); Translational Cancer Research Unit, GZA Hospitals St. Augustinus, Antwerp, Belgium (PBV).
Henriett ButzAffiliations of authors: Department of Medical Biophysics, University of Toronto, Toronto, Canada (EAK, FSF, RSK); Physical Sciences Platform (MY, FSF) and Biological Sciences Platform (CRL, SM, RSK), Sunnybrook Research Institute, Toronto, Canada; Department of Biomedical Engineering, Technion - Israel Institute of Technology, Haifa, Israel (ABZ); Keenan Research Centre, St. Michael's Hospital, Toronto, Canada (HB, GMY); The Breast Cancer Now Toby Robins Research Centre, Mary-Jean Mitchell Green Building, The Institute of Cancer Research, London, UK (FD, PBV, ARR); Translational Cancer Research Unit, GZA Hospitals St. Augustinus, Antwerp, Belgium (PBV).
Shan ManAffiliations of authors: Department of Medical Biophysics, University of Toronto, Toronto, Canada (EAK, FSF, RSK); Physical Sciences Platform (MY, FSF) and Biological Sciences Platform (CRL, SM, RSK), Sunnybrook Research Institute, Toronto, Canada; Department of Biomedical Engineering, Technion - Israel Institute of Technology, Haifa, Israel (ABZ); Keenan Research Centre, St. Michael's Hospital, Toronto, Canada (HB, GMY); The Breast Cancer Now Toby Robins Research Centre, Mary-Jean Mitchell Green Building, The Institute of Cancer Research, London, UK (FD, PBV, ARR); Translational Cancer Research Unit, GZA Hospitals St. Augustinus, Antwerp, Belgium (PBV).
Frances DaleyAffiliations of authors: Department of Medical Biophysics, University of Toronto, Toronto, Canada (EAK, FSF, RSK); Physical Sciences Platform (MY, FSF) and Biological Sciences Platform (CRL, SM, RSK), Sunnybrook Research Institute, Toronto, Canada; Department of Biomedical Engineering, Technion - Israel Institute of Technology, Haifa, Israel (ABZ); Keenan Research Centre, St. Michael's Hospital, Toronto, Canada (HB, GMY); The Breast Cancer Now Toby Robins Research Centre, Mary-Jean Mitchell Green Building, The Institute of Cancer Research, London, UK (FD, PBV, ARR); Translational Cancer Research Unit, GZA Hospitals St. Augustinus, Antwerp, Belgium (PBV).
Peter B VermeulenAffiliations of authors: Department of Medical Biophysics, University of Toronto, Toronto, Canada (EAK, FSF, RSK); Physical Sciences Platform (MY, FSF) and Biological Sciences Platform (CRL, SM, RSK), Sunnybrook Research Institute, Toronto, Canada; Department of Biomedical Engineering, Technion - Israel Institute of Technology, Haifa, Israel (ABZ); Keenan Research Centre, St. Michael's Hospital, Toronto, Canada (HB, GMY); The Breast Cancer Now Toby Robins Research Centre, Mary-Jean Mitchell Green Building, The Institute of Cancer Research, London, UK (FD, PBV, ARR); Translational Cancer Research Unit, GZA Hospitals St. Augustinus, Antwerp, Belgium (PBV).
George M YousefAffiliations of authors: Department of Medical Biophysics, University of Toronto, Toronto, Canada (EAK, FSF, RSK); Physical Sciences Platform (MY, FSF) and Biological Sciences Platform (CRL, SM, RSK), Sunnybrook Research Institute, Toronto, Canada; Department of Biomedical Engineering, Technion - Israel Institute of Technology, Haifa, Israel (ABZ); Keenan Research Centre, St. Michael's Hospital, Toronto, Canada (HB, GMY); The Breast Cancer Now Toby Robins Research Centre, Mary-Jean Mitchell Green Building, The Institute of Cancer Research, London, UK (FD, PBV, ARR); Translational Cancer Research Unit, GZA Hospitals St. Augustinus, Antwerp, Belgium (PBV).
F Stuart FosterAffiliations of authors: Department of Medical Biophysics, University of Toronto, Toronto, Canada (EAK, FSF, RSK); Physical Sciences Platform (MY, FSF) and Biological Sciences Platform (CRL, SM, RSK), Sunnybrook Research Institute, Toronto, Canada; Department of Biomedical Engineering, Technion - Israel Institute of Technology, Haifa, Israel (ABZ); Keenan Research Centre, St. Michael's Hospital, Toronto, Canada (HB, GMY); The Breast Cancer Now Toby Robins Research Centre, Mary-Jean Mitchell Green Building, The Institute of Cancer Research, London, UK (FD, PBV, ARR); Translational Cancer Research Unit, GZA Hospitals St. Augustinus, Antwerp, Belgium (PBV).
Andrew R ReynoldsAffiliations of authors: Department of Medical Biophysics, University of Toronto, Toronto, Canada (EAK, FSF, RSK); Physical Sciences Platform (MY, FSF) and Biological Sciences Platform (CRL, SM, RSK), Sunnybrook Research Institute, Toronto, Canada; Department of Biomedical Engineering, Technion - Israel Institute of Technology, Haifa, Israel (ABZ); Keenan Research Centre, St. Michael's Hospital, Toronto, Canada (HB, GMY); The Breast Cancer Now Toby Robins Research Centre, Mary-Jean Mitchell Green Building, The Institute of Cancer Research, London, UK (FD, PBV, ARR); Translational Cancer Research Unit, GZA Hospitals St. Augustinus, Antwerp, Belgium (PBV).
Robert S KerbelAffiliations of authors: Department of Medical Biophysics, University of Toronto, Toronto, Canada (EAK, FSF, RSK); Physical Sciences Platform (MY, FSF) and Biological Sciences Platform (CRL, SM, RSK), Sunnybrook Research Institute, Toronto, Canada; Department of Biomedical Engineering, Technion - Israel Institute of Technology, Haifa, Israel (ABZ); Keenan Research Centre, St. Michael's Hospital, Toronto, Canada (HB, GMY); The Breast Cancer Now Toby Robins Research Centre, Mary-Jean Mitchell Green Building, The Institute of Cancer Research, London, UK (FD, PBV, ARR); Translational Cancer Research Unit, GZA Hospitals St. Augustinus, Antwerp, Belgium (PBV).
St. Michael's Hospital · CAGZA Ziekenhuizen Campus Sint-Augustinus · BEUniversity of Toronto · CAInstitute of Cancer Research · GBTechnion – Israel Institute of Technology · IL

Funding

CIHR
6 · The paper itself

Abstract

backgroundThe anti-angiogenic Sorafenib is the only approved systemic therapy for advanced hepatocellular carcinoma (HCC). However, acquired resistance limits its efficacy. An emerging theory to explain intrinsic resistance to other anti-angiogenic drugs is 'vessel co-option,' ie, the ability of tumors to hijack the existing vasculature in organs such as the lungs or liver, thus limiting the need for sprouting angiogenesis. Vessel co-option has not been evaluated as a potential mechanism for acquired resistance to anti-angiogenic agents.

methodsTo study sorafenib resistance mechanisms, we used an orthotopic human HCC model (n = 4-11 per group), where tumor cells are tagged with a secreted protein biomarker to monitor disease burden and response to therapy. Histopathology, vessel perfusion assessed by contrast-enhanced ultrasound, and miRNA sequencing and quantitative real-time polymerase chain reaction were used to monitor changes in tumor biology.

resultsWhile sorafenib initially inhibited angiogenesis and stabilized tumor growth, no angiogenic 'rebound' effect was observed during development of resistance unless therapy was stopped. Instead, resistant tumors became more locally infiltrative, which facilitated extensive incorporation of liver parenchyma and the co-option of liver-associated vessels. Up to 75% (±10.9%) of total vessels were provided by vessel co-option in resistant tumors relative to 23.3% (±10.3%) in untreated controls. miRNA sequencing implicated pro-invasive signaling and epithelial-to-mesenchymal-like transition during resistance development while functional imaging further supported a shift from angiogenesis to vessel co-option.

conclusionsThis is the first documentation of vessel co-option as a mechanism of acquired resistance to anti-angiogenic therapy and could have important implications including the potential therapeutic benefits of targeting vessel co-option in conjunction with vascular endothelial growth factor receptor signaling.

Indexed as

Drug Resistance, NeoplasmActinsAnimalsAntigens, CD34Antineoplastic AgentsBlood VesselsCarcinoma, HepatocellularContrast MediaDisease Models, AnimalEpithelial-Mesenchymal TransitionHomeodomain ProteinsHumansLiverLiver NeoplasmsMaleMiceACTA2 protein, humanActinsAntigens, CD34Antineoplastic AgentsContrast MediaHomeodomain ProteinsMicroRNAsNiacinamideOsteopontinPhenylurea CompoundsRepressor ProteinsSorafenibSpp1 protein, mouseVascular Endothelial Growth Factor Avascular endothelial growth factor A, mouseVEGFA protein, humanVimentinZEB2 protein, humanZinc Finger E-box-Binding Homeobox 1Zinc Finger E-box Binding Homeobox 2

Identifiers

PMID27059374
PMCPMC5017954
OpenAlexW2334067795

What OpenQuestion holds

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LicenceCC BY-NC
Read underepoch 390

Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.