Co-option of Liver Vessels and Not Sprouting Angiogenesis Drives Acquired Sorafenib Resistance in Hepatocellular Carcinoma.
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Date
2016-04-08Author
Kuczynski, EA
Yin, M
Bar-Zion, A
Lee, CR
Butz, H
Man, S
Daley, F
Vermeulen, PB
Yousef, GM
Foster, FS
Reynolds, AR
Kerbel, RS
Type
Journal Article
Metadata
Show full item recordAbstract
BACKGROUND: The 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. METHODS: To 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. RESULTS: While 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. CONCLUSIONS: This 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.
Collections
Subject
Liver
Blood Vessels
Animals
Humans
Mice
Mice, SCID
Carcinoma, Hepatocellular
Liver Neoplasms
Neoplasm Invasiveness
Disease Models, Animal
Neovascularization, Pathologic
Phenylurea Compounds
Niacinamide
Vimentin
Actins
Vascular Endothelial Growth Factor A
Homeodomain Proteins
Repressor Proteins
MicroRNAs
Antineoplastic Agents
Antigens, CD34
Contrast Media
Ultrasonography
Sequence Analysis, RNA
Neoplasm Transplantation
Signal Transduction
Up-Regulation
Drug Resistance, Neoplasm
Male
Osteopontin
Epithelial-Mesenchymal Transition
Zinc Finger E-box-Binding Homeobox 1
Zinc Finger E-box Binding Homeobox 2
Sorafenib
Research team
Tumour Biology
Language
eng
Date accepted
2016-02-08
License start date
2016-08
Citation
Journal of the National Cancer Institute, 2016, 108 (8)
Publisher
OXFORD UNIV PRESS INC