In:
PLOS ONE, Public Library of Science (PLoS), Vol. 17, No. 7 ( 2022-7-20), p. e0266522-
Abstract:
Radiofrequency ablation (RFA) of intrahepatic tumors induces distant tumor growth through activation of interleukin 6/signal transducer and activator of transcription 3 (STAT3)/hepatocyte growth factor (HGF)/tyrosine-protein kinase Met (c-MET) pathway. Yet, the predominant cellular source still needs to be identified as specific roles of the many types of periablational infiltrating immune cells requires further clarification. Here we report the key role of activated myofibroblasts in RFA-induced tumorigenesis and successful pharmacologic blockade. Murine models simulating RF tumorigenic effects on a macrometastatic tumor and intrahepatic micrometastatic deposits after liver ablation and a macrometastatic tumor after kidney ablation were used. Immune assays of ablated normal parenchyma demonstrated significantly increased numbers of activated myofibroblasts in the periablational rim, as well as increased HGF levels, recruitment other cellular infiltrates; macrophages, dendritic cells and natural killer cells, HGF dependent growth factors; fibroblast growth factor-19 (FGF-19) and receptor of Vascular Endothelial Growth Factor-1 (VEGFR-1), and proliferative indices; Ki-67 and CD34 for microvascular density. Furthermore, macrometastatic models demonstrated accelerated distant tumor growth at 7d post-RFA while micrometastatic models demonstrated increased intrahepatic deposit size and number at 14 and 21 days post-RFA. Multi-day atorvastatin, a selective fibroblast inhibitor, inhibited RFA-induced HGF and downstream growth factors, cellular markers and proliferative indices. Specifically, atorvastatin treatment reduced cellular and proliferative indices to baseline levels in the micrometastatic models, however only partially in macrometastatic models. Furthermore, adjuvant atorvastatin completely inhibited accelerated growth of macrometastasis and negated increased micrometastatic intrahepatic burden. Thus, activated myofibroblasts drive RF-induced tumorigenesis at a cellular level via induction of the HGF/c-MET/STAT3 axis, and can be successfully pharmacologically suppressed.
Type of Medium:
Online Resource
ISSN:
1932-6203
DOI:
10.1371/journal.pone.0266522
DOI:
10.1371/journal.pone.0266522.g001
DOI:
10.1371/journal.pone.0266522.g002
DOI:
10.1371/journal.pone.0266522.g003
DOI:
10.1371/journal.pone.0266522.g004
DOI:
10.1371/journal.pone.0266522.g005
DOI:
10.1371/journal.pone.0266522.t001
DOI:
10.1371/journal.pone.0266522.t002
DOI:
10.1371/journal.pone.0266522.t003
DOI:
10.1371/journal.pone.0266522.s001
DOI:
10.1371/journal.pone.0266522.s002
DOI:
10.1371/journal.pone.0266522.r001
DOI:
10.1371/journal.pone.0266522.r002
DOI:
10.1371/journal.pone.0266522.r003
DOI:
10.1371/journal.pone.0266522.r004
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2022
detail.hit.zdb_id:
2267670-3
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