PMID- 29737948 OWN - NLM STAT- MEDLINE DCOM- 20180910 LR - 20211204 IS - 1527-1315 (Electronic) IS - 0033-8419 (Print) IS - 0033-8419 (Linking) VI - 288 IP - 3 DP - 2018 Sep TI - Heat Stress and Hepatic Laser Thermal Ablation Induce Hepatocellular Carcinoma Growth: Role of PI3K/mTOR/AKT Signaling. PG - 730-738 LID - 10.1148/radiol.2018172944 [doi] AB - Purpose To determine if heat stress and hepatic laser thermal ablation induce hepatocellular carcinoma (HCC) growth and to identify growth factors induced by heat stress. Materials and Methods Non-heat-stressed HCC cells were cocultured with HCC cells or hepatocytes that were heat stressed at 37 degrees C (physiologic), 45 degrees C (moderate), or 50 degrees C (severe) for 10 minutes and proliferation monitored with bioluminescence imaging for up to 6 days after heat stress (three experiments). Rats bearing orthotopic N1S1 HCC were randomly assigned to undergo immediate sham or laser thermal (3 W for 60 or 90 seconds; hereafter, 3Wx60s and 3Wx90s, respectively) ablation of the median (local) or left (distant) hepatic lobe, and tumor growth was monitored with magnetic resonance imaging for up to 18 days after ablation (six or more rats per group). Experiments were repeated with rats randomly assigned to receive either the adjuvant phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor (NVP-BEZ235) or the vehicle control. Heat-stressed HCC cells and hepatocytes were analyzed by using microarray or quantitative real-time polymerase chain reaction analysis for growth factor expression (three or more experiments). Groups were compared by using one- or two-way analysis of variance, and post hoc pairwise comparison was performed with the Dunnett test. Results There were more non-heat-stressed HCC cells when cells were cocultured with cells subjected to moderate but not physiologic or severe heat stress (P < .001 for both). Local intrahepatic N1S1 tumors were larger at day 18 in the 3Wx60s (mean, 3102 mm(3) +/- 463 [standard error]; P = .004) and 3Wx90s (mean, 3538 mm(3) +/- 667; P < .001) groups than in the sham group (mean, 1363 mm(3) +/- 361) but not in distant intrahepatic tumors (P = .31). Adjuvant BEZ235 resulted in smaller N1S1 tumors in the BEZ235 and laser thermal ablation group than in the vehicle control and laser thermal ablation group (mean, 1731 mm(3) +/- 1457 vs 3844 mm(3) +/- 2400, P < .001). Moderate heat stress induced expression of growth factors in HCC cells and hepatocytes, including heparin-binding growth factor, fibroblast growth factor 21, and nerve growth factor (range, 2.9-66.9-fold; P < .05). Conclusion Moderate heat stress and laser thermal ablation induce hepatocellular carcinoma growth, which is prevented with adjuvant PI3K/mTOR/protein kinase B inhibition. CI - (c) RSNA, 2018 Online supplemental material is available for this article. FAU - Jondal, Danielle E AU - Jondal DE AUID- ORCID: 0000-0001-9447-9646 AD - From the Department of Radiology (D.E.J., S.M.T., K.A.B., B.E.K., J.L.A., M.R.C., D.A.W.) and Division of Gastroenterology and Hepatology (L.R.R.), Mayo Clinic School of Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905; and Department of Health Sciences Research, Mayo Clinic School of Medicine, Jacksonville, Fla (R.E.C.). FAU - Thompson, Scott M AU - Thompson SM AUID- ORCID: 0000-0001-7853-3278 AD - From the Department of Radiology (D.E.J., S.M.T., K.A.B., B.E.K., J.L.A., M.R.C., D.A.W.) and Division of Gastroenterology and Hepatology (L.R.R.), Mayo Clinic School of Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905; and Department of Health Sciences Research, Mayo Clinic School of Medicine, Jacksonville, Fla (R.E.C.). FAU - Butters, Kim A AU - Butters KA AD - From the Department of Radiology (D.E.J., S.M.T., K.A.B., B.E.K., J.L.A., M.R.C., D.A.W.) and Division of Gastroenterology and Hepatology (L.R.R.), Mayo Clinic School of Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905; and Department of Health Sciences Research, Mayo Clinic School of Medicine, Jacksonville, Fla (R.E.C.). FAU - Knudsen, Bruce E AU - Knudsen BE AD - From the Department of Radiology (D.E.J., S.M.T., K.A.B., B.E.K., J.L.A., M.R.C., D.A.W.) and Division of Gastroenterology and Hepatology (L.R.R.), Mayo Clinic School of Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905; and Department of Health Sciences Research, Mayo Clinic School of Medicine, Jacksonville, Fla (R.E.C.). FAU - Anderson, Jill L AU - Anderson JL AD - From the Department of Radiology (D.E.J., S.M.T., K.A.B., B.E.K., J.L.A., M.R.C., D.A.W.) and Division of Gastroenterology and Hepatology (L.R.R.), Mayo Clinic School of Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905; and Department of Health Sciences Research, Mayo Clinic School of Medicine, Jacksonville, Fla (R.E.C.). FAU - Carter, Rickey E AU - Carter RE AD - From the Department of Radiology (D.E.J., S.M.T., K.A.B., B.E.K., J.L.A., M.R.C., D.A.W.) and Division of Gastroenterology and Hepatology (L.R.R.), Mayo Clinic School of Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905; and Department of Health Sciences Research, Mayo Clinic School of Medicine, Jacksonville, Fla (R.E.C.). FAU - Roberts, Lewis R AU - Roberts LR AD - From the Department of Radiology (D.E.J., S.M.T., K.A.B., B.E.K., J.L.A., M.R.C., D.A.W.) and Division of Gastroenterology and Hepatology (L.R.R.), Mayo Clinic School of Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905; and Department of Health Sciences Research, Mayo Clinic School of Medicine, Jacksonville, Fla (R.E.C.). FAU - Callstrom, Matthew R AU - Callstrom MR AD - From the Department of Radiology (D.E.J., S.M.T., K.A.B., B.E.K., J.L.A., M.R.C., D.A.W.) and Division of Gastroenterology and Hepatology (L.R.R.), Mayo Clinic School of Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905; and Department of Health Sciences Research, Mayo Clinic School of Medicine, Jacksonville, Fla (R.E.C.). FAU - Woodrum, David A AU - Woodrum DA AD - From the Department of Radiology (D.E.J., S.M.T., K.A.B., B.E.K., J.L.A., M.R.C., D.A.W.) and Division of Gastroenterology and Hepatology (L.R.R.), Mayo Clinic School of Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905; and Department of Health Sciences Research, Mayo Clinic School of Medicine, Jacksonville, Fla (R.E.C.). LA - eng GR - R01 CA177686/CA/NCI NIH HHS/United States GR - TL1 RR024152/RR/NCRR NIH HHS/United States GR - TL1 TR000137/TR/NCATS NIH HHS/United States GR - UL1 RR024150/RR/NCRR NIH HHS/United States PT - Journal Article DEP - 20180508 PL - United States TA - Radiology JT - Radiology JID - 0401260 RN - 0 (Carrier Proteins) RN - 0 (PI3KAP protein, rat) RN - EC 2.7.1.1 (mTOR protein, rat) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Animals MH - Carcinoma, Hepatocellular/diagnostic imaging/*pathology MH - Carrier Proteins/*genetics MH - Cell Proliferation MH - Disease Models, Animal MH - *Heat-Shock Response MH - *Laser Therapy MH - Liver/diagnostic imaging/pathology MH - Liver Neoplasms/diagnostic imaging/*pathology MH - Magnetic Resonance Imaging MH - Male MH - Proto-Oncogene Proteins c-akt/*genetics MH - Rats MH - Rats, Sprague-Dawley MH - Signal Transduction/genetics MH - TOR Serine-Threonine Kinases/*genetics PMC - PMC6122226 EDAT- 2018/05/09 06:00 MHDA- 2018/09/11 06:00 PMCR- 2019/09/01 CRDT- 2018/05/09 06:00 PHST- 2018/05/09 06:00 [pubmed] PHST- 2018/09/11 06:00 [medline] PHST- 2018/05/09 06:00 [entrez] PHST- 2019/09/01 00:00 [pmc-release] AID - 10.1148/radiol.2018172944 [doi] PST - ppublish SO - Radiology. 2018 Sep;288(3):730-738. doi: 10.1148/radiol.2018172944. Epub 2018 May 8.