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Published in: European Radiology 1/2018

01-01-2018 | Molecular Imaging

Non-invasive monitoring of the therapeutic response in sorafenib-treated hepatocellular carcinoma based on photoacoustic imaging

Authors: Seunghyun Lee, Jung Hoon Kim, Jae Hwan Lee, Jeong Hwa Lee, Joon Koo Han

Published in: European Radiology | Issue 1/2018

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Abstract

Purpose

We investigated the changes of tissue oxygen saturation (sO2) in sorafenib-treated HCC (hepatocelluar carcinoma) mouse models using photoacoustic imaging (PI).

Materials and Methods

Nude mice, implanted with human HCC (HepG2-RFP) cells in the liver, were randomised to the sorafenib-treated group (n = 21) or the control group (n = 20). Tumour volume and sO2 were measured by PI at baseline and then one week later, and radiant efficiency (RE) and therapeutic response were analysed by fluorescence imaging and histologic analysis.

Results

Sorafenib was effective in treating HCC by evaluating necrotic fraction, apoptosis index, and microvessel density (MVD). One week after treatment, the sO2 of HCC and residual healthy liver tissue decreased, and the hypoxia inducible factor-1α (HIF-1α) protein expression of HCC increased, correlating with the apoptosis index. The ΔsO2 in HCC showed a significantly positive correlation with the necrotic fraction and the apoptosis index of tumour and a negative correlation with the MVD of tumour.

Conclusion

Sorafenib treatment results in changes of sO2 in HCC and liver parenchyma and induces the accumulation of HIF-1α by hypoxic environment. sO2 as measured by PI, can be a useful marker for non-invasive monitoring of the therapeutic response in orthotopic HCC mouse models.

Key Points

Hypoxia is a characteristic feature of the tumour microenvironment
It is important to monitor sO 2 in HCC during sorafenib treatment
PI is useful for non-invasive monitoring of sO 2 in HCC.
• ΔsO 2 in HCC showed a significantly correlation with tumour response.
Appendix
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Literature
1.
go back to reference Sun HC, Tang ZY (2004) Angiogenesis in hepatocellular carcinoma: the retrospectives and perspectives. J Cancer Res Clin Oncol 130:307–319CrossRefPubMed Sun HC, Tang ZY (2004) Angiogenesis in hepatocellular carcinoma: the retrospectives and perspectives. J Cancer Res Clin Oncol 130:307–319CrossRefPubMed
3.
go back to reference Wigerup C, Pahlman S, Bexell D (2016) Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer. Pharmacol Ther 164:152–169CrossRefPubMed Wigerup C, Pahlman S, Bexell D (2016) Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer. Pharmacol Ther 164:152–169CrossRefPubMed
4.
go back to reference Taketomi A (2016) Clinical trials of antiangiogenic therapy for hepatocellular carcinoma. Int J Clin Oncol 21:213–218CrossRefPubMed Taketomi A (2016) Clinical trials of antiangiogenic therapy for hepatocellular carcinoma. Int J Clin Oncol 21:213–218CrossRefPubMed
5.
6.
go back to reference Welker MW, Trojan J (2011) Anti-angiogenesis in hepatocellular carcinoma treatment: Current evidence and future perspectives. World J Gastroenterol 17:3075–3081PubMedCentralPubMed Welker MW, Trojan J (2011) Anti-angiogenesis in hepatocellular carcinoma treatment: Current evidence and future perspectives. World J Gastroenterol 17:3075–3081PubMedCentralPubMed
7.
go back to reference Llovet JM, Ricci S, Mazzaferro V et al (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359:378–390CrossRefPubMed Llovet JM, Ricci S, Mazzaferro V et al (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359:378–390CrossRefPubMed
8.
go back to reference Yamada D, Kobayashi S, Yamamoto H et al (2012) Role of the hypoxia-related gene, JMJD1A, in hepatocellular carcinoma: clinical impact on recurrence after hepatic resection. Ann Surg Oncol 19(Suppl 3):S355–364CrossRefPubMed Yamada D, Kobayashi S, Yamamoto H et al (2012) Role of the hypoxia-related gene, JMJD1A, in hepatocellular carcinoma: clinical impact on recurrence after hepatic resection. Ann Surg Oncol 19(Suppl 3):S355–364CrossRefPubMed
9.
go back to reference Yip C, Blower PJ, Goh V, Landau DB, Cook GJ (2015) Molecular imaging of hypoxia in non-small-cell lung cancer. Eur J Nucl Med Mol Imaging 42:956–976CrossRefPubMed Yip C, Blower PJ, Goh V, Landau DB, Cook GJ (2015) Molecular imaging of hypoxia in non-small-cell lung cancer. Eur J Nucl Med Mol Imaging 42:956–976CrossRefPubMed
10.
go back to reference Fatema CN, Zhao SJ, Zhao Y et al (2014) Dual tracer evaluation of dynamic changes in intratumoral hypoxic and proliferative states after radiotherapy of human head and neck cancer xenografts using radiolabeled FMISO and FLT. Bmc Cancer 14 Fatema CN, Zhao SJ, Zhao Y et al (2014) Dual tracer evaluation of dynamic changes in intratumoral hypoxic and proliferative states after radiotherapy of human head and neck cancer xenografts using radiolabeled FMISO and FLT. Bmc Cancer 14
11.
go back to reference Raes F, Sobilo J, Le Mee M et al (2016) High Resolution Ultrasound and Photoacoustic Imaging of Orthotopic Lung Cancer in Mice: New Perspectives for Onco-Pharmacology. Plos One 11, e0153532CrossRefPubMedCentralPubMed Raes F, Sobilo J, Le Mee M et al (2016) High Resolution Ultrasound and Photoacoustic Imaging of Orthotopic Lung Cancer in Mice: New Perspectives for Onco-Pharmacology. Plos One 11, e0153532CrossRefPubMedCentralPubMed
12.
go back to reference Gerling M, Zhao Y, Nania S et al (2014) Real-time assessment of tissue hypoxia in vivo with combined photoacoustics and high-frequency ultrasound. Theranostics 4:604–613CrossRefPubMedCentralPubMed Gerling M, Zhao Y, Nania S et al (2014) Real-time assessment of tissue hypoxia in vivo with combined photoacoustics and high-frequency ultrasound. Theranostics 4:604–613CrossRefPubMedCentralPubMed
13.
go back to reference Needles A, Heinmiller A, Sun J et al (2013) Development and initial application of a fully integrated photoacoustic micro-ultrasound system. IEEE Trans Ultrason Ferroelectr Freq Control 60:888–897CrossRefPubMed Needles A, Heinmiller A, Sun J et al (2013) Development and initial application of a fully integrated photoacoustic micro-ultrasound system. IEEE Trans Ultrason Ferroelectr Freq Control 60:888–897CrossRefPubMed
14.
go back to reference Rich LJ, Seshadri M (2015) Photoacoustic imaging of vascular hemodynamics: validation with blood oxygenation level-dependent MR imaging. Radiology 275:110–118CrossRefPubMed Rich LJ, Seshadri M (2015) Photoacoustic imaging of vascular hemodynamics: validation with blood oxygenation level-dependent MR imaging. Radiology 275:110–118CrossRefPubMed
15.
go back to reference Murakami M, Zhao S, Zhao Y et al (2012) Evaluation of changes in the tumor microenvironment after sorafenib therapy by sequential histology and 18F-fluoromisonidazole hypoxia imaging in renal cell carcinoma. Int J Oncol 41:1593–1600CrossRefPubMedCentralPubMed Murakami M, Zhao S, Zhao Y et al (2012) Evaluation of changes in the tumor microenvironment after sorafenib therapy by sequential histology and 18F-fluoromisonidazole hypoxia imaging in renal cell carcinoma. Int J Oncol 41:1593–1600CrossRefPubMedCentralPubMed
16.
go back to reference Wilhelm SM, Carter C, Tang L et al (2004) BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 64:7099–7109CrossRefPubMed Wilhelm SM, Carter C, Tang L et al (2004) BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 64:7099–7109CrossRefPubMed
17.
go back to reference Ayers GD, McKinley ET, Zhao P et al (2010) Volume of Preclinical Xenograft Tumors Is More Accurately Assessed by Ultrasound Imaging Than Manual Caliper Measurements. J Ultrasound Med 29:891–901CrossRefPubMedCentralPubMed Ayers GD, McKinley ET, Zhao P et al (2010) Volume of Preclinical Xenograft Tumors Is More Accurately Assessed by Ultrasound Imaging Than Manual Caliper Measurements. J Ultrasound Med 29:891–901CrossRefPubMedCentralPubMed
18.
go back to reference Zhou J, Zheng W, Cao L, Liu M, Han F, Li A (2010) Antiangiogenic tumor treatment: noninvasive monitoring with contrast pulse sequence imaging for contrast-enhanced grayscale ultrasound. Acad Radiol 17:646–651CrossRefPubMed Zhou J, Zheng W, Cao L, Liu M, Han F, Li A (2010) Antiangiogenic tumor treatment: noninvasive monitoring with contrast pulse sequence imaging for contrast-enhanced grayscale ultrasound. Acad Radiol 17:646–651CrossRefPubMed
19.
go back to reference Yamashita YI, Shimada M, Hasegawa H et al (2001) Electroporation-mediated interleukin-12 gene therapy for hepatocellular carcinoma in the mice model. Cancer Res 61:1005–1012PubMed Yamashita YI, Shimada M, Hasegawa H et al (2001) Electroporation-mediated interleukin-12 gene therapy for hepatocellular carcinoma in the mice model. Cancer Res 61:1005–1012PubMed
21.
go back to reference Degasperi A, Birtwistle MR, Volinsky N, Rauch J, Kolch W, Kholodenko BN (2014) Evaluating strategies to normalise biological replicates of Western blot data. Plos One 9, e87293CrossRefPubMedCentralPubMed Degasperi A, Birtwistle MR, Volinsky N, Rauch J, Kolch W, Kholodenko BN (2014) Evaluating strategies to normalise biological replicates of Western blot data. Plos One 9, e87293CrossRefPubMedCentralPubMed
22.
go back to reference Laufer J, Delpy D, Elwell C, Beard P (2007) Quantitative spatially resolved measurement of tissue chromophore concentrations using photoacoustic spectroscopy: application to the measurement of blood oxygenation and haemoglobin concentration. Phys Med Biol 52:141–168CrossRefPubMed Laufer J, Delpy D, Elwell C, Beard P (2007) Quantitative spatially resolved measurement of tissue chromophore concentrations using photoacoustic spectroscopy: application to the measurement of blood oxygenation and haemoglobin concentration. Phys Med Biol 52:141–168CrossRefPubMed
23.
go back to reference Mallidi S, Watanabe K, Timerman D, Schoenfeld D, Hasan T (2015) Prediction of Tumor Recurrence and Therapy Monitoring Using Ultrasound-Guided Photoacoustic Imaging. Theranostics 5:289–301CrossRefPubMedCentralPubMed Mallidi S, Watanabe K, Timerman D, Schoenfeld D, Hasan T (2015) Prediction of Tumor Recurrence and Therapy Monitoring Using Ultrasound-Guided Photoacoustic Imaging. Theranostics 5:289–301CrossRefPubMedCentralPubMed
24.
go back to reference Miyata A, Ishizawa T, Kamiya M, 9 et al (2014) Photoacoustic Tomography of Human Hepatic Malignancies Using Intraoperative Indocyanine Green Fluorescence Imaging. Plos One 7:9(11):e112667CrossRef Miyata A, Ishizawa T, Kamiya M, 9 et al (2014) Photoacoustic Tomography of Human Hepatic Malignancies Using Intraoperative Indocyanine Green Fluorescence Imaging. Plos One 7:9(11):e112667CrossRef
25.
26.
go back to reference Chang YS, Adnane J, Trail PA et al (2007) Sorafenib (BAY 43-9006) inhibits tumor growth and vascularization and induces tumor apoptosis and hypoxia in RCC xenograft models. Cancer Chemother Pharmacol 59:561–574CrossRefPubMed Chang YS, Adnane J, Trail PA et al (2007) Sorafenib (BAY 43-9006) inhibits tumor growth and vascularization and induces tumor apoptosis and hypoxia in RCC xenograft models. Cancer Chemother Pharmacol 59:561–574CrossRefPubMed
27.
go back to reference Chen Y, Huang Y, Reiberger T et al (2014) Differential effects of sorafenib on liver versus tumor fibrosis mediated by stromal-derived factor 1 alpha/C-X-C receptor type 4 axis and myeloid differentiation antigen-positive myeloid cell infiltration in mice. Hepatology 59:1435–1447CrossRefPubMedCentralPubMed Chen Y, Huang Y, Reiberger T et al (2014) Differential effects of sorafenib on liver versus tumor fibrosis mediated by stromal-derived factor 1 alpha/C-X-C receptor type 4 axis and myeloid differentiation antigen-positive myeloid cell infiltration in mice. Hepatology 59:1435–1447CrossRefPubMedCentralPubMed
28.
go back to reference Liang YJ, Zheng TS, Song RP et al (2013) Hypoxia-Mediated Sorafenib Resistance Can Be Overcome by EF24 Through Von Hippel-Lindau Tumor Suppressor-Dependent HIF-1 alpha Inhibition in Hepatocellular Carcinoma. Hepatology 57:1847–1857CrossRefPubMed Liang YJ, Zheng TS, Song RP et al (2013) Hypoxia-Mediated Sorafenib Resistance Can Be Overcome by EF24 Through Von Hippel-Lindau Tumor Suppressor-Dependent HIF-1 alpha Inhibition in Hepatocellular Carcinoma. Hepatology 57:1847–1857CrossRefPubMed
29.
go back to reference Xu HT, Zhao L, Fang QJ et al (2014) MiR-338-3p Inhibits Hepatocarcinoma Cells and Sensitizes These Cells to Sorafenib by Targeting Hypoxia-Induced Factor 1 alpha. Plos One 9 Xu HT, Zhao L, Fang QJ et al (2014) MiR-338-3p Inhibits Hepatocarcinoma Cells and Sensitizes These Cells to Sorafenib by Targeting Hypoxia-Induced Factor 1 alpha. Plos One 9
30.
go back to reference Liu LP, Ho RLK, Chen GG, Lai PBS (2012) Sorafenib Inhibits Hypoxia-Inducible Factor-1 alpha Synthesis: Implications for Antiangiogenic Activity in Hepatocellular Carcinoma. Clin Cancer Res 18:5662–5671CrossRefPubMed Liu LP, Ho RLK, Chen GG, Lai PBS (2012) Sorafenib Inhibits Hypoxia-Inducible Factor-1 alpha Synthesis: Implications for Antiangiogenic Activity in Hepatocellular Carcinoma. Clin Cancer Res 18:5662–5671CrossRefPubMed
31.
go back to reference Zheng X, Wang X, Mao H, Wu W, Liu B, Jiang X (2015) Hypoxia-specific ultrasensitive detection of tumours and cancer cells in vivo. Nat Commun 6:5834CrossRefPubMed Zheng X, Wang X, Mao H, Wu W, Liu B, Jiang X (2015) Hypoxia-specific ultrasensitive detection of tumours and cancer cells in vivo. Nat Commun 6:5834CrossRefPubMed
32.
go back to reference Harada H, Inoue M, Itasaka S et al (2012) Cancer cells that survive radiation therapy acquire HIF-1 activity and translocate towards tumour blood vessels. Nature Communications 3 Harada H, Inoue M, Itasaka S et al (2012) Cancer cells that survive radiation therapy acquire HIF-1 activity and translocate towards tumour blood vessels. Nature Communications 3
33.
go back to reference Kim KR, Moon HE, Kim KW (2002) Hypoxia-induced angiogenesis in human hepatocellular carcinoma. J Mol Med (Berl) 80:703–714CrossRef Kim KR, Moon HE, Kim KW (2002) Hypoxia-induced angiogenesis in human hepatocellular carcinoma. J Mol Med (Berl) 80:703–714CrossRef
35.
go back to reference Hu F, Deng X, Yang X et al (2015) Hypoxia upregulates Rab11-family interacting protein 4 through HIF-1 alpha to promote the metastasis of hepatocellular carcinoma. Oncogene 34:6007–6017CrossRefPubMed Hu F, Deng X, Yang X et al (2015) Hypoxia upregulates Rab11-family interacting protein 4 through HIF-1 alpha to promote the metastasis of hepatocellular carcinoma. Oncogene 34:6007–6017CrossRefPubMed
36.
go back to reference Li H, Chen J, Zen W et al (2015) Effect of hypoxia inducible factor-1 antisense oligonucleotide on liver cancer. Int J Clin Exp Med 8:12650–12655PubMedCentralPubMed Li H, Chen J, Zen W et al (2015) Effect of hypoxia inducible factor-1 antisense oligonucleotide on liver cancer. Int J Clin Exp Med 8:12650–12655PubMedCentralPubMed
37.
go back to reference Unruh A, Ressel A, Mohamed HG et al (2003) The hypoxia-inducible factor-1 alpha is a negative factor for tumor therapy. Oncogene 22:3213–3220CrossRefPubMed Unruh A, Ressel A, Mohamed HG et al (2003) The hypoxia-inducible factor-1 alpha is a negative factor for tumor therapy. Oncogene 22:3213–3220CrossRefPubMed
38.
go back to reference Sugimoto K, Moriyasu F, Saito K et al (2013) Hepatocellular carcinoma treated with sorafenib: early detection of treatment response and major adverse events by contrast-enhanced US. Liver Int 33:605–615CrossRefPubMed Sugimoto K, Moriyasu F, Saito K et al (2013) Hepatocellular carcinoma treated with sorafenib: early detection of treatment response and major adverse events by contrast-enhanced US. Liver Int 33:605–615CrossRefPubMed
39.
go back to reference Mejias M, Garcia-Pras E, Tiani C, Miquel R, Bosch J, Fernandez M (2009) Beneficial Effects of Sorafenib on Splanchnic, Intrahepatic, and Portocollateral Circulations in Portal Hypertensive and Cirrhotic Rats. Hepatology 49:1245–1256CrossRefPubMed Mejias M, Garcia-Pras E, Tiani C, Miquel R, Bosch J, Fernandez M (2009) Beneficial Effects of Sorafenib on Splanchnic, Intrahepatic, and Portocollateral Circulations in Portal Hypertensive and Cirrhotic Rats. Hepatology 49:1245–1256CrossRefPubMed
40.
go back to reference Wilhelm S, Carter C, Lynch M et al (2006) Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov 5:835–844CrossRefPubMed Wilhelm S, Carter C, Lynch M et al (2006) Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov 5:835–844CrossRefPubMed
41.
go back to reference Yang XZ, Dou S, Sun TM, Mao CQ, Wang HX, Wang J (2011) Systemic delivery of siRNA with cationic lipid assisted PEG-PLA nanoparticles for cancer therapy. J Control Release 156:203–211CrossRefPubMed Yang XZ, Dou S, Sun TM, Mao CQ, Wang HX, Wang J (2011) Systemic delivery of siRNA with cationic lipid assisted PEG-PLA nanoparticles for cancer therapy. J Control Release 156:203–211CrossRefPubMed
42.
go back to reference Yan CH, Yang M, Li ZZ et al (2014) Suppression of orthotopically implanted hepatocarcinoma in mice by umbilical cord-derived mesenchymal stem cells with sTRAIL gene expression driven by AFP promoter. Biomaterials 35:3035–3043CrossRefPubMed Yan CH, Yang M, Li ZZ et al (2014) Suppression of orthotopically implanted hepatocarcinoma in mice by umbilical cord-derived mesenchymal stem cells with sTRAIL gene expression driven by AFP promoter. Biomaterials 35:3035–3043CrossRefPubMed
43.
go back to reference Ben Mousa A (2008) Sorafenib in the treatment of advanced hepatocellular carcinoma. Saudi J Gastroenterol 14:40–42CrossRefPubMed Ben Mousa A (2008) Sorafenib in the treatment of advanced hepatocellular carcinoma. Saudi J Gastroenterol 14:40–42CrossRefPubMed
Metadata
Title
Non-invasive monitoring of the therapeutic response in sorafenib-treated hepatocellular carcinoma based on photoacoustic imaging
Authors
Seunghyun Lee
Jung Hoon Kim
Jae Hwan Lee
Jeong Hwa Lee
Joon Koo Han
Publication date
01-01-2018
Publisher
Springer Berlin Heidelberg
Published in
European Radiology / Issue 1/2018
Print ISSN: 0938-7994
Electronic ISSN: 1432-1084
DOI
https://doi.org/10.1007/s00330-017-4960-3

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