Skip to main content
Top
Published in: Hepatology International 3/2014

01-07-2014 | Review Article

Role of circulating tumor cells and cancer stem cells in hepatocellular carcinoma

Authors: Ivonne Nel, Paul David, Guido G. H. Gerken, Joerg F. Schlaak, Andreas-Claudius Hoffmann

Published in: Hepatology International | Issue 3/2014

Login to get access

Abstract

Circulating tumor cells (CTC) and cancer stem cells (CSC) have been proposed as tools for detection and characterization of disease and individualization of therapy in patients with many solid tumors. Several automated and semi-automated techniques for identification and isolation of these cells from blood have been proposed and reviewed mostly focusing on their feasibility. In this mini review we summarize the recent relevant literature on this topic and discuss the clinical usability of measuring CTC and CSC in peripheral blood in patients with hepatocellular carcinoma (HCC). Besides literature, the basis for this evaluation was the authors’ experience with treating HCC and research experience on CSC and CTC. Few original reports and reviews have been published focusing on CTC and CSC in HCC. Though HCC is one of the five most common malignancies worldwide only recently these cells have come into focus for detection and characterization of this disease that is characterized by high plasticity and malignancy. A focused and prospective validation of the clinical usability of detecting these cells in HCC is still needed, but results seem promising that they may add great benefit for early detection and individualization of therapy.
Literature
1.
go back to reference Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011;61:69–90PubMedCrossRef Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011;61:69–90PubMedCrossRef
2.
go back to reference Ertle J, Dechene A, Sowa JP, Penndorf V, Herzer K, Kaiser G, et al. Non-alcoholic fatty liver disease progresses to hepatocellular carcinoma in the absence of apparent cirrhosis. Int J Cancer 2011;128:2436–2443PubMedCrossRef Ertle J, Dechene A, Sowa JP, Penndorf V, Herzer K, Kaiser G, et al. Non-alcoholic fatty liver disease progresses to hepatocellular carcinoma in the absence of apparent cirrhosis. Int J Cancer 2011;128:2436–2443PubMedCrossRef
3.
4.
go back to reference Hoffmann AC, Vallbohmer D, Grimminger P, Metzger R, Prenzel KL, Hoelscher AH, et al. Preoperative survivin mRNA detection in peripheral blood is an independent predictor of outcome in esophageal carcinoma. Pharmacogenomics 2010;11:341–347PubMedCrossRef Hoffmann AC, Vallbohmer D, Grimminger P, Metzger R, Prenzel KL, Hoelscher AH, et al. Preoperative survivin mRNA detection in peripheral blood is an independent predictor of outcome in esophageal carcinoma. Pharmacogenomics 2010;11:341–347PubMedCrossRef
5.
go back to reference Yu M, Bardia A, Wittner BS, Stott SL, Smas ME, Ting DT, et al. Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science 2013;339:580–584PubMedCentralPubMedCrossRef Yu M, Bardia A, Wittner BS, Stott SL, Smas ME, Ting DT, et al. Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science 2013;339:580–584PubMedCentralPubMedCrossRef
6.
go back to reference Fidler IJ. Tumor heterogeneity and the biology of cancer invasion and metastasis. Cancer Res 1978;38:2651–2660PubMed Fidler IJ. Tumor heterogeneity and the biology of cancer invasion and metastasis. Cancer Res 1978;38:2651–2660PubMed
8.
go back to reference Gradilone A, Raimondi C, Nicolazzo C, Petracca A, Gandini O, Vincenzi B, et al. Circulating tumour cells lacking cytokeratin in breast cancer: the importance of being mesenchymal. J Cell Mol Med 2011;15:1066–1070PubMedCrossRef Gradilone A, Raimondi C, Nicolazzo C, Petracca A, Gandini O, Vincenzi B, et al. Circulating tumour cells lacking cytokeratin in breast cancer: the importance of being mesenchymal. J Cell Mol Med 2011;15:1066–1070PubMedCrossRef
9.
go back to reference Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 2008;133:704–715PubMedCentralPubMedCrossRef Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 2008;133:704–715PubMedCentralPubMedCrossRef
10.
go back to reference Nel I, Gauler T, Hoffmann AC. Circulating tumor cell composition and outcome in patients with solid tumors. Int J Clin Pharmacol Ther. 2014;52:74–75PubMedCrossRef Nel I, Gauler T, Hoffmann AC. Circulating tumor cell composition and outcome in patients with solid tumors. Int J Clin Pharmacol Ther. 2014;52:74–75PubMedCrossRef
11.
go back to reference Riethdorf S, Pantel K. Advancing personalized cancer therapy by detection and characterization of circulating carcinoma cells. Ann N Y Acad Sci 2010;1210:66–77PubMedCrossRef Riethdorf S, Pantel K. Advancing personalized cancer therapy by detection and characterization of circulating carcinoma cells. Ann N Y Acad Sci 2010;1210:66–77PubMedCrossRef
12.
go back to reference Bitting RL, Boominathan R, Rao C, Kemeny G, Foulk B, Garcia-Blanco MA, et al. Development of a method to isolate circulating tumor cells using mesenchymal-based capture. Methods 2013;64:129–136PubMedCrossRef Bitting RL, Boominathan R, Rao C, Kemeny G, Foulk B, Garcia-Blanco MA, et al. Development of a method to isolate circulating tumor cells using mesenchymal-based capture. Methods 2013;64:129–136PubMedCrossRef
13.
go back to reference Wu LJ, Pan YD, Pei XY, Chen H, Nguyen S, Kashyap A, et al. Capturing circulating tumor cells of hepatocellular carcinoma. Cancer Lett 2012;326:17–22PubMedCrossRef Wu LJ, Pan YD, Pei XY, Chen H, Nguyen S, Kashyap A, et al. Capturing circulating tumor cells of hepatocellular carcinoma. Cancer Lett 2012;326:17–22PubMedCrossRef
15.
go back to reference Zhang Y, Li J, Cao L, Xu W, Yin Z. Circulating tumor cells in hepatocellular carcinoma: detection techniques, clinical implications, and future perspectives. Semin Oncol 2012;39:449–460PubMedCrossRef Zhang Y, Li J, Cao L, Xu W, Yin Z. Circulating tumor cells in hepatocellular carcinoma: detection techniques, clinical implications, and future perspectives. Semin Oncol 2012;39:449–460PubMedCrossRef
16.
go back to reference Alix-Panabieres C, Pantel K. Technologies for detection of circulating tumor cells: facts and vision. Lab Chip 2014;14:57–62PubMedCrossRef Alix-Panabieres C, Pantel K. Technologies for detection of circulating tumor cells: facts and vision. Lab Chip 2014;14:57–62PubMedCrossRef
17.
go back to reference Krebs MG, Hou JM, Sloane R, Lancashire L, Priest L, Nonaka D, et al. Analysis of circulating tumor cells in patients with non-small cell lung cancer using epithelial marker-dependent and -independent approaches. Journal of Thoracic Oncology 2012;7:306–315PubMedCrossRef Krebs MG, Hou JM, Sloane R, Lancashire L, Priest L, Nonaka D, et al. Analysis of circulating tumor cells in patients with non-small cell lung cancer using epithelial marker-dependent and -independent approaches. Journal of Thoracic Oncology 2012;7:306–315PubMedCrossRef
18.
go back to reference Nel I, Ertlel JM, Baba HA, Weber F, Sitek B, Stephan C, et al. A novel method for the detection of different subgroups of circulating tumor cells in patients with hepatocellular carcinoma. Hepatology 2012;56:457A Nel I, Ertlel JM, Baba HA, Weber F, Sitek B, Stephan C, et al. A novel method for the detection of different subgroups of circulating tumor cells in patients with hepatocellular carcinoma. Hepatology 2012;56:457A
19.
go back to reference Nel I, Baba HA, Ertle J, Weber F, Sitek B, Eisenacher M, et al. Individual profiling of circulating tumor cell composition and therapeutic outcome in patients with hepatocellular carcinoma. Transl Oncol 2013;6:420–428PubMedCentralPubMedCrossRef Nel I, Baba HA, Ertle J, Weber F, Sitek B, Eisenacher M, et al. Individual profiling of circulating tumor cell composition and therapeutic outcome in patients with hepatocellular carcinoma. Transl Oncol 2013;6:420–428PubMedCentralPubMedCrossRef
20.
go back to reference Campos M, Luque R, Jimenez J, Martinez R, Warleta F, Sanchez-Quesada C, et al. Simultaneous phenotypic and genetic characterization of single circulating tumor cells from colon cancer patients. Histol Histopathol 2013;6(5):872–879 Campos M, Luque R, Jimenez J, Martinez R, Warleta F, Sanchez-Quesada C, et al. Simultaneous phenotypic and genetic characterization of single circulating tumor cells from colon cancer patients. Histol Histopathol 2013;6(5):872–879
21.
go back to reference Marrinucci D, Bethel K, Kolatkar A, Luttgen MS, Malchiodi M, Baehring F, et al. Fluid biopsy in patients with metastatic prostate, pancreatic and breast cancers. Phys Biol 2012;9:016003PubMedCentralPubMedCrossRef Marrinucci D, Bethel K, Kolatkar A, Luttgen MS, Malchiodi M, Baehring F, et al. Fluid biopsy in patients with metastatic prostate, pancreatic and breast cancers. Phys Biol 2012;9:016003PubMedCentralPubMedCrossRef
22.
go back to reference Waguri N, Suda T, Nomoto M, Kawai H, Mita Y, Kuroiwa T, et al. Sensitive and specific detection of circulating cancer cells in patients with hepatocellular carcinoma; detection of human telomerase reverse transcriptase messenger RNA after immunomagnetic separation. Clin Cancer Res 2003;9:3004–3011PubMed Waguri N, Suda T, Nomoto M, Kawai H, Mita Y, Kuroiwa T, et al. Sensitive and specific detection of circulating cancer cells in patients with hepatocellular carcinoma; detection of human telomerase reverse transcriptase messenger RNA after immunomagnetic separation. Clin Cancer Res 2003;9:3004–3011PubMed
23.
go back to reference Vona G, Estepa L, Beroud C, Damotte D, Capron F, Nalpas B, et al. Impact of cytomorphological detection of circulating tumor cells in patients with liver cancer. Hepatology 2004;39:792–797PubMedCrossRef Vona G, Estepa L, Beroud C, Damotte D, Capron F, Nalpas B, et al. Impact of cytomorphological detection of circulating tumor cells in patients with liver cancer. Hepatology 2004;39:792–797PubMedCrossRef
24.
go back to reference Guo J, Yao F, Lou Y, Xu C, Xiao B, Zhou W, et al. Detecting carcinoma cells in peripheral blood of patients with hepatocellular carcinoma by immunomagnetic beads and rt-PCR. J Clin Gastroenterol 2007;41:783–788PubMedCrossRef Guo J, Yao F, Lou Y, Xu C, Xiao B, Zhou W, et al. Detecting carcinoma cells in peripheral blood of patients with hepatocellular carcinoma by immunomagnetic beads and rt-PCR. J Clin Gastroenterol 2007;41:783–788PubMedCrossRef
25.
go back to reference Yang ZF, Ngai P, Ho DW, Yu WC, Ng MN, Lau CK, et al. Identification of local and circulating cancer stem cells in human liver cancer. Hepatology 2008;47:919–928PubMedCrossRef Yang ZF, Ngai P, Ho DW, Yu WC, Ng MN, Lau CK, et al. Identification of local and circulating cancer stem cells in human liver cancer. Hepatology 2008;47:919–928PubMedCrossRef
26.
go back to reference Xu W, Cao L, Chen L, Li J, Zhang XF, Qian HH, et al. Isolation of circulating tumor cells in patients with hepatocellular carcinoma using a novel cell separation strategy. Clin Cancer Res 2011;17:3783–3793PubMedCrossRef Xu W, Cao L, Chen L, Li J, Zhang XF, Qian HH, et al. Isolation of circulating tumor cells in patients with hepatocellular carcinoma using a novel cell separation strategy. Clin Cancer Res 2011;17:3783–3793PubMedCrossRef
27.
go back to reference Fan ZC, Yan J, Liu GD, Tan XY, Weng XF, Wu WZ, et al. Real-time monitoring of rare circulating hepatocellular carcinoma cells in an orthotopic model by in vivo flow cytometry assesses resection on metastasis. Cancer Res 2012;72:2683–2691PubMedCrossRef Fan ZC, Yan J, Liu GD, Tan XY, Weng XF, Wu WZ, et al. Real-time monitoring of rare circulating hepatocellular carcinoma cells in an orthotopic model by in vivo flow cytometry assesses resection on metastasis. Cancer Res 2012;72:2683–2691PubMedCrossRef
28.
go back to reference Sun YF, Xu Y, Yang XR, Guo W, Zhang X, Qiu SJ, et al. Circulating stem cell-like epithelial cell adhesion molecule-positive tumor cells indicate poor prognosis of hepatocellular carcinoma after curative resection. Hepatology 2013;57:1458–1468PubMedCrossRef Sun YF, Xu Y, Yang XR, Guo W, Zhang X, Qiu SJ, et al. Circulating stem cell-like epithelial cell adhesion molecule-positive tumor cells indicate poor prognosis of hepatocellular carcinoma after curative resection. Hepatology 2013;57:1458–1468PubMedCrossRef
29.
go back to reference Liu S, Li N, Yu X, Xiao X, Cheng K, Hu J, et al. Expression of intercellular adhesion molecule 1 by hepatocellular carcinoma stem cells and circulating tumor cells. Gastroenterology 2013;144(1031–1041):e1010 Liu S, Li N, Yu X, Xiao X, Cheng K, Hu J, et al. Expression of intercellular adhesion molecule 1 by hepatocellular carcinoma stem cells and circulating tumor cells. Gastroenterology 2013;144(1031–1041):e1010
30.
go back to reference Schulze K, Gasch C, Staufer K, Nashan B, Lohse AW, Pantel K, et al. Presence of EpCAM-positive circulating tumor cells as biomarker for systemic disease strongly correlates to survival in patients with hepatocellular carcinoma. Int J Cancer 2013;133:2165–2171PubMedCrossRef Schulze K, Gasch C, Staufer K, Nashan B, Lohse AW, Pantel K, et al. Presence of EpCAM-positive circulating tumor cells as biomarker for systemic disease strongly correlates to survival in patients with hepatocellular carcinoma. Int J Cancer 2013;133:2165–2171PubMedCrossRef
31.
go back to reference Schulze K, Beneken C, Staufer K, Nashan B, Lohse AW, Pantel K, et al. Detection of Epcam-Positive Circulating Tumor Cells in Patients with Hepatocellular Carcinoma—a Pilot Study. Hepatology 2011;54:1357a Schulze K, Beneken C, Staufer K, Nashan B, Lohse AW, Pantel K, et al. Detection of Epcam-Positive Circulating Tumor Cells in Patients with Hepatocellular Carcinoma—a Pilot Study. Hepatology 2011;54:1357a
32.
go back to reference Gao P, Jiao SC, Bai L, Wang H, Jing FF, Yang JL. Detection of circulating tumour cells in gastric and hepatocellular carcinoma: a systematic review. J Int Med Res 2013;41:923–933PubMedCrossRef Gao P, Jiao SC, Bai L, Wang H, Jing FF, Yang JL. Detection of circulating tumour cells in gastric and hepatocellular carcinoma: a systematic review. J Int Med Res 2013;41:923–933PubMedCrossRef
33.
34.
go back to reference Yang ZF, Ho DW, Ng MN, Lau CK, Yu WC, Ngai P, et al. Significance of CD90 + cancer stem cells in human liver cancer. Cancer Cell 2008;13:153–166PubMedCrossRef Yang ZF, Ho DW, Ng MN, Lau CK, Yu WC, Ngai P, et al. Significance of CD90 + cancer stem cells in human liver cancer. Cancer Cell 2008;13:153–166PubMedCrossRef
36.
go back to reference Yamashita T, Ji J, Budhu A, Forgues M, Yang W, Wang HY, et al. EpCAM-positive hepatocellular carcinoma cells are tumor-initiating cells with stem/progenitor cell features. Gastroenterology 2009;136:1012–1024PubMedCentralPubMedCrossRef Yamashita T, Ji J, Budhu A, Forgues M, Yang W, Wang HY, et al. EpCAM-positive hepatocellular carcinoma cells are tumor-initiating cells with stem/progenitor cell features. Gastroenterology 2009;136:1012–1024PubMedCentralPubMedCrossRef
37.
go back to reference Zhu Z, Hao X, Yan M, Yao M, Ge C, Gu J, et al. Cancer stem/progenitor cells are highly enriched in CD133 + CD44 + population in hepatocellular carcinoma. Int J Cancer 2010;126:2067–2078PubMedCrossRef Zhu Z, Hao X, Yan M, Yao M, Ge C, Gu J, et al. Cancer stem/progenitor cells are highly enriched in CD133 + CD44 + population in hepatocellular carcinoma. Int J Cancer 2010;126:2067–2078PubMedCrossRef
38.
go back to reference Kim SR, Kudo M, Hino O, Han KH, Chung YH, Lee HS. Organizing Committee of Japan-Korea Liver S. Epidemiology of hepatocellular carcinoma in Japan and Korea. A review. Oncology 2008;75(Suppl 1):13–16PubMedCrossRef Kim SR, Kudo M, Hino O, Han KH, Chung YH, Lee HS. Organizing Committee of Japan-Korea Liver S. Epidemiology of hepatocellular carcinoma in Japan and Korea. A review. Oncology 2008;75(Suppl 1):13–16PubMedCrossRef
39.
go back to reference Libbrecht L, Roskams T. Hepatic progenitor cells in human liver diseases. Semin Cell Dev Biol 2002;13:389–396PubMedCrossRef Libbrecht L, Roskams T. Hepatic progenitor cells in human liver diseases. Semin Cell Dev Biol 2002;13:389–396PubMedCrossRef
40.
go back to reference Viatour P, Ehmer U, Saddic LA, Dorrell C, Andersen JB, Lin C, et al. Notch signaling inhibits hepatocellular carcinoma following inactivation of the RB pathway. J Exp Med 2011;208:1963–1976PubMedCentralPubMedCrossRef Viatour P, Ehmer U, Saddic LA, Dorrell C, Andersen JB, Lin C, et al. Notch signaling inhibits hepatocellular carcinoma following inactivation of the RB pathway. J Exp Med 2011;208:1963–1976PubMedCentralPubMedCrossRef
41.
go back to reference Clarke MF, Dick JE, Dirks PB, Eaves CJ, Jamieson CH, Jones DL, et al. Cancer stem cells–perspectives on current status and future directions: aACR Workshop on cancer stem cells. Cancer Res 2006;66:9339–9344PubMedCrossRef Clarke MF, Dick JE, Dirks PB, Eaves CJ, Jamieson CH, Jones DL, et al. Cancer stem cells–perspectives on current status and future directions: aACR Workshop on cancer stem cells. Cancer Res 2006;66:9339–9344PubMedCrossRef
42.
go back to reference Yamashita T, Budhu A, Forgues M, Wang XW. Activation of hepatic stem cell marker EpCAM by Wnt-beta-catenin signaling in hepatocellular carcinoma. Cancer Res 2007;67:10831–10839PubMedCrossRef Yamashita T, Budhu A, Forgues M, Wang XW. Activation of hepatic stem cell marker EpCAM by Wnt-beta-catenin signaling in hepatocellular carcinoma. Cancer Res 2007;67:10831–10839PubMedCrossRef
43.
go back to reference Chen K, Huang YH, Chen JL. Understanding and targeting cancer stem cells: therapeutic implications and challenges. Acta Pharmacol Sin 2013;34:732–740PubMedCentralPubMedCrossRef Chen K, Huang YH, Chen JL. Understanding and targeting cancer stem cells: therapeutic implications and challenges. Acta Pharmacol Sin 2013;34:732–740PubMedCentralPubMedCrossRef
44.
go back to reference Smith LM, Nesterova A, Ryan MC, Duniho S, Jonas M, Anderson M, et al. CD133/prominin-1 is a potential therapeutic target for antibody-drug conjugates in hepatocellular and gastric cancers. Br J Cancer 2008;99:100–109PubMedCentralPubMedCrossRef Smith LM, Nesterova A, Ryan MC, Duniho S, Jonas M, Anderson M, et al. CD133/prominin-1 is a potential therapeutic target for antibody-drug conjugates in hepatocellular and gastric cancers. Br J Cancer 2008;99:100–109PubMedCentralPubMedCrossRef
45.
go back to reference Lee TK, Castilho A, Ma S, Ng IO. Liver cancer stem cells: implications for a new therapeutic target. Liver Int 2009;29:955–965PubMedCrossRef Lee TK, Castilho A, Ma S, Ng IO. Liver cancer stem cells: implications for a new therapeutic target. Liver Int 2009;29:955–965PubMedCrossRef
46.
go back to reference Klopp AH, Spaeth EL, Dembinski JL, Woodward WA, Munshi A, Meyn RE, et al. Tumor irradiation increases the recruitment of circulating mesenchymal stem cells into the tumor microenvironment. Cancer Res 2007;67:11687–11695PubMedCrossRef Klopp AH, Spaeth EL, Dembinski JL, Woodward WA, Munshi A, Meyn RE, et al. Tumor irradiation increases the recruitment of circulating mesenchymal stem cells into the tumor microenvironment. Cancer Res 2007;67:11687–11695PubMedCrossRef
47.
go back to reference Uchibori R, Okada T, Ito T, Urabe M, Mizukami H, Kume A, et al. Retroviral vector-producing mesenchymal stem cells for targeted suicide cancer gene therapy. J Gene Med 2009;11:373–81PubMedCrossRef Uchibori R, Okada T, Ito T, Urabe M, Mizukami H, Kume A, et al. Retroviral vector-producing mesenchymal stem cells for targeted suicide cancer gene therapy. J Gene Med 2009;11:373–81PubMedCrossRef
Metadata
Title
Role of circulating tumor cells and cancer stem cells in hepatocellular carcinoma
Authors
Ivonne Nel
Paul David
Guido G. H. Gerken
Joerg F. Schlaak
Andreas-Claudius Hoffmann
Publication date
01-07-2014
Publisher
Springer India
Published in
Hepatology International / Issue 3/2014
Print ISSN: 1936-0533
Electronic ISSN: 1936-0541
DOI
https://doi.org/10.1007/s12072-014-9539-3

Other articles of this Issue 3/2014

Hepatology International 3/2014 Go to the issue
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.