Research progress of hepatocellular carcinoma expressing “stemness”-related markers_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

 WANG Haiqing , FENG Xielin

Department of Hepato-Biliary-Pancreatic Surgery, Sichuan Cancer Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610041, P. R. China;

Corresponding author：

WANG Haiqing, Email: 541026814@qq.com

Keywords：

hepatocellular carcinoma; stemness; marker; prognosis

DOI：

10.7507/1007-9424.201803051

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To summarize clinicopathological characteristics and prognosis of hepatocellular carcinoma (HCC) expressing " stemness”-related markers. Method The clinical researches on HCC expressing " stemness”-related markers in recent years were reviewed. Results The HCC expressing " stemness”-related markers was the special subtype with the aggressive biological behavior as compared with the conventional HCC, which were associated with the increased serum α-fetoprotein level, vascular invasion, larger tumor, poor differentiation, and poor clinical outcome. The approved " stemness”-related markers included EpCAM, CD133, K19, and CD44, which often co-expressed and had their own characteristics. The presentation of " stemness”-related marker was heterogeneous and it increased the difficulty to carry on the research of therapeutic agents targeted against this aggressive HCC. Conclusion HCC expressing " stemness”-related marker is a special subtype with a strong invasiveness, which provides a new direction of targeting therapy for HCC.

Citation： WANG Haiqing, FENG Xielin. Research progress of hepatocellular carcinoma expressing “stemness”-related markers. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2018, 25(10): 1264-1269. doi: 10.7507/1007-9424.201803051 Copy

1.	Kim H, Yoo JE, Cho JY, et al. Telomere length, TERT and shelterin complex proteins in hepatocellular carcinomas expressing " stemness”-related markers. J Hepatol, 2013, 59(4): 746-752.
2.	Calderaro J, Couchy G, Imbeaud S, et al. Histological subtypes of hepatocellular carcinoma are related to gene mutations and molecular tumour classification. J Hepatol, 2017, 67(4): 727-738.
3.	Ma S, Chan KW, Hu L, et al. Identification and characterization of tumorigenic liver cancer stem/progenitor cells. Gastroenterology, 2007, 132(7): 2542-2556.
4.	Govaere O, Roskams T. Pathogenesis and prognosis of hepatocellular carcinoma at the cellular and molecular levels. Clin Liver Dis, 2015, 19(2): 261-276.
5.	江春平. 未来肝癌治疗的新靶点—肝癌干细胞. 世界华人消化杂志, 2009, 17(8): 743-746.
6.	Kim H, Park YN. Hepatocellular carcinomas expressing ‘stemness’-related markers: clinicopathological characteristics. Dig Dis, 2014, 32(6): 778-785.
7.	Marquardt JU, Thorgeirsson SS. Stem cells in hepatocarcinogenesis: evidence from genomic data. Semin Liver Dis, 2010, 30(1): 26-34.
8.	Thorgeirsson SS. Stemness and reprogramming in liver cancer. Hepatology, 2016, 63(4): 1068-1070.
9.	Thorgeirsson SS. Stemness in liver cancer. Dig Dis, 2017, 35(4): 387-389.
10.	Govaere O, Komuta M, Berkers J, et al. Keratin 19: a key role player in the invasion of human hepatocellular carcinomas. Gut, 2014, 63(4): 674-685.
11.	Kim H, Choi GH, Na DC, et al. Human hepatocellular carcinomas with " Stemness”-related marker expression: keratin 19 expression and a poor prognosis. Hepatology, 2011, 54(5): 1707-1717.
12.	Fartoux L, Decaens T. Contribution of biomarkers and imaging in the management of hepatocellular carcinoma. Clin Res Hepatol Gastroenterol, 2011, 35(Suppl 1): S21-S30.
13.	Yamashita T, Forgues M, Wang W, et al. EpCAM and alpha-fetoprotein expression defines novel prognostic subtypes of hepatocellular carcinoma. Cancer Res, 2008, 68(5): 1451-1461.
14.	邢龙彬, 高英堂. 肝癌干细胞表面标志物研究进展. 世界华人消化杂志, 2016, 24(31): 4231-4237.
15.	Chan AW, Tong JH, Chan SL, et al. Expression of stemness markers (CD133 and EpCAM) in prognostication of hepatocellular carcinoma. Histopathology, 2014, 64(7): 935-950.
16.	Qiu L, Li H, Fu S, et al. Surface markers of liver cancer stem cells and innovative targeted-therapy strategies for HCC. Oncol Lett, 2018, 15(2): 2039-2048.
17.	Lan X, Wu YZ, Wang Y, et al. CD133 silencing inhibits stemness properties and enhances chemoradiosensitivity in CD133-positive liver cancer stem cells. Int J Mol Med, 2013, 31(2): 315-324.
18.	Fatourou E, Koskinas J, Karandrea D, et al. Keratin 19 protein expression is an independent predictor of survival in human hepatocellular carcinoma. Eur J Gastroenterol Hepatol, 2015, 27(9): 1094-1102.
19.	Guo Z, Li LQ, Jiang JH, et al. Cancer stem cell markers correlate with early recurrence and survival in hepatocellular carcinoma. World J Gastroenterol, 2014, 20(8): 2098-2106.
20.	Liu K, Hao M, Ouyang Y, et al. CD133⁺ cancer stem cells promoted by VEGF accelerate the recurrence of hepatocellular carcinoma. Sci Rep, 2017, 7: 41499.
21.	Rozeik MS, Hammam OA, Ali AI, et al. Evaluation of CD44 and CD133 as markers of liver cancer stem cells in Egyptian patients with HCV-induced chronic liver diseases versus hepatocellular carcinoma. Electron Physician, 2017, 9(7): 4708-4717.
22.	Gao Y, Ruan B, Liu W, et al. Knockdown of CD44 inhibits the invasion and metastasis of hepatocellular carcinoma both in vitro and in vivo by reversing epithelial-mesenchymal transition. Oncotarget, 2015, 6(10): 7828-7837.
23.	Yamanaka C, Wada H, Eguchi H, et al. Clinical significance of CD13 and epithelial mesenchymal transition (EMT) markers in hepatocellular carcinoma. Jpn J Clin Oncol, 2018, 48(1): 52-60.
24.	Hoshida Y, Toffanin S, Lachenmayer A, et al. Molecular classification and novel targets in hepatocellular carcinoma: recent advancements. Semin Liver Dis, 2010, 30(1): 35-51.
25.	Lirdprapamongkol K, Chiablaem K, Sila-Asna M, et al. Exploring stemness gene expression and vasculogenic mimicry capacity in well- and poorly-differentiated hepatocellular carcinoma cell lines. Biochem Biophys Res Commun, 2012, 422(3): 429-435.
26.	Tan PS, Nakagawa S, Goossens N, et al. Clinicopathological indices to predict hepatocellular carcinoma molecular classification. Liver Int, 2016, 36(1): 108-118.
27.	Scheel C, Weinberg RA. Cancer stem cells and epithelial-mesenchymal transition: concepts and molecular links. Semin Cancer Biol, 2012, 22(5-6): 396-403.
28.	Lo RC, Leung CO, Chok KS, et al. Variation of stemness markers expression in tumor nodules from synchronous multi-focal hepatocellular carcinoma—an immunohistochemical study. Diagn Pathol, 2017, 12(1): 56.
29.	Kumagai A, Kondo F, Sano K, et al. Immunohistochemical study of hepatocyte, cholangiocyte and stem cell markers of hepatocellular carcinoma: the second report: relationship with tumor size and cell differentiation. J Hepatobiliary Pancreat Sci, 2016, 23(7): 414-421.
30.	Nahm JH, Rhee H, Kim H, et al. Increased expression of stemness markers and altered tumor stroma in hepatocellular carcinoma under TACE-induced hypoxia: A biopsy and resection matched study. Oncotarget, 2017, 8(59): 99359-99371.
31.	Ikemoto T, Shimada M, Yamada S. Pathophysiology of recurrent hepatocellular carcinoma after radiofrequency ablation. Hepatol Res, 2017, 47(1): 23-30.
32.	Ouyang Y, Liu K, Hao M, et al. Radiofrequency ablation-increased CXCL10 is associated with earlier recurrence of hepatocellular carcinoma by promoting stemness. Tumour Biol, 2016, 37(3): 3697-3704.
33.	Yamada S, Utsunomiya T, Morine Y, et al. Expressions of hypoxia-inducible factor-1 and epithelial cell adhesion molecule are linked with aggressive local recurrence of hepatocellular carcinoma after radiofrequency ablation therapy. Ann Surg Oncol, 2014, 21(Suppl 3): S436-S442.
34.	Durnez A, Verslype C, Nevens F, et al. The clinicopathological and prognostic relevance of cytokeratin 7 and 19 expression in hepatocellular carcinoma. A possible progenitor cell origin. Histopathology, 2006, 49(2): 138-151.
35.	Jeong HT, Kim MJ, Kim YE, et al. MRI features of hepatocellular carcinoma expressing progenitor cell markers. Liver Int, 2012, 32(3): 430-440.
36.	Ma YC, Yang JY, Yan LN. Relevant markers of cancer stem cells indicate a poor prognosis in hepatocellular carcinoma patients: a meta-analysis. Eur J Gastroenterol Hepatol, 2013, 25(9): 1007-1016.
37.	Dai XM, Yang SL, Zheng XM, et al. CD133 expression and α-fetoprotein levels define novel prognostic subtypes of HBV-associated hepatocellular carcinoma: A long-term follow-up analysis. Oncol Lett, 2018, 15(3): 2985-2991.
38.	Jin Y, Liang ZY, Zhou WX, et al. Combination with CK19 might increase the prognostic power of Hep Par 1 in hepatocellular carcinoma after curative resection. J Invest Surg, 2017, 31: 1-8.
39.	Zhao Q, Zhou H, Liu Q, et al. Prognostic value of the expression of cancer stem cell-related markers CD133 and CD44 in hepatocellular carcinoma: From patients to patient-derived tumor xenograft models. Oncotarget, 2016, 7(30): 47431-47443.
40.	Dai XM, Huang T, Yang SL, et al. Peritumoral EpCAM is an independent prognostic marker after curative resection of HBV-related hepatocellular carcinoma. Dis Markers, 2017, 2017: 8495326.
41.	Chen YL, Lin PY, Ming YZ, et al. The effects of the location of cancer stem cell marker CD133 on the prognosis of hepatocellular carcinoma patients. BMC Cancer, 2017, 17(1): 474.
42.	Bahnassy AA, Zekri AR, El-Bastawisy A, et al. Circulating tumor and cancer stem cells in hepatitis C virus-associated liver disease. World J Gastroenterol, 2014, 20(48): 18240-18248.
43.	Zhou Y, Wang B, Wu J, et al. Association of preoperative EpCAM circulating tumor cells and peripheral Treg cell levels with early recurrence of hepatocellular carcinoma following radical hepatic resection. BMC Cancer, 2016, 16: 506.
44.	Hao S, Chen S, Tu C, et al. Anterior approach to improve the prognosis in hcc patients via decreasing dissemination of EpCAM⁺ circulating tumor cells. J Gastrointest Surg, 2017, 21(7): 1112-1120.
45.	Zhou DS, Wang HB, Zhou ZG, et al. TACC3 promotes stemness and is a potential therapeutic target in hepatocellular carcinoma. Oncotarget, 2015, 6(27): 24163-24177.
46.	Lin S, Zhou S, Jiang S, et al. NEK2 regulates stem-like properties and predicts poor prognosis in hepatocellular carcinoma. Oncol Rep, 2016, 36(2): 853-862.

1. Kim H, Yoo JE, Cho JY, et al. Telomere length, TERT and shelterin complex proteins in hepatocellular carcinomas expressing " stemness”-related markers. J Hepatol, 2013, 59(4): 746-752.
2. Calderaro J, Couchy G, Imbeaud S, et al. Histological subtypes of hepatocellular carcinoma are related to gene mutations and molecular tumour classification. J Hepatol, 2017, 67(4): 727-738.
3. Ma S, Chan KW, Hu L, et al. Identification and characterization of tumorigenic liver cancer stem/progenitor cells. Gastroenterology, 2007, 132(7): 2542-2556.
4. Govaere O, Roskams T. Pathogenesis and prognosis of hepatocellular carcinoma at the cellular and molecular levels. Clin Liver Dis, 2015, 19(2): 261-276.
5. 江春平. 未来肝癌治疗的新靶点—肝癌干细胞. 世界华人消化杂志, 2009, 17(8): 743-746.
6. Kim H, Park YN. Hepatocellular carcinomas expressing ‘stemness’-related markers: clinicopathological characteristics. Dig Dis, 2014, 32(6): 778-785.
7. Marquardt JU, Thorgeirsson SS. Stem cells in hepatocarcinogenesis: evidence from genomic data. Semin Liver Dis, 2010, 30(1): 26-34.
8. Thorgeirsson SS. Stemness and reprogramming in liver cancer. Hepatology, 2016, 63(4): 1068-1070.
9. Thorgeirsson SS. Stemness in liver cancer. Dig Dis, 2017, 35(4): 387-389.
10. Govaere O, Komuta M, Berkers J, et al. Keratin 19: a key role player in the invasion of human hepatocellular carcinomas. Gut, 2014, 63(4): 674-685.
11. Kim H, Choi GH, Na DC, et al. Human hepatocellular carcinomas with " Stemness”-related marker expression: keratin 19 expression and a poor prognosis. Hepatology, 2011, 54(5): 1707-1717.
12. Fartoux L, Decaens T. Contribution of biomarkers and imaging in the management of hepatocellular carcinoma. Clin Res Hepatol Gastroenterol, 2011, 35(Suppl 1): S21-S30.
13. Yamashita T, Forgues M, Wang W, et al. EpCAM and alpha-fetoprotein expression defines novel prognostic subtypes of hepatocellular carcinoma. Cancer Res, 2008, 68(5): 1451-1461.
14. 邢龙彬, 高英堂. 肝癌干细胞表面标志物研究进展. 世界华人消化杂志, 2016, 24(31): 4231-4237.
15. Chan AW, Tong JH, Chan SL, et al. Expression of stemness markers (CD133 and EpCAM) in prognostication of hepatocellular carcinoma. Histopathology, 2014, 64(7): 935-950.
16. Qiu L, Li H, Fu S, et al. Surface markers of liver cancer stem cells and innovative targeted-therapy strategies for HCC. Oncol Lett, 2018, 15(2): 2039-2048.
17. Lan X, Wu YZ, Wang Y, et al. CD133 silencing inhibits stemness properties and enhances chemoradiosensitivity in CD133-positive liver cancer stem cells. Int J Mol Med, 2013, 31(2): 315-324.
18. Fatourou E, Koskinas J, Karandrea D, et al. Keratin 19 protein expression is an independent predictor of survival in human hepatocellular carcinoma. Eur J Gastroenterol Hepatol, 2015, 27(9): 1094-1102.
19. Guo Z, Li LQ, Jiang JH, et al. Cancer stem cell markers correlate with early recurrence and survival in hepatocellular carcinoma. World J Gastroenterol, 2014, 20(8): 2098-2106.
20. Liu K, Hao M, Ouyang Y, et al. CD133⁺ cancer stem cells promoted by VEGF accelerate the recurrence of hepatocellular carcinoma. Sci Rep, 2017, 7: 41499.
21. Rozeik MS, Hammam OA, Ali AI, et al. Evaluation of CD44 and CD133 as markers of liver cancer stem cells in Egyptian patients with HCV-induced chronic liver diseases versus hepatocellular carcinoma. Electron Physician, 2017, 9(7): 4708-4717.
22. Gao Y, Ruan B, Liu W, et al. Knockdown of CD44 inhibits the invasion and metastasis of hepatocellular carcinoma both in vitro and in vivo by reversing epithelial-mesenchymal transition. Oncotarget, 2015, 6(10): 7828-7837.
23. Yamanaka C, Wada H, Eguchi H, et al. Clinical significance of CD13 and epithelial mesenchymal transition (EMT) markers in hepatocellular carcinoma. Jpn J Clin Oncol, 2018, 48(1): 52-60.
24. Hoshida Y, Toffanin S, Lachenmayer A, et al. Molecular classification and novel targets in hepatocellular carcinoma: recent advancements. Semin Liver Dis, 2010, 30(1): 35-51.
25. Lirdprapamongkol K, Chiablaem K, Sila-Asna M, et al. Exploring stemness gene expression and vasculogenic mimicry capacity in well- and poorly-differentiated hepatocellular carcinoma cell lines. Biochem Biophys Res Commun, 2012, 422(3): 429-435.
26. Tan PS, Nakagawa S, Goossens N, et al. Clinicopathological indices to predict hepatocellular carcinoma molecular classification. Liver Int, 2016, 36(1): 108-118.
27. Scheel C, Weinberg RA. Cancer stem cells and epithelial-mesenchymal transition: concepts and molecular links. Semin Cancer Biol, 2012, 22(5-6): 396-403.
28. Lo RC, Leung CO, Chok KS, et al. Variation of stemness markers expression in tumor nodules from synchronous multi-focal hepatocellular carcinoma—an immunohistochemical study. Diagn Pathol, 2017, 12(1): 56.
29. Kumagai A, Kondo F, Sano K, et al. Immunohistochemical study of hepatocyte, cholangiocyte and stem cell markers of hepatocellular carcinoma: the second report: relationship with tumor size and cell differentiation. J Hepatobiliary Pancreat Sci, 2016, 23(7): 414-421.
30. Nahm JH, Rhee H, Kim H, et al. Increased expression of stemness markers and altered tumor stroma in hepatocellular carcinoma under TACE-induced hypoxia: A biopsy and resection matched study. Oncotarget, 2017, 8(59): 99359-99371.
31. Ikemoto T, Shimada M, Yamada S. Pathophysiology of recurrent hepatocellular carcinoma after radiofrequency ablation. Hepatol Res, 2017, 47(1): 23-30.
32. Ouyang Y, Liu K, Hao M, et al. Radiofrequency ablation-increased CXCL10 is associated with earlier recurrence of hepatocellular carcinoma by promoting stemness. Tumour Biol, 2016, 37(3): 3697-3704.
33. Yamada S, Utsunomiya T, Morine Y, et al. Expressions of hypoxia-inducible factor-1 and epithelial cell adhesion molecule are linked with aggressive local recurrence of hepatocellular carcinoma after radiofrequency ablation therapy. Ann Surg Oncol, 2014, 21(Suppl 3): S436-S442.
34. Durnez A, Verslype C, Nevens F, et al. The clinicopathological and prognostic relevance of cytokeratin 7 and 19 expression in hepatocellular carcinoma. A possible progenitor cell origin. Histopathology, 2006, 49(2): 138-151.
35. Jeong HT, Kim MJ, Kim YE, et al. MRI features of hepatocellular carcinoma expressing progenitor cell markers. Liver Int, 2012, 32(3): 430-440.
36. Ma YC, Yang JY, Yan LN. Relevant markers of cancer stem cells indicate a poor prognosis in hepatocellular carcinoma patients: a meta-analysis. Eur J Gastroenterol Hepatol, 2013, 25(9): 1007-1016.
37. Dai XM, Yang SL, Zheng XM, et al. CD133 expression and α-fetoprotein levels define novel prognostic subtypes of HBV-associated hepatocellular carcinoma: A long-term follow-up analysis. Oncol Lett, 2018, 15(3): 2985-2991.
38. Jin Y, Liang ZY, Zhou WX, et al. Combination with CK19 might increase the prognostic power of Hep Par 1 in hepatocellular carcinoma after curative resection. J Invest Surg, 2017, 31: 1-8.
39. Zhao Q, Zhou H, Liu Q, et al. Prognostic value of the expression of cancer stem cell-related markers CD133 and CD44 in hepatocellular carcinoma: From patients to patient-derived tumor xenograft models. Oncotarget, 2016, 7(30): 47431-47443.
40. Dai XM, Huang T, Yang SL, et al. Peritumoral EpCAM is an independent prognostic marker after curative resection of HBV-related hepatocellular carcinoma. Dis Markers, 2017, 2017: 8495326.
41. Chen YL, Lin PY, Ming YZ, et al. The effects of the location of cancer stem cell marker CD133 on the prognosis of hepatocellular carcinoma patients. BMC Cancer, 2017, 17(1): 474.
42. Bahnassy AA, Zekri AR, El-Bastawisy A, et al. Circulating tumor and cancer stem cells in hepatitis C virus-associated liver disease. World J Gastroenterol, 2014, 20(48): 18240-18248.
43. Zhou Y, Wang B, Wu J, et al. Association of preoperative EpCAM circulating tumor cells and peripheral Treg cell levels with early recurrence of hepatocellular carcinoma following radical hepatic resection. BMC Cancer, 2016, 16: 506.
44. Hao S, Chen S, Tu C, et al. Anterior approach to improve the prognosis in hcc patients via decreasing dissemination of EpCAM⁺ circulating tumor cells. J Gastrointest Surg, 2017, 21(7): 1112-1120.
45. Zhou DS, Wang HB, Zhou ZG, et al. TACC3 promotes stemness and is a potential therapeutic target in hepatocellular carcinoma. Oncotarget, 2015, 6(27): 24163-24177.
46. Lin S, Zhou S, Jiang S, et al. NEK2 regulates stem-like properties and predicts poor prognosis in hepatocellular carcinoma. Oncol Rep, 2016, 36(2): 853-862.

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Research progress of hepatocellular carcinoma expressing “stemness”-related markers

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