CD133: a potential indicator for differentiation and prognosis of human cholangiocarcinoma

BMC Cancer

Linni Fan³  Furong He³  Hongxiang Liu²  Jin Zhu³  Yixiong Liu³  Zhiyong Yin¹  Lu Wang³  Ying Guo³  Zhe Wang³  Qingguo Yan³  Gaosheng Huang³ 

[1] Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China

[2] Department of Histopathology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 2QQ, UK

[3] State Key Laboratory of Cancer Biology and Department of Pathology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China

关键词: Prognosis;    Differentiation;    Immunohistochemistry;    Cholangiocarcinoma;    CD133;   

Others  :  1080815
DOI  :  10.1186/1471-2407-11-320

 received in 2010-12-30, accepted in 2011-07-29,  发布年份 2011

【 摘 要 】

Background

CD133 is known to be a cancer stem cell (CSC) marker. However, recent studies have revealed that CD133 is not restricted to CSC but to be expressed not only in human normal tissues but also in some cancers and could serve as a prognostic factor for the patients. Nevertheless, the expression of CD133 in human cholangiocarcinoma (CC) is rare and our study is to detect the expression and explore the potential functions of CD133 in human CC.

Methods

Fifty-nine cases, comprised of 5 normal liver tissues and 54 consecutive CC specimens (21 well-differentiated, 12 moderately-differentiated and 21 poorly-differentiated), were included in the study. Immunohistochemical stainning with CD133 protein was carried out, and statistical analyses were performed.

Results

CD133 was found to express in all 5 normal livers and 40 out of 54 (74%) CC tissues with different subcellular localization. In the well, moderately and poorly differentiated cases, the numbers of CD133 positive cases were 19 (19 of 21, 90%), 10 (10 of 12, 83%) and 11 (11 of 21, 52%) respectively. Further statistical analyses indicated that the expression and different subcellular localization of CD133 were significantly correlated with the differentiation status of tumors (P = 0.004, P = 0.009). Among 23 patients followed up for survival, the median survival was 4 months for fourteen CD133 negative patients but 14 months for nine CD133 positive ones. In univariate survival analysis, CD133 negative expression correlated with poor prognosis while CD133 positive expression predicted a favorable outcome of CC patients (P = 0.001).

Conclusions

Our study demonstrates that CD133 expression correlates with the differentiation of CC and indicates that CD133 is a potential indicator for differentiation and prognosis of human CC.

【 授权许可】

   
2011 Fan et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

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Figure 3.

【 参考文献 】

• [1]Yin AH, Miraglia S, Zanjani ED, Almeida-Porada G, Ogawa M, Leary AG, Olweus J, Kearney J, Buck DW: AC133, a novel marker for human hematopoietic stem and progenitor cells. Blood 1997, 90(12):5002-5012.
• [2]Miraglia S, Godfrey W, Yin AH, Atkins K, Warnke R, Holden JT, Bray RA, Waller EK, Buck DW: A novel five-transmembrane hematopoietic stem cell antigen: isolation, characterization, and molecular cloning. Blood 1997, 90(12):5013-5021.
• [3]Weigmann A, Corbeil D, Hellwig A, Huttner WB: Prominin, a novel microvilli-specific polytopic membrane protein of the apical surface of epithelial cells, is targeted to plasmalemmal protrusions of non-epithelial cells. Proc Natl Acad Sci USA 1997, 94(23):12425-12430.
• [4]Corbeil D, Roper K, Hellwig A, Tavian M, Miraglia S, Watt SM, Simmons PJ, Peault B, Buck DW, Huttner WB: The human AC133 hematopoietic stem cell antigen is also expressed in epithelial cells and targeted to plasma membrane protrusions. J Biol Chem 2000, 275(8):5512-5520.
• [5]Corbeil D, Roper K, Fargeas CA, Joester A, Huttner WB: Prominin: a story of cholesterol, plasma membrane protrusions and human pathology. Traffic 2001, 2(2):82-91.
• [6]Mizrak D, Brittan M, Alison MR: CD133: molecule of the moment. J Pathol 2008, 214(1):3-9.
• [7]Burkert J, Wright NA, Alison MR: Stem cells and cancer: an intimate relationship. J Pathol 2006, 209(3):287-297.
• [8]Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C, De Maria R: Identification and expansion of human colon-cancer-initiating cells. Nature 2007, 445(7123):111-115.
• [9]Todaro M, Alea MP, Di Stefano AB, Cammareri P, Vermeulen L, Iovino F, Tripodo C, Russo A, Gulotta G, Medema JP, et al.: Colon cancer stem cells dictate tumor growth and resist cell death by production of interleukin-4. Cell Stem Cell 2007, 1(4):389-402.
• [10]Collins AT, Berry PA, Hyde C, Stower MJ, Maitland NJ: Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res 2005, 65(23):10946-10951.
• [11]Kasper S: Exploring the origins of the normal prostate and prostate cancer stem cell. Stem Cell Rev 2008, 4(3):193-201.
• [12]Hermann PC, Huber SL, Herrler T, Aicher A, Ellwart JW, Guba M, Bruns CJ, Heeschen C: Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell 2007, 1(3):313-323.
• [13]Bruno S, Bussolati B, Grange C, Collino F, Graziano ME, Ferrando U, Camussi G: CD133+ renal progenitor cells contribute to tumor angiogenesis. Am J Pathol 2006, 169(6):2223-2235.
• [14]Uchida N, Buck DW, He D, Reitsma MJ, Masek M, Phan TV, Tsukamoto AS, Gage FH, Weissman IL: Direct isolation of human central nervous system stem cells. Proc Natl Acad Sci USA 2000, 97(26):14720-14725.
• [15]Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J, Dirks PB: Identification of a cancer stem cell in human brain tumors. Cancer Res 2003, 63(18):5821-5828.
• [16]Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD, Dirks PB: Identification of human brain tumour initiating cells. Nature 2004, 432(7015):396-401.
• [17]Beier D, Wischhusen J, Dietmaier W, Hau P, Proescholdt M, Brawanski A, Bogdahn U, Beier CP: CD133 expression and cancer stem cells predict prognosis in high-grade oligodendroglial tumors. Brain Pathol 2008, 18(3):370-377.
• [18]Suetsugu A, Nagaki M, Aoki H, Motohashi T, Kunisada T, Moriwaki H: Characterization of CD133+ hepatocellular carcinoma cells as cancer stem/progenitor cells. Biochem Biophys Res Commun 2006, 351(4):820-824.
• [19]Yin S, Li J, Hu C, Chen X, Yao M, Yan M, Jiang G, Ge C, Xie H, Wan D, et al.: CD133 positive hepatocellular carcinoma cells possess high capacity for tumorigenicity. Int J Cancer 2007, 120(7):1444-1450.
• [20]Immervoll H, Hoem D, Sakariassen PO, Steffensen OJ, Molven A: Expression of the "stem cell marker" CD133 in pancreas and pancreatic ductal adenocarcinomas. BMC Cancer 2008, 8:48. BioMed Central Full Text
• [21]Horst D, Kriegl L, Engel J, Kirchner T, Jung A: CD133 expression is an independent prognostic marker for low survival in colorectal cancer. Br J Cancer 2008.
• [22]Song W, Li H, Tao K, Li R, Song Z, Zhao Q, Zhang F, Dou K: Expression and clinical significance of the stem cell marker CD133 in hepatocellular carcinoma. Int J Clin Pract 2008, 62(8):1212-1218.
• [23]Shimada M, Sugimoto K, Iwahashi S, Utsunomiya T, Morine Y, Imura S, Ikemoto T: CD133 expression is a potential prognostic indicator in intrahepatic cholangiocarcinoma. J Gastroenterol 2010, 45(8):896-902.
• [24]Nakanuma YSB, Vatanasapt V, Leong AS-Y, Ponchon T, Ishak KG: Intrahepatic cholangiocarcinoma. In World Health Organization classification of tumours Pathology and genetics of tumours of the digestive system. Edited by Hamilton SR AL. Lyon: France:IARC Press; 2000:173-180.
• [25]Kojima M, Ishii G, Atsumi N, Fujii S, Saito N, Ochiai A: Immunohistochemical detection of CD133 expression in colorectal cancer: a clinicopathological study. Cancer Sci 2008, 99(8):1578-1583.
• [26]Lyman Ott ML: An introduction to statistical methods and data analysis. 6th edition. Belmont: Cengage Learning; 2008.
• [27]Florek M, Haase M, Marzesco AM, Freund D, Ehninger G, Huttner WB, Corbeil D: Prominin-1/CD133, a neural and hematopoietic stem cell marker, is expressed in adult human differentiated cells and certain types of kidney cancer. Cell Tissue Res 2005, 319(1):15-26.
• [28]Shmelkov SV, Butler JM, Hooper AT, Hormigo A, Kushner J, Milde T, St Clair R, Baljevic M, White I, Jin DK, et al.: CD133 expression is not restricted to stem cells, and both CD133+ and CD133- metastatic colon cancer cells initiate tumors. J Clin Invest 2008, 118(6):2111-2120.
• [29]Marzesco AM, Janich P, Wilsch-Brauninger M, Dubreuil V, Langenfeld K, Corbeil D, Huttner WB: Release of extracellular membrane particles carrying the stem cell marker prominin-1 (CD133) from neural progenitors and other epithelial cells. J Cell Sci 2005, 118(Pt 13):2849-2858.
• [30]Jaszai J, Janich P, Farkas LM, Fargeas CA, Huttner WB, Corbeil D: Differential expression of Prominin-1 (CD133) and Prominin-2 in major cephalic exocrine glands of adult mice. Histochem Cell Biol 2007, 128(5):409-419.
• [31]Jaszai J, Fargeas CA, Florek M, Huttner WB, Corbeil D: Focus on molecules: prominin-1 (CD133). Exp Eye Res 2007, 85(5):585-586.
• [32]Sapkota GP, Cummings L, Newell FS, Armstrong C, Bain J, Frodin M, Grauert M, Hoffmann M, Schnapp G, Steegmaier M, et al.: BI-D1870 is a specific inhibitor of the p90 RSK (ribosomal S6 kinase) isoforms in vitro and in vivo. Biochem J 2007, 401(1):29-38.
• [33]Karbanova J, Missol-Kolka E, Fonseca AV, Lorra C, Janich P, Hollerova H, Jaszai J, Ehrmann J, Kolar Z, Liebers C, et al.: The Stem Cell Marker CD133 (Prominin-1) is Expressed in Various Human Glandular Epithelia. J Histochem Cytochem 2008.
• [34]Bidlingmaier S, Zhu X, Liu B: The utility and limitations of glycosylated human CD133 epitopes in defining cancer stem cells. J Mol Med 2008, 86(9):1025-1032.
• [35]Zeppernick F, Ahmadi R, Campos B, Dictus C, Helmke BM, Becker N, Lichter P, Unterberg A, Radlwimmer B, Herold-Mende CC: Stem cell marker CD133 affects clinical outcome in glioma patients. Clin Cancer Res 2008, 14(1):123-129.
• [36]Maeda S, Shinchi H, Kurahara H, Mataki Y, Maemura K, Sato M, Natsugoe S, Aikou T, Takao S: CD133 expression is correlated with lymph node metastasis and vascular endothelial growth factor-C expression in pancreatic cancer. Br J Cancer 2008, 98(8):1389-1397.
• [37]Fargeas CA, Joester A, Missol-Kolka E, Hellwig A, Huttner WB, Corbeil D: Identification of novel Prominin-1/CD133 splice variants with alternative C-termini and their expression in epididymis and testis. J Cell Sci 2004, 117(Pt 18):4301-4311.
• [38]Shmelkov SV, Jun L, St Clair R, McGarrigle D, Derderian CA, Usenko JK, Costa C, Zhang F, Guo X, Rafii S: Alternative promoters regulate transcription of the gene that encodes stem cell surface protein AC133. Blood 2004, 103(6):2055-2061.