World Journal of Surgical Oncology | |
Lgr5 is a potential marker of colorectal carcinoma stem cells that correlates with patient survival | |
Lin Chen1  Hong-Qing Xi1  Xiao-Song Wu1  | |
[1] Department of General Surgery, Chinese People’s Liberation Army General Hospital, 28 Fuxing Road, Beijing, 100853, China | |
关键词: Cancer stem cells; Prognosis; Lgr5; Colorectal cancer; | |
Others : 826915 DOI : 10.1186/1477-7819-10-244 |
|
received in 2012-07-01, accepted in 2012-10-31, 发布年份 2012 | |
【 摘 要 】
Background
Lgr5 (leucine-rich-repeat-containing G-protein-coupled receptor 5) has recently been identified as an intestinal stem cell marker. In order to determine whether Lgr5 is a potential marker of cancer stem cells, we investigated whether Lgr5 expression correlated with Ki-67 expression and prognosis in colorectal carcinoma.
Methods
Lgr5 and Ki-67 expression were evaluated by immunohistochemistry in 192 colorectal carcinoma specimens. Selection of side population (SP) cells was performed by staining with Hoechest 33342, and Lgr5 expression in Colo205 SP cells was then detected by immunofluorescence.
Results
Lgr5 expression was significantly higher in carcinoma than in normal mucosa (P=0.001). Lgr5 was positively correlated with histological grade (P=0.001), depth of invasion (P=0.001), lymph node metastasis (P=0.001), distant metastasis (P=0.004), pTNM stage (P=0.001), and Ki-67 (r=0.446, P=0.001). Multivariate analysis showed that the effect of Lgr5 on survival was independent of Ki-67 (P=0.037). In the in vitro study, Hoechst low-staining cells were counted in 7% of the Colo205 colon cancer cell line population, and Lgr5 expression was strikingly stronger in Hoechst low-staining cells than in high-staining cells (P=0.001).
Conclusions
These findings suggest that Lgr5 may play an important role in the progression and prognosis of colorectal carcinoma, and may be a potential new therapeutic target for the treatment of colorectal cancer patients. It may also be considered as a potential marker for colorectal cancer stem cells (CSCs).
【 授权许可】
2012 Wu et al.; licensee BioMed Central Ltd.
【 预 览 】
Files | Size | Format | View |
---|---|---|---|
20140713104529928.pdf | 2093KB | download | |
Figure 3. | 79KB | Image | download |
Figure 2. | 49KB | Image | download |
Figure 1. | 145KB | Image | download |
【 图 表 】
Figure 1.
Figure 2.
Figure 3.
【 参考文献 】
- [1]Odoux C, Fohrer H, Hoppo T, Guzik L, Stolz DB, Lewis DW, Gollin SM, Gamblin TC, Geller DA, Lagasse E: A stochastic model for cancer stem cell origin in metastatic colon cancer. Cancer Res 2008, 68:6932-6941.
- [2]Kondo T, Setoguchi T, Taga T: Persistence of a small subpopulation of cancer stem-like cells in the C6 glioma cell line. Proc Natl Acad Sci U S A 2004, 101:781-786.
- [3]Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF: Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A 2003, 100:3983-3988.
- [4]Compton CC: Colorectal carcinoma: diagnostic, prognostic, and molecular features. Mod Pathol 2003, 16:376-388.
- [5]Alwan A: World Health Organization. Disaster Med Public Health Prep 2007, 1:7-8.
- [6]Al-Hajj M, Becker MW, Wicha M, Weissman I, Clarke MF: Therapeutic implications of cancer stem cells. Curr Opin Genet Dev 2004, 14:43-47.
- [7]Becker L, Huang Q, Mashimo H: Immunostaining of Lgr5, an intestinal stem cell marker, in normal and premalignant human gastrointestinal tissue. ScientificWorldJournal 2008, 8:1168-1176.
- [8]Van der Flier LG, Sabates-Bellver J, Oving I, Haegebarth A, De Palo M, Anti M, Van Gijn ME, Suijkerbuijk S, Van de Wetering M, Marra G, Clevers H: The intestinal Wnt/TCF signature. Gastroenterology 2007, 132:628-632.
- [9]Segditsas S, Sieber O, Deheragoda M, East P, Rowan A, Jeffery R, Nye E, Clark S, Spencer-Dene B, Stamp G, Poulsom R, Suraweera N, Silver A, Ilyas M, Tomlinson I: Putative direct and indirect Wnt targets identified through consistent gene expression changes in APC-mutant intestinal adenomas from humans and mice. Hum Mol Genet 2008, 17:3864-3875.
- [10]Yamamoto Y, Sakamoto M, Fujii G, Tsuiji H, Kenetaka K, Asaka M, Hirohashi S: Overexpression of orphan G-protein-coupled receptor, Gpr49, in human hepatocellular carcinomas with beta-catenin mutations. Hepatology 2003, 37:528-533.
- [11]Barker N, van Es JH, Kuipers J, Kujala P, van den Born M, Cozijnsen M, Haegebarth A, Korving J, Begthel H, Peters PJ, Clevers H: Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 2007, 449:1003-1007.
- [12]Uchida H, Yamazaki K, Fukuma M, Yamada T, Hayashida T, Hasegawa H, Kitajima M, Kitagawa Y, Sakamoto M: Overexpression of leucine-rich repeat-containing G protein-coupled receptor 5 in colorectal cancer. Cancer Sci 2010, 101:1731-1737.
- [13]McClanahan T, Koseoglu S, Smith K, Grein J, Gustafson E, Black S, Kirschmeier P, Samatar AA: Identification of overexpression of orphan G protein-coupled receptor GPR49 in human colon and ovarian primary tumors. Cancer Biol Ther 2006, 5:419-426.
- [14]Tanese K, Fukuma M, Yamada T, Mori T, Yoshikawa T, Watanabe W, Ishiko A, Amagai M, Nishikawa T, Sakamoto M: G-protein-coupled receptor GPR49 is up-regulated in basal cell carcinoma and promotes cell proliferation and tumor formation. Am J Pathol 2008, 173:835-843.
- [15]Becker L, Huang Q, Mashimo H: Lgr5, an intestinal stem cell marker, is abnormally expressed in Barrett’s esophagus and esophageal adenocarcinoma. Dis Esophagus 2010, 23:168-174.
- [16]Barker N, Ridgway RA, van Es JH, van de Wetering M, Begthel H, van den Born M, Danenberg E, Clarke AR, Sansom OJ, Clevers H: Crypt stem cells as the cells-of-origin of intestinal cancer. Nature 2009, 457:608-611.
- [17]Vermeulen L, Todaro M, de Sousa Mello F, Sprick MR, Kemper K, Perez Alea M, Richel DJ, Stassi G, Medema JP: Single-cell cloning of colon cancer stem cells reveals a multi-lineage differentiation capacity. Proc Natl Acad Sci U S A 2008, 105:13427-13432.
- [18]Takeda K, Kinoshita I, Shimizu Y, Matsuno Y, Shichinohe T, Dosaka-Akita H: Expression of LGR5, an intestinal stem cell marker, during each stage of colorectal tumorigenesis. Anticancer Res 2011, 31:263-270.
- [19]Takahashi H, Ishii H, Nishida N, Takemasa I, Mizushima T, Ikeda M, Yokobori T, Mimori K, Yamamoto H, Sekimoto M, Doki Y, Mori M: Significance of Lgr5(+ve) cancer stem cells in the colon and rectum. Ann Surg Oncol 2011, 18:1166-1174.
- [20]Wolf NS, Kone A, Priestley GV, Bartelmez SH: In vivo and in vitro characterization of long-term repopulating primitive hematopoietic cells isolated by sequential Hoechst 33342-rhodamine 123 FACS selection. Exp Hematol 1993, 21:614-622.
- [21]Leemhuis T, Yoder MC, Grigsby S, Aguero B, Eder P, Srour EF: Isolation of primitive human bone marrow hematopoietic progenitor cells using Hoechst 33342 and Rhodamine 123. Exp Hematol 1996, 24:1215-1224.
- [22]Bradford GB, Williams B, Rossi R, Bertoncello I: Quiescence, cycling, and turnover in the primitive hematopoietic stem cell compartment. Exp Hematol 1997, 25:445-453.
- [23]Zhao P, Li Y, Lu Y: Aberrant expression of CD133 protein correlates with Ki-67 expression and is a prognostic marker in gastric adenocarcinoma. BMC Cancer 2010, 10:218. BioMed Central Full Text
- [24]Hao XP, Willis JE, Pretlow TG, Rao JS, MacLennan GT, Talbot IC, Pretlow TP: Loss of fragile histidine triad expression in colorectal carcinomas and premalignant lesions. Cancer Res 2000, 60:18-21.
- [25]Fan XS, Wu HY, Yu HP, Zhou Q, Zhang YF, Huang Q: Expression of Lgr5 in human colorectal carcinogenesis and its potential correlation with beta-catenin. Int J Colorectal Dis 2010, 25:583-590.
- [26]Hirschmann-Jax C, Foster AE, Wulf GG, Nuchtern JG, Jax TW, Gobel U, Goodell MA, Brenner MK: A distinct “side population” of cells with high drug efflux capacity in human tumor cells. Proc Natl Acad Sci U S A 2004, 101:14228-14233.
- [27]Goodell MA, Brose K, Paradis G, Conner AS, Mulligan RC: Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. J Exp Med 1996, 183:1797-1806.
- [28]Al-Hajj M: Cancer stem cells and oncology therapeutics. Curr Opin Oncol 2007, 19:61-64.
- [29]Dirks PB: Cancer: stem cells and brain tumours. Nature 2006, 444:687-688.
- [30]Setoguchi T, Taga T, Kondo T: Cancer stem cells persist in many cancer cell lines. Cell Cycle 2004, 3:414-415.
- [31]Massard C, Deutsch E, Soria JC: Tumour stem cell-targeted treatment: elimination or differentiation. Ann Oncol 2006, 17:1620-1624.
- [32]Huang J, Chen K, Gong W, Dunlop NM, Wang JM: G-protein coupled chemoattractant receptors and cancer. Front Biosci 2008, 13:3352-3363.
- [33]Jaks V, Barker N, Kasper M, van Es JH, Snippert HJ, Clevers H, Toftgard R: Lgr5 marks cycling, yet long-lived, hair follicle stem cells. Nat Genet 2008, 40:1291-1299.
- [34]Ieta K, Tanaka F, Haraguchi N, Kita Y, Sakashita H, Mimori K, Matsumoto T, Inoue H, Kuwano H, Mori M: Biological and genetic characteristics of tumor-initiating cells in colon cancer. Ann Surg Oncol 2008, 15:638-648.
- [35]Patrawala L, Calhoun T, Schneider-Broussard R, Zhou J, Claypool K, Tang DG: Side population is enriched in tumorigenic, stem-like cancer cells, whereas ABCG2+ and ABCG2- cancer cells are similarly tumorigenic. Cancer Res 2005, 65:6207-6219.
- [36]Telford WG, Frolova EG: Discrimination of the Hoechst side population in mouse bone marrow with violet and near-ultraviolet laser diodes. Cytometry A 2004, 57:45-52.
- [37]O’Brien CA, Pollett A, Gallinger S, Dick JE: A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 2007, 445:106-110.
- [38]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, 445:111-115.
- [39]Choi D, Lee HW, Hur KY, Kim JJ, Park GS, Jang SH, Song YS, Jang KS, Paik SS: Cancer stem cell markers CD133 and CD24 correlate with invasiveness and differentiation in colorectal adenocarcinoma. World J Gastroenterol 2009, 15:2258-2264.
- [40]Shmelkov SV, Butler JM, Hooper AT, Hormigo A, Kushner J, Milde T, St Clair R, Baljevic M, White I, Jin DK, Chadburn A, Murphy AJ, Valenzuela DM, Gale NW, Thurston G, Yancopoulos GD, D’Angelica M, Kemeny N, Lyden D, Rafii S: CD133 expression is not restricted to stem cells, and both CD133+ and CD133- metastatic colon cancer cells initiate tumors. J Clin Invest 2008, 118:2111-2120.
- [41]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, 99:1285-1289.
- [42]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, 99:1578-1583.