CD133 expression predicts lung metastasis and poor prognosis in osteosarcoma patients: A clinical and experimental study

He,Aina; Qi,Weixiang; Huang,Yujing; Feng,Tao; Chen,Jie; Sun,Yuanjue; Shen,Zan; Yao,Yang

doi:10.3892/etm.2012.603

CD133 expression predicts lung metastasis and poor prognosis in osteosarcoma patients: A clinical and experimental study

Authors:
- Aina He
- Weixiang Qi
- Yujing Huang
- Tao Feng
- Jie Chen
- Yuanjue Sun
- Zan Shen
- Yang Yao
View Affiliations

Affiliations: Department of Oncology, The Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai 200233, P.R. China, Department of Pathology, The Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai 200233, P.R. China
Published online on: June 8, 2012 https://doi.org/10.3892/etm.2012.603
Pages: 435-441

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Identifying prognostic factors for osteosarcoma (OS) aids in the selection of patients who require more aggressive management. CD133 has been found to be a prognostic factor of certain tumor types. However, the association between CD133 expression and the prognosis of OS remains unknown. In this study, we analyzed the association of CD133 expression in OS with clinical factors and overall survival, and further investigated its potential role in metastasis in vitro. We found CD133 expression in 65.7% (46/70) of OS samples using immunohistochemistry, and it was positively correlated with lung metastasis analyzed by Chi-square test (P=0.002) and shorter overall survival time using the Kaplan-Meier method compared by log-rank test (P=0.000). Multivariate analysis showed that CD133 expression was an independent prognostic factor of patients with OS. To test for direct participation of CD133, we separated CD133+ and CD133- cells in the MG63 cell line using magnetic-activated cell sorting and found that CD133+ cells were more active in migration by scratch wound-healing assay and invasion by Matrigel invasion assay compared with CD133- cells. Elevated mRNA expression of the stemness gene octamer-binding transcription factor 4 (Oct-4) and NANOG, and the metastasis-related receptor C-X-C chemokine receptor type 4 (CXCR4) were also found in CD133+ cells by reverse transcription-polymerase chain reaction. Thus, expression of CD133 was correlated with lung metastasis and poor prognosis in OS patients. CD133+ cells may be a type of cancer stem cell with high expression of self-renewal capacity and metastasis-related genes.

View Figures

View References

1.	Arndt CA and Crist WM: Common musculoskeletal tumors of childhood and adolescence. N Engl J Med. 341:342–352. 1999. View Article : Google Scholar : PubMed/NCBI
2.	Ottaviani G and Jaffe N: The epidemiology of osteosarcoma. Cancer Treat Res. 152:3–13. 2009. View Article : Google Scholar
3.	Ozaki T, Flege S, Kevric M, et al: Osteosarcoma of the pelvis: experience of the Cooperative Osteosarcoma Study Group. J Clin Oncol. 21:334–341. 2003. View Article : Google Scholar : PubMed/NCBI
4.	Saeter G, Hoie J, Stenwig AE, Johansson AK, Hannisdal E and Solheim OP: Systemic relapse of patients with osteogenic sarcoma. Prognostic factors for long term survival. Cancer. 75:1084–1093. 1995. View Article : Google Scholar : PubMed/NCBI
5.	Tabone MD, Kalifa C, Rodary C, Raquin M, Valteau-Couanet D and Lemerle J: Osteosarcoma recurrences in pediatric patients previously treated with intensive chemotherapy. J Clin Oncol. 12:2614–2620. 1994.PubMed/NCBI
6.	Ham SJ, Schraffordt Koops H, van der Graaf WT, van Horn JR, Postma L and Hoekstra HJ: Historical, current and future aspects of osteosarcoma treatment. Eur J Surg Oncol. 24:584–600. 1998. View Article : Google Scholar : PubMed/NCBI
7.	Lin F, Zheng SE, Shen Z, et al: Relationships between levels of CXCR4 and VEGF and blood-borne metastasis and survival in patients with osteosarcoma. Med Oncol. 28:649–653. 2010. View Article : Google Scholar : PubMed/NCBI
8.	Lee JA, Kim MS, Kim DH, et al: Relative tumor burden predicts metastasis-free survival in pediatric osteosarcoma. Pediatr Blood Cancer. 50:195–200. 2008. View Article : Google Scholar : PubMed/NCBI
9.	Yang J, Yang D, Cogdell D, et al: APEX1 gene amplification and its protein overexpression in osteosarcoma: correlation with recurrence, metastasis, and survival. Technol Cancer Res Treat. 9:161–169. 2010. View Article : Google Scholar : PubMed/NCBI
10.	Yin AH, Miraglia S, Zanjani ED, et al: AC133, a novel marker for human hematopoietic stem and progenitor cells. Blood. 90:5002–5012. 1997.PubMed/NCBI
11.	Weigmann A, Corbeil D, Hellwig A and 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. 94:12425–12430. 1997. View Article : Google Scholar
12.	Yin S, Li J, Hu C, et al: CD133 positive hepatocellular carcinoma cells possess high capacity for tumorigenicity. Int J Cancer. 120:1444–1450. 2007. View Article : Google Scholar : PubMed/NCBI
13.	Monzani E, Facchetti F, Galmozzi E, et al: Melanoma contains CD133 and ABCG2 positive cells with enhanced tumourigenic potential. Eur J Cancer. 43:935–946. 2007. View Article : Google Scholar : PubMed/NCBI
14.	Terry J and Nielsen T: Expression of CD133 in synovial sarcoma. Appl Immunohistochem Mol Morphol. 18:159–165. 2009. View Article : Google Scholar
15.	Tirino V, Desiderio V, d’Aquino R, et al: Detection and characterization of CD133⁺ cancer stem cells in human solid tumours. PLoS One. 3:e34692008. View Article : Google Scholar : PubMed/NCBI
16.	Li J, Liu W, Zhao K, et al: Diallyl trisulfide reverses drug resistance and lowers the ratio of CD133⁺ cells in conjunction with methotrexate in a human osteosarcoma drug-resistant cell subline. Mol Med Report. 2:245–252. 2009.PubMed/NCBI
17.	Veselska R, Hermanova M, Loja T, et al: Nestin expression in osteosarcomas and derivation of nestin/CD133 positive osteosarcoma cell lines. BMC Cancer. 8:3002008. View Article : Google Scholar : PubMed/NCBI
18.	Song W, Li H, Tao K, et al: Expression and clinical significance of the stem cell marker CD133 in hepatocellular carcinoma. Int J Clin Pract. 62:1212–1218. 2008. View Article : Google Scholar : PubMed/NCBI
19.	Horst D, Kriegl L, Engel J, Kirchner T and Jung A: CD133 expression is an independent prognostic marker for low survival in colorectal cancer. Br J Cancer. 99:1285–1289. 2008. View Article : Google Scholar : PubMed/NCBI
20.	Zhang J, Guo X, Chang DY, Rosen DG, Mercado-Uribe I and Liu J: CD133 expression associated with poor prognosis in ovarian cancer. Mod Pathol. 25:456–464. 2011. View Article : Google Scholar
21.	Qin Q, Sun Y, Fei M, et al: Expression of putative stem marker nestin and CD133 in advanced serous ovarian cancer. Neoplasma. 1–2. 2012.PubMed/NCBI
22.	Fan L, He F, Liu H, et al: CD133: a potential indicator for differentiation and prognosis of human cholangiocarcinoma. BMC Cancer. 11:3202011. View Article : Google Scholar : PubMed/NCBI
23.	Li S, Li Z, Guo F, et al: miR-223 regulates migration and invasion by targeting Artemin in human esophageal carcinoma. J Biomed Sci. 18:242011. View Article : Google Scholar : PubMed/NCBI
24.	Kojima M, Ishii G, Atsumi N, Fujii S, Saito N and Ochiai A: Immunohistochemical detection of CD133 expression in colorectal cancer: a clinicopathological study. Cancer Sci. 99:1578–1583. 2008. View Article : Google Scholar : PubMed/NCBI
25.	Tang N, Song WX, Luo J, Haydon RC and He TC: Osteosarcoma development and stem cell differentiation. Clin Orthop Relat Res. 466:2114–2130. 2008. View Article : Google Scholar : PubMed/NCBI
26.	Wion D and Berger F: Cancer stem cells. N Engl J Med. 355:2703author reply 2703. 2006. View Article : Google Scholar : PubMed/NCBI
27.	Pardal R, Clarke MF and Morrison SJ: Applying the principles of stem-cell biology to cancer. Nat Rev Cancer. 3:895–902. 2003. View Article : Google Scholar : PubMed/NCBI
28.	Liu B, Ma W, Jha RK and Gurung K: Cancer stem cells in osteosarcoma: recent progress and perspective. Acta Oncol. 50:1142–1150. 2011. View Article : Google Scholar : PubMed/NCBI
29.	Gibbs CP, Kukekov VG, Reith JD, et al: Stem-like cells in bone sarcomas: implications for tumorigenesis. Neoplasia. 7:967–976. 2005. View Article : Google Scholar : PubMed/NCBI
30.	Singh SK, Hawkins C, Clarke ID, et al: Identification of human brain tumour initiating cells. Nature. 432:396–401. 2004. View Article : Google Scholar : PubMed/NCBI
31.	Ricci-Vitiani L, Lombardi DG, Pilozzi E, et al: Identification and expansion of human colon-cancer-initiating cells. Nature. 445:111–115. 2007. View Article : Google Scholar : PubMed/NCBI
32.	Niwa H, Miyazaki J and Smith AG: Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells. Nat Genet. 24:372–376. 2000. View Article : Google Scholar : PubMed/NCBI
33.	Looijenga LH, Stoop H, de Leeuw HP, et al: POU5F1 (OCT3/4) identifies cells with pluripotent potential in human germ cell tumors. Cancer Res. 63:2244–2250. 2003.PubMed/NCBI
34.	Mitsui K, Tokuzawa Y, Itoh H, et al: The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Cell. 113:631–642. 2003. View Article : Google Scholar : PubMed/NCBI
35.	Wang L, Park P and Lin CY: Characterization of stem cell attributes in human osteosarcoma cell lines. Cancer Biol Ther. 8:543–552. 2009. View Article : Google Scholar : PubMed/NCBI
36.	Hermann PC, Huber SL, Herrler T, et al: Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell. 1:313–323. 2007. View Article : Google Scholar : PubMed/NCBI
37.	Adhikari AS, Agarwal N, Wood BM, et al: CD117 and Stro-1 identify osteosarcoma tumor-initiating cells associated with metastasis and drug resistance. Cancer Res. 70:4602–4612. 2010. View Article : Google Scholar : PubMed/NCBI