Molecular characterization of CD133+ cancer stem-like cells in endometrial cancer

Nakamura,Mitsuhiro; Zhang,Xiuzhi; Mizumoto,Yasunari; Maida,Yoshiko; Bono,Yukiko; Takakura,Masahiro; Kyo,Satoru

doi:10.3892/ijo.2013.2230

Molecular characterization of CD133+ cancer stem-like cells in endometrial cancer

Authors:
- Mitsuhiro Nakamura
- Xiuzhi Zhang
- Yasunari Mizumoto
- Yoshiko Maida
- Yukiko Bono
- Masahiro Takakura
- Satoru Kyo
View Affiliations

Affiliations: Department of Obstetrics and Gynecology, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa 920-8641, Japan
Published online on: December 23, 2013 https://doi.org/10.3892/ijo.2013.2230
Pages: 669-677

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

A small subset of cells with CD133 expression is thought to have increased chemoresistance and tumorigenicity, features of cancer stem cells (CSCs); the molecular mechanisms by which these properties arise remain unclear. We characterized CD133+ endometrial cancer cells based on microarray analyses of Ishikawa cells. Of the genes upregulated in CD133+ cells compared with CD133- cells, we noted several key factors involved in the aggressive behavior of cells, including ABCG2 and matrix metalloproteinase (MMP). Flow cytometric analyses identified a side-cell population (SP) with CSC features in Ishikawa cells, and they were found to be more enriched in CD133+ cells than CD133- cells. In particular, CD133+/SP cells exhibited higher proliferative and colony‑forming activity than CD133+/non-SP cells. Matrigel invasion assay revealed that CD133+ cells have enhanced invasive capacity with elevated MT1-MMP expression. siRNA‑based knockdown of MT1-MMP largely abolished the invasive capacity of CD133+ cells, but not CD133- cells due to low levels of constitutive MT1-MMP1 expression. These findings demonstrate that increased chemoresistance and tumorigenic potential of CD133+ cells are at least partly attributed to an enriched SP fraction as well as increased MMP-1 expression. These results will be of assistance in the establishment of molecular target therapy to CSCs in endometrial cancer.

View Figures

View References

1.	Matsuda T, Marugame T, Kamo K, et al: Cancer incidence and incidence rates in Japan in 2006: Based on data from 15 population-based cancer registries in the monitoring of cancer incidence in Japan (MCIJ) project. Jpn J Clin Oncol. 42:139–147. 2012. View Article : Google Scholar : PubMed/NCBI
2.	Kyo S: Endometrial cancer stem cells: Are they a possible therapeutic target? Curr Obstet Gynecol Rep. 2:1–10. 2013. View Article : Google Scholar
3.	Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ and Clarke MF: Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA. 100:3983–3988. 2003. View Article : Google Scholar : PubMed/NCBI
4.	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
5.	Bao S, Wu Q, McLendon RE, Hao Y, Shi Q and Hjelmeland AB: Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 444:756–760. 2006. View Article : Google Scholar : PubMed/NCBI
6.	Gu G, Yuan J, Wills M and Kasper S: Prostate cancer cells with stem cell characteristics reconstitute the original human tumor in vivo. Cancer Res. 67:4807–4815. 2007. View Article : Google Scholar : PubMed/NCBI
7.	Miki J, Furusato B, Li H, et al: Identification of putative stem cell markers, CD133 and CXCR4, in hTERT-immortalized primary nonmalignant and malignant tumor-derived human prostate epithelial cell lines and in prostate cancer specimens. Cancer Res. 67:3153–3161. 2007. View Article : Google Scholar
8.	Eramo A, Lotti F, Sette G, et al: Identification and expansion of the tumorigenic lung cancer stem cell population. Cell Death Differ. 15:504–514. 2008. View Article : Google Scholar : PubMed/NCBI
9.	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
10.	O’Brien CA, Pollett A, Gallinger S and Dick JE: A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature. 445:106–110. 2007.PubMed/NCBI
11.	Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M and Peschle C: Identification and expansion of human colon cancer - initiating cells. Nature. 445:111–115. 2007. View Article : Google Scholar : PubMed/NCBI
12.	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
13.	Rutella S, Bonanno G, Procoli A, et al: Cells with characteristics of cancer stem/progenitor cells express the CD133 antigen in human endometrial tumors. Clin Cancer Res. 15:4299–4311. 2009. View Article : Google Scholar : PubMed/NCBI
14.	Nakamura M, Kyo S, Zhang B, et al: Prognostic impact of CD133 expression as a tumor-initiating cell marker in endometrial cancer. Hum Pathol. 41:1516–1529. 2010. View Article : Google Scholar : PubMed/NCBI
15.	Nakamura M, Bodily JM, Beglin M, Kyo S, Inoue M and Laimins LA: Hypoxia-specific stabilization of HIF-1alpha by human papillomaviruses. Virology. 387:442–448. 2009. View Article : Google Scholar : PubMed/NCBI
16.	Mizumoto Y, Kyo S, Mori N, et al: Activation of ERK1/2 occurs independently of KRAS or BRAF status in endometrial cancer and is associated with favorable prognosis. Cancer Sci. 98:652–658. 2007. View Article : Google Scholar : PubMed/NCBI
17.	Mizumoto Y, Kyo S, Ohno S, et al: Creation of tumorigenic human endometrial epithelial cells with intact chromosomes by introducing defined genetic elements. Oncogene. 25:5673–5682. 2006. View Article : Google Scholar : PubMed/NCBI
18.	Kato K, Takao T, Kuboyama A, et al: Endometrial cancer side-population cells show prominent migration and have a potential to differentiate into the mesenchymal cell lineage. Am J Pathol. 176:381–392. 2010. View Article : Google Scholar : PubMed/NCBI
19.	Visvader JE and Lindeman GJ: Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer. 8:755–768. 2008. View Article : Google Scholar : PubMed/NCBI
20.	Maeda S, Shinchi H, Kurahara H, et al: CD133 expression is correlated with lymph node metastasis and vascular endothelial growth factor-C expression in pancreatic cancer. Br J Cancer. 98:1389–1397. 2008. View Article : Google Scholar : PubMed/NCBI
21.	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
22.	Ma S, Lee TK, Zheng BJ, Chan KW and Guan XY: CD133⁺ HCC cancer stem cells confer chemoresistance by preferential expression of the Akt/PKB survival pathway. Oncogene. 27:1749–1758. 2008.
23.	Kim M, Turnquist H, Jackson J, et al: The multidrug resistance transporter ABCG2 (breast cancer resistance protein 1) effluxes Hoechst 33342 and is overexpressed in hematopoietic stem cells. Clin Cancer Res. 8:22–28. 2002.PubMed/NCBI
24.	Doyle LA and Ross DD: Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2). Oncogene. 22:7340–7358. 2003. View Article : Google Scholar : PubMed/NCBI
25.	Chiba T, Kita K, Zheng YW, et al: Side population purified from hepatocellular carcinoma cells harbors cancer stem cell-like properties. Hepatology. 44:240–251. 2006. View Article : Google Scholar : PubMed/NCBI
26.	Ho MM, Ng AV, Lam S and Hung JY: Side population in human lung cancer cell lines and tumors is enriched with stem-like cancer cells. Cancer Res. 67:4827–4833. 2007. View Article : Google Scholar : PubMed/NCBI
27.	Szotek PP, Pieretti-Vanmarcke R, Masiakos PT, et al: Ovarian cancer side population defines cells with stem cell-like characteristics and Mullerian Inhibiting Substance responsiveness. Proc Natl Acad Sci USA. 103:11154–11159. 2006. View Article : Google Scholar : PubMed/NCBI
28.	Christgen M, Ballmaier M, Bruchhardt H, von Wasielewski R, Kreipe H and Lehmann U: Identification of a distinct side population of cancer cells in the Cal-51 human breast carcinoma cell line. Mol Cell Biochem. 306:201–212. 2007. View Article : Google Scholar : PubMed/NCBI
29.	Wang YH, Li F, Luo B, et al: A side population of cells from a human pancreatic carcinoma cell line harbors cancer stem cell characteristics. Neoplasma. 56:371–378. 2009. View Article : Google Scholar : PubMed/NCBI
30.	Annabi B, Rojas-Sutterlin S, Laflamme C, et al: Tumor environment dictates medulloblastoma cancer stem cell expression and invasive phenotype. Mol Cancer Res. 6:907–916. 2008. View Article : Google Scholar : PubMed/NCBI
31.	Kohga K, Tatsumi T, Takehara T, et al: Expression of CD133 confers malignant potential by regulating metalloproteinases in human hepatocellular carcinoma. J Hepatol. 52:872–879. 2010. View Article : Google Scholar : PubMed/NCBI
32.	Kabashima A, Higuchi H, Takaishi H, et al: Side population of pancreatic cancer cells predominates in TGF-beta-mediated epithelial to mesenchymal transition and invasion. Int J Cancer. 124:2771–2279. 2009. View Article : Google Scholar : PubMed/NCBI
33.	Armstrong AJ, Marengo MS, Oltean S, et al: Circulating tumor cells from patients with advanced prostate and breast cancer display both epithelial and mesenchymal markers. Mol Cancer Res. 9:997–1007. 2011. View Article : Google Scholar : PubMed/NCBI
34.	Oda K, Arakawa H, Tanaka T, et al: p53AIP1, a potential mediator of p53-dependent apoptosis, and its regulation by Ser-46-phosphorylated p53. Cell. 102:849–862. 2000. View Article : Google Scholar : PubMed/NCBI