CD49f-positive cell population efficiently enriches colon cancer-initiating cells

Haraguchi,Naotsugu; Ishii,Hideshi; Mimori,Koshi; Ohta,Katsuya; Uemura,Mamoru; Nishimura,Junichi; Hata,Taishi; Takemasa,Ichiro; Mizushima,Tsunekazu; Yamamoto,Hirofumi; Doki,Yuichiro; Mori,Masaki

doi:10.3892/ijo.2013.1955

CD49f-positive cell population efficiently enriches colon cancer-initiating cells

Authors:
- Naotsugu Haraguchi
- Hideshi Ishii
- Koshi Mimori
- Katsuya Ohta
- Mamoru Uemura
- Junichi Nishimura
- Taishi Hata
- Ichiro Takemasa
- Tsunekazu Mizushima
- Hirofumi Yamamoto
- Yuichiro Doki
- Masaki Mori
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Affiliations: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan, Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan, Department of Surgery, Kyushu University Beppu Hospital, Beppu, Oita 874-0838, Japan
Published online on: May 24, 2013 https://doi.org/10.3892/ijo.2013.1955
Pages: 425-430

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Abstract

Cancer stem cells (CSCs) also known as cancer-initiating cells (CICs) show high tumorigenic activity and high chemo- and radiation resistance. It is, therefore, important to identify CSCs reliably to develop novel curative cancer treatments. In this study, we re-evaluated CSC markers of colorectal cancer for their cellular differentiation and tumorigenic activity, with the aim to identify reliable CSC markers. The rates of change in CD44, CD133, CD166, CD24, CD49f and CXCR4 expression during sodium butyrate (NaBT)-induced cell differentiation were assessed in HT29 and Caco2 colon cancer cell lines. Expression levels of target markers were assessed in clinical CRC samples. Tumorigenic activity was assessed on isolated cell fractions identified by multicolor flow cytometric analysis. In the cell differentiation assay, the average percent change was higher in CD44 (-98.2%) and CD49f (-74.4%) compared to CD133 (-17.9%) and CD166 (-49.4%). Expression of CD24 and CXCR4 appeared random in HT29 and Caco2. Expression of CD44, CD49f, CD133 and CD166 was confirmed in all four clinical CRC samples. Limiting dilution assay of CD44- and CD133-expressing cells revealed that only the CD133+CD44+ population possessed tumorigenic activity. Tumorigenesis was not affected by CD166 expression. Highly tumorigenic cells could be enriched in samples with higher CD49f expression; CD49f+ cells showed high tumorigenesis, whereas CD133+ and CD44+ cells that were negative for CD49f exhibited no tumorigenic activity. Multicolor analysis revealed that CD49f+ cells localized in CD44+ and CD133+ cell fractions. These findings demonstrated that CD49f is an important marker for identifying colorectal CSCs and suggest that the CD49f+ cell fraction may be the best candidate for colorectal CSCs.

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1.	Lapidot T, Sirard C, Vormoor J, et al: A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature. 367:645–648. 1994. View Article : Google Scholar : PubMed/NCBI
2.	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
3.	Kim CF, Jackson EL, Woolfenden AE, et al: Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell. 121:823–835. 2005. View Article : Google Scholar : PubMed/NCBI
4.	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
5.	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
6.	Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C and De Maria R: Identification and expansion of human colon-cancer-initiating cells. Nature. 445:111–115. 2007. View Article : Google Scholar : PubMed/NCBI
7.	Ieta K, Tanaka F, Haraguchi N, et al: Biological and genetic characteristics of tumor-initiating cells in colon cancer. Ann Surg Oncol. 15:638–648. 2007. View Article : Google Scholar : PubMed/NCBI
8.	Dalerba P, Dylla SJ, Park IK, et al: Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci USA. 104:10158–10163. 2007. View Article : Google Scholar : PubMed/NCBI
9.	Vermeulen L, Todaro M, de Sousa Mello F, et al: Single-cell cloning of colon cancer stem cells reveals a multi-lineage differentiation capacity. Proc Natl Acad Sci USA. 105:13427–13432. 2008. View Article : Google Scholar : PubMed/NCBI
10.	Huang EH, Hynes MJ, Zhang T, et al: Aldehyde dehydrogenase 1 is a marker for normal and malignant human colonic stem cells (SC) and tracks SC overpopulation during colon tumorigenesis. Cancer Res. 69:3382–3389. 2009. View Article : Google Scholar
11.	Todaro M, Francipane MG, Medema JP and Stassi G: Colon cancer stem cells: promise of targeted therapy. Gastroenterology. 138:2151–2162. 2010. View Article : Google Scholar : PubMed/NCBI
12.	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
13.	Liu R, Wang X, Chen GY, et al: The prognostic role of a gene signature from tumorigenic breast-cancer cells. N Engl J Med. 356:217–226. 2007. View Article : Google Scholar : PubMed/NCBI
14.	Pang R, Law WL, Chu AC, et al: A subpopulation of CD26⁺ cancer stem cells with metastatic capacity in human colorectal cancer. Cell Stem Cell. 6:603–615. 2010.
15.	Cordenonsi M, Zanconato F, Azzolin L, et al: The Hippo transducer TAZ confers cancer stem cell-related traits on breast cancer cells. Cell. 147:759–772. 2011. View Article : Google Scholar : PubMed/NCBI
16.	Kitayama J, Nagawa H, Tsuno N, et al: Laminin mediates tethering and spreading of colon cancer cells in physiological shear flow. Br J Cancer. 80:1927–1934. 1999. View Article : Google Scholar : PubMed/NCBI
17.	Daemi N, Thomasset N, Lissitzky JC, et al: Anti-beta4 integrin antibodies enhance migratory and invasive abilities of human colon adenocarcinoma cells and their MMP-2 expression. Int J Cancer. 85:850–856. 2000. View Article : Google Scholar : PubMed/NCBI
18.	Enns A, Gassmann P, Schlüter K, Korb T, Spiegel HU, Senninger N and Haier J: Integrins can directly mediate metastatic tumor cell adhesion within the liver sinusoids. J Gastrointest Surg. 8:1049–1059. 2004. View Article : Google Scholar : PubMed/NCBI
19.	Dydensborg AB, Teller IC, Groulx JF, et al: Integrin alpha6Bbeta4 inhibits colon cancer cell proliferation and c-Myc activity. BMC Cancer. 9:2232009. View Article : Google Scholar : PubMed/NCBI
20.	Sakthianandeswaren A, Christie M, D’Andreti C, et al: PHLDA1 expression marks the putative epithelial stem cells and contributes to intestinal tumorigenesis. Cancer Res. 71:3709–3719. 2011. View Article : Google Scholar : PubMed/NCBI
21.	Robertson JH, Yang SY, Winslet MC and Seifalian AM: Functional blocking of specific integrins inhibit colonic cancer migration. Clin Exp Metastasis. 26:769–780. 2009. View Article : Google Scholar : PubMed/NCBI
22.	Vanharanta S, Shu W, Brenet F, et al: Epigenetic expansion of VHL-HIF signal output drives multiorgan metastasis in renal cancer. Nat Med. 19:50–56. 2013. View Article : Google Scholar : PubMed/NCBI
23.	Wu B, Chien EY, Mol CD, et al: Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists. Science. 330:1066–1071. 2010. View Article : Google Scholar : PubMed/NCBI
24.	Murphy PM: Chemokines and the molecular basis of cancer metastasis. N Engl J Med. 345:833–835. 2001. View Article : Google Scholar : PubMed/NCBI
25.	Liotta LA: An attractive force in metastasis. Nature. 410:24–25. 2001. View Article : Google Scholar : PubMed/NCBI
26.	Müller A, Homey B, Soto H, et al: Involvement of chemokine receptors in breast cancer metastasis. Nature. 410:50–56. 2001.PubMed/NCBI
27.	Ikushima H, Todo T, Ino Y, Takahashi M, Miyazawa K and Miyazono K: Autocrine TGF-beta signaling maintains tumorigenicity of glioma-initiating cells through Sry-related HMG-box factors. Cell Stem Cell. 5:504–514. 2009. View Article : Google Scholar : PubMed/NCBI
28.	Piccirillo SG, Reynolds BA, Zanetti N, et al: Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells. Nature. 444:761–765. 2006. View Article : Google Scholar : PubMed/NCBI
29.	Chirasani SR, Sternjak A, Wend P, et al: Bone morphogenetic protein-7 release from endogenous neural precursor cells suppresses the tumourigenicity of stem-like glioblastoma cells. Brain. 133:1961–1972. 2010. View Article : Google Scholar : PubMed/NCBI
30.	Lombardo Y, Scopelliti A, Cammareri P, et al: Bone morphogenetic protein 4 induces differentiation of colorectal cancer stem cells and increases their response to chemotherapy in mice. Gastroenterology. 140:297–309. 2011. View Article : Google Scholar : PubMed/NCBI
31.	Haraguchi N, Ohkuma M, Sakashita H, et al: 133⁺CD44⁺ population efficiently enriches colon cancer initiating cells. Ann Surg Oncol. 15:2927–2933. 2008.
32.	Sussman NL, Eliakim R, Rubin D, Perlmutter DH, DeSchryver-Kecskemeti K and Alpers DH: Intestinal alkaline phosphatase is secreted bidirectionally from villous enterocytes. Am J Physiol. 257:G14–G23. 1989.PubMed/NCBI
33.	Augeron C and Laboisse CL: Emergence of permanently differentiated cell clones in a human colonic cancer cell line in culture after treatment with sodium butyrate. Cancer Res. 44:3961–3969. 1984.PubMed/NCBI
34.	Jo M, Eastman BM, Webb DL, Stoletov K, Klemke R and Gonias SL: Cell signaling by urokinase-type plasminogen activator receptor induces stem cell-like properties in breast cancer cells. Cancer Res. 70:8948–8958. 2010. View Article : Google Scholar : PubMed/NCBI
35.	Liao CP, Adisetiyo H, Liang M and Roy-Burman P: Cancer-associated fibroblasts enhance the gland-forming capability of prostate cancer stem cells. Cancer Res. 70:7294–7303. 2010. View Article : Google Scholar : PubMed/NCBI
36.	Lathia JD, Gallagher J, Heddleston JM, et al: Integrin alpha 6 regulates glioblastoma stem cells. Stem Cell. 6:421–432. 2010.PubMed/NCBI