p75 neurotrophin receptor expression is a characteristic of the mitotically quiescent cancer stem cell population present in esophageal squamous cell carcinoma

Yamaguchi,Tetsuji; Okumura,Tomoyuki; Hirano,Katsuhisa; Watanabe,Toru; Nagata,Takuya; Shimada,Yutaka; Tsukada,Kazuhiro

doi:10.3892/ijo.2016.3432

p75 neurotrophin receptor expression is a characteristic of the mitotically quiescent cancer stem cell population present in esophageal squamous cell carcinoma

Authors:
- Tetsuji Yamaguchi
- Tomoyuki Okumura
- Katsuhisa Hirano
- Toru Watanabe
- Takuya Nagata
- Yutaka Shimada
- Kazuhiro Tsukada
View Affiliations

Affiliations: Department of Surgery and Science, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama City, Toyama 930-0194, Japan, Department of Nanobio Drug Discovery, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
Published online on: March 10, 2016 https://doi.org/10.3892/ijo.2016.3432
Pages: 1943-1954

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

Mitotically quiescent cancer stem cells (CSC) are hypothesized to exhibit a more aggressive phenotype involving greater therapeutic resistance and metastasis. The aim of our study was to develop a method for identifying quiescent CSC in esophageal squamous cell carcinoma (ESCC) based on their expression of the p75 neurotrophin receptor (p75NTR) and other proposed CSC markers, such as CD44 and CD90. Double immunostaining of surgical ESCC specimens revealed that the mean Ki-67-labeling index of the p75NTR-positive cells was significantly lower than that of the p75NTR-negative cells. Real-time PCR analysis of sorted fractions of ESCC cell lines (KYSE cells) revealed that stem cell-related genes (Nanog, p63 and Bmi-1) and epithelial-mesenchymal transition (EMT)-related genes (N-cadherin and fibronectin) were expressed at significantly higher levels in the p75NTR-positive fractions than in the CD44-positive or CD90-positive fractions. In addition, the p75NTR-positive fractions exhibited significantly higher colony formation in vitro, significantly enhanced tumor formation in mice, and significantly greater chemoresistance against cisplatin (CDDP) than the CD44‑positive or CD90‑positive fractions. Furthermore, in both the cultured cells and those from the mouse xenograft tumors, the p75NTR‑positive/CD44-negative and p75NTR‑positive/CD90-negative KYSE cell fractions contained significantly higher proportions of mitotically quiescent cells. These results suggest that the mitotically quiescent CSC population in ESCC can be identified and isolated based on their p75NTR expression, providing researchers with a novel diagnostic and therapeutic target.

View Figures

View References

1	Li L and Bhatia R: Stem cell quiescence. Clin Cancer Res. 17:4936–4941. 2011. View Article : Google Scholar : PubMed/NCBI
2	Pece S, Tosoni D, Confalonieri S, Mazzarol G, Vecchi M, Ronzoni S, Bernard L, Viale G, Pelicci PG and Di Fiore PP: Biological and molecular heterogeneity of breast cancers correlates with their cancer stem cell content. Cell. 140:62–73. 2010. View Article : Google Scholar : PubMed/NCBI
3	Okumura T, Shimada Y, Imamura M and Yasumoto S: Neurotrophin receptor p75(NTR) characterizes human esophageal keratinocyte stem cells in vitro. Oncogene. 22:4017–4026. 2003. View Article : Google Scholar : PubMed/NCBI
4	Okumura T, Shimada Y, Sakurai T, Hori R, Nagata T, Sakai Y and Tsukada K: Abnormal cell proliferation in the p75NTR-positive basal cell compartment of the esophageal epithelium during squamous carcinogenesis. Dis Esophagus. 28:634–643. 2015. View Article : Google Scholar
5	Okumura T, Tsunoda S, Mori Y, Ito T, Kikuchi K, Wang TC, Yasumoto S and Shimada Y: The biological role of the low-affinity p75 neurotrophin receptor in esophageal squamous cell carcinoma. Clin Cancer Res. 12:5096–5103. 2006. View Article : Google Scholar : PubMed/NCBI
6	Huang SD, Yuan Y, Liu XH, Gong DJ, Bai CG, Wang F, Luo JH and Xu ZY: Self-renewal and chemotherapy resistance of p75NTR positive cells in esophageal squamous cell carcinomas. BMC Cancer. 9:92009. View Article : Google Scholar : PubMed/NCBI
7	Zhao JS, Li WJ, Ge D, Zhang PJ, Li JJ, Lu CL, Ji XD, Guan DX, Gao H, Xu LY, et al: Tumor initiating cells in esophageal squamous cell carcinomas express high levels of CD44. PLoS One. 6:e214192011. View Article : Google Scholar : PubMed/NCBI
8	Tang KH, Dai YD, Tong M, Chan YP, Kwan PS, Fu L, Qin YR, Tsao SW, Lung HL, Lung ML, et al: A CD90(+) tumor-initiating cell population with an aggressive signature and metastatic capacity in esophageal cancer. Cancer Res. 73:2322–2332. 2013. View Article : Google Scholar : PubMed/NCBI
9	Shimada Y, Okumura T, Sekine S, Moriyama M, Sawada S, Matsui K, Yoshioka I, Hojo S, Yoshida T, Nagata T, et al: Expression analysis of iPS cell - inductive genes in esophageal squamous cell carcinoma by tissue microarray. Anticancer Res. 32:5507–5514. 2012.PubMed/NCBI
10	Shimada Y, Imamura M, Wagata T, Yamaguchi N and Tobe T: Characterization of 21 newly established esophageal cancer cell lines. Cancer. 69:277–284. 1992. View Article : Google Scholar : PubMed/NCBI
11	Sekine S, Shimada Y, Nagata T, Moriyama M, Omura T, Yoshioka I, Hori R, Matsui K, Sawada S, Okumura T, et al: Establishment and characterization of a new human gallbladder carcinoma cell line. Anticancer Res. 32:3211–3218. 2012.PubMed/NCBI
12	Dick JE: Stem cell concepts renew cancer research. Blood. 112:4793–4807. 2008. View Article : Google Scholar : PubMed/NCBI
13	Liotta F, Querci V, Mannelli G, Santarlasci V, Maggi L, Capone M, Rossi MC, Mazzoni A, Cosmi L, Romagnani S, et al: Mesenchymal stem cells are enriched in head neck squamous cell carcinoma, correlates with tumour size and inhibit T-cell proliferation. Br J Cancer. 112:745–754. 2015. View Article : Google Scholar : PubMed/NCBI
14	Chung MT, Liu C, Hyun JS, Lo DD, Montoro DT, Hasegawa M, Li S, Sorkin M, Rennert R, Keeney M, et al: CD90 (Thy-1)-positive selection enhances osteogenic capacity of human adipose-derived stromal cells. Tissue Eng Part A. 19:989–997. 2013. View Article : Google Scholar :
15	Haeryfar SMM and Hoskin DW: Thy-1: More than a mouse pan-T cell marker. J Immunol. 173:3581–3588. 2004. View Article : Google Scholar : PubMed/NCBI
16	Tsunoda S, Okumura T, Ito T, Mori Y, Soma T, Watanabe G, Kaganoi J, Itami A, Sakai Y and Shimada Y: Significance of nerve growth factor overexpression and its autocrine loop in oesophageal squamous cell carcinoma. Br J Cancer. 95:322–330. 2006. View Article : Google Scholar : PubMed/NCBI
17	Roesch A, Fukunaga-Kalabis M, Schmidt EC, Zabierowski SE, Brafford PA, Vultur A, Basu D, Gimotty P, Vogt T and Herlyn M: A temporarily distinct subpopulation of slow-cycling melanoma cells is required for continuous tumor growth. Cell. 141:583–594. 2010. View Article : Google Scholar : PubMed/NCBI
18	Gao MQ, Choi YP, Kang S, Youn JH and Cho NH: CD24⁺ cells from hierarchically organized ovarian cancer are enriched in cancer stem cells. Oncogene. 29:2672–2680. 2010. View Article : Google Scholar : PubMed/NCBI
19	Dembinski JL and Krauss S: Characterization and functional analysis of a slow cycling stem cell-like subpopulation in pancreas adenocarcinoma. Clin Exp Metastasis. 26:611–623. 2009. View Article : Google Scholar : PubMed/NCBI
20	Mani SA, Guo W, Liao M-J, Eaton EN, Ayyanan A, Zhou AY, Brooks M, Reinhard F, Zhang CC, Shipitsin M, et al: The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 133:704–715. 2008. View Article : Google Scholar : PubMed/NCBI
21	Roeder I, Horn M, Glauche I, Hochhaus A, Mueller MC and Loeffler M: Dynamic modeling of imatinib-treated chronic myeloid leukemia: Functional insights and clinical implications. Nat Med. 12:1181–1184. 2006. View Article : Google Scholar : PubMed/NCBI
22	Zhang B, Strauss AC, Chu S, Li M, Ho Y, Shiang KD, Snyder DS, Huettner CS, Shultz L, Holyoake T, et al: Effective targeting of quiescent chronic myelogenous leukemia stem cells by histone deacetylase inhibitors in combination with imatinib mesylate. Cancer Cell. 17:427–442. 2010. View Article : Google Scholar : PubMed/NCBI
23	Tomellini E, Touil Y, Lagadec C, Julien S, Ostyn P, Ziental-Gelus N, Meignan S, Lengrand J, Adriaenssens E, Polakowska R, et al: Nerve growth factor and proNGF simultaneously promote symmetric self-renewal, quiescence, and epithelial to mesenchymal transition to enlarge the breast cancer stem cell compartment. Stem Cells. 33:342–353. 2015. View Article : Google Scholar
24	Wilson A, Laurenti E, Oser G, van der Wath RC, Blanco-Bose W, Jaworski M, Offner S, Dunant CF, Eshkind L, Bockamp E, et al: Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair. Cell. 135:1118–1129. 2008. View Article : Google Scholar : PubMed/NCBI
25	Buczacki S, Davies RJ and Winton DJ: Stem cells, quiescence and rectal carcinoma: An unexplored relationship and potential therapeutic target. Br J Cancer. 105:1253–1259. 2011. View Article : Google Scholar : PubMed/NCBI
26	Chaffer CL, Marjanovic ND, Lee T, Bell G, Kleer CG, Reinhardt F, D'Alessio AC, Young RA and Weinberg RA: Poised chromatin at the ZEB1 promoter enables breast cancer cell plasticity and enhances tumorigenicity. Cell. 154:61–74. 2013. View Article : Google Scholar : PubMed/NCBI