Abstract
CD133 (prominin-1) is a transmembrane glycoprotein expressed on the surface of normal and cancer stem cells (tumor-initiating cells), progenitor cells, rod photoreceptor cells and a variety of epithelial cells. Although CD133 is widely used as a marker of various somatic and putative cancer stem cells, its contribution to the fundamental properties of cancer cells, such as tumorigenesis and differentiation, remains to be elucidated. In the present report, we found that CD133 was expressed in several neuroblastoma (NB) cell lines/tumor samples. Intriguingly, CD133 repressed NB cell differentiation, for example neurite extension and the expression of differentiation marker proteins, and was decreased by several differentiation stimuli, but accelerated cell proliferation, anchorage-independent colony formation and in vivo tumor formation of NB cells. NB cell line and primary tumor-sphere experiments indicated that the molecular mechanism of CD133-related differentiation suppression in NB was in part dependent on neurotrophic receptor RET tyrosine kinase regulation. RET transcription was suppressed by CD133 in NB cells and glial cell line-derived neurotrophic factor treatment failed to induce RET in CD133-expressing cells; RET overexpression rescued CD133-related inhibition of neurite elongation. Of note, CD133-related NB cell differentiation and RET repression were mainly dependent on p38MAPK and PI3K/Akt pathways. Furthermore, CD133 has a function in growth and RET expression in NB cell line- and primary tumor cell-derived tumor spheres. To the best of our knowledge, this is the first report of the function of CD133 in cancer cells and our findings may be applied to improve differentiation induction therapy for NB patients.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Aoyama M, Ozaki T, Inuzuka H, Tomotsune D, Hirato J, Okamoto Y et al. (2005). LMO3 interacts with neuronal transcription factor, HEN2, and acts as an oncogene in neuroblastoma. Cancer Res 65: 4587–4597.
Boivin D, Labbé D, Fontaine N, Lamy S, Beaulieu E, Gingras D et al. (2009). The stem cell marker CD133 (prominin-1) is phosphorylated on cytoplasmic tyrosine-828 and tyrosine-852 by Src and Fyn tyrosine kinases. Biochemistry 48: 3998–4007.
Brodeur GM, Sawada T, Tsuchida Y, Voute PA (eds) (2000). Neuroblastoma. Elsevier Science: Amsterdam.
Collins AT, Berry PA, Hyde C, Stower MJ, Maitland NJ . (2005). Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res 65: 10946–10951.
Corbeil D, Roper K, Hellwig A, Tavian M, Miraglia S, Watt SM et al. (2000). The human AC133 hematopoietic stem cell antigen is also expressed in epithelial cells and targeted to plasma membrane protrusions. J Biol Chem 275: 5512–5520.
Corbeil D, Fargeas CA, Huttner WB . (2001). Rat prominin, like its mouse and human orthologues, is a pentaspan membrane glycoprotein. Biochem Biophys Res Commun 285: 939–944.
Crowder RJ, Enomoto H, Yang M, Johnson Jr EM, Milbrandt J . (2004). Dok-6, a Novel p62 Dok family member, promotes Ret-mediated neurite outgrowth. J Biol Chem 279: 42072–42081.
D'Alessio A, De Vita G, Calì G, Nitsch L, Fusco A, Vecchio G et al. (1995). Expression of the RET oncogene induces differentiation of SK-N-BE neuroblastoma cells. Cell Growth Differ 6: 1387–1394.
Enomoto H, Crawford PA, Gorodinsky A, Heuckeroth RO, Johnson Jr EM, Milbrandt J . (2001). RET signaling is essential for migration, axonal growth and axon guidance of developing sympathetic neurons. Development 128: 3963–3974.
Enomoto H, Heuckeroth RO, Golden JP, Johnson EM, Milbrandt J . (2000). Development of cranial parasympathetic ganglia requires sequential actions of GDNF and neurturin. Development 127: 4877–4889.
Fan X, Matsui W, Khaki L, Stearns D, Chun J, Li YM et al. (2006). Notch pathway inhibition depletes stem-like cells and blocks engraftment in embryonal brain tumors. Cancer Res 66: 7445–7452.
Hansford LM, McKee AE, Zhang L, George RE, Gerstle JT, Thorner PS et al. (2007). Neuroblastoma cells isolated from bone marrow metastases contain a naturally enriched tumor-initiating cell. Cancer Res 67: 11234–11243.
Hasegawa K, Nakamura T, Harvey M, Ikeda Y, Oberg A, Figini M et al. (2006). The use of a tropism-modified measles virus in folate receptor-targeted virotherapy of ovarian cancer. Clin Cancer Res 12: 6170–6178.
Itoh F, Ishizaka Y, Tahira T, Yamamoto M, Miya A, Imai K et al. (1992). Identification and analysis of the ret proto-oncogene promoter region in neuroblastoma cell lines and medullary thyroid carcinomas from MEN2A patients. Oncogene 7: 1201–1206.
Iehara T, Hosoi H, Akazawa K, Matsumoto Y, Yamamoto K, Suita S et al. (2006). MYCN gene amplification is a powerful prognostic factor even in infantile neuroblastoma detected by mass screening. Br J Cancer 94: 1510–1515.
Jordan CT, Guzman ML, Noble M . (2006). Cancer stem cells. N Engl J Med 355: 1253–1261.
Kaplan D, Matsumoto K, Lucarelli E, Thiele CJ . (1993). Induction of TrkB by retinoic acid mediates biologic responsiveness to BDNF and differentiation of human neuroblastoma cells. Eukaryotic Signal Transduction Group. Neuron 11: 321–331.
Kaneko M, Tsuchida Y, Mugishima H, Ohnuma N, Yamamoto K, Kawa K et al. (2002). Intensified chemotherapy increases the survival rates in patients with stage 4 neuroblastoma with MYCN amplification. J Pediatr Hematol Oncol 24: 613–621.
Klein R . (1994). Role of neurotrophins in mouse neuronal development. FASEB J 8: 738–744.
Kurata K, Yanagisawa R, Ohira M, Kitagawa M, Nakagawara A, Kamijo T . (2008). Stress via p53 pathway causes apoptosis by mitochondrial Noxa upregulation in doxorubicin-treated neuroblastoma cells. Oncogene 27: 741–754.
Ma S, Lee TK, Zheng BJ, Chan KW, Guan XY . (2007). CD133+ HCC cancer stem cells confer chemoresistance by preferential expression of the Akt/PKB survival pathway. Oncogene 27: 1749–1758.
Maris JM, Hogarty MD, Bagatell R, Cohn SL . (2007). Neuroblastoma. Lancet 369: 2106–2120.
Maw MA, Corbeil D, Koch J, Hellwig A, Wilson-Wheeler JC, Bridges RJ et al. (2000). A frameshift mutation in prominin (mouse)-like 1 causes human retinal degeneration. Hum Mol Genet 9: 27–34.
Miki J, Furusato B, Li H, Gu Y, Takahashi H, Egawa S et al. (2007). 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.
Monzani E, Facchetti F, Galmozzi E, Corsini E, Benetti A, Cavazzin C et al. (2007). Melanoma contains CD133 and ABCG2 positive cells with enhanced tumourigenic potential. Eur J Cancer 43: 935–946.
Myers SM, Eng C, Ponder BA, Mulligan LM . (1995). Characterization of RET proto-oncogene 3′ splicing variants and polyadenylation sites: a novel C-terminus for RET. Oncogene 11: 2039–2045.
Nakanishi H, Ozaki T, Nakamura Y, Hashizume K, Iwanaka T, Nakagawara A . (2007). Purification of human primary neuroblastomas by magnetic beads and their in vitro culture. Oncol Rep 17: 1315–1320.
Nikolova T, Wu M, Brumbarov K, Alt R, Opitz H, Boheler KR et al. (2007). WNT-conditioned media differentially affect the proliferation and differentiation of cord blood-derived CD133+ cells in vitro. Differentiation 75: 100–111.
O'Brien CA, Pollett A, Gallinger S, Dick JE . (2007). A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445: 106–110.
Ochiai H, Takenobu H, Nakagawa A, Yamaguchi Y, Kimura M, Ohira M et al. (2010). Bmi1 is a MYCN target gene that regulates tumorigenesis through repression of KIF1Bβ and TSLC1 in neuroblastoma. Oncogene 29: 2681–2690.
Ohira M, Morohashi A, Inuzuka H, Shishikura T, Kawamoto T, Kageyama H et al. (2003). Expression profiling and characterization of 4200 genes cloned from primary neuroblastomas: identification of 305 genes differentially expressed between favorable and unfavorable subsets. Oncogene 22: 5525–5536.
Olempska M, Eisenach PA, Ammerpohl O, Ungefroren H, Fandrich F, Kalthoff H . (2007). Detection of tumor stem cell markers in pancreatic carcinoma cell lines. Hepatobiliary Pancreat Dis Int 6: 92–97.
Peterson S, Bogenmann E . (2004). The RET and TRKA pathways collaborate to regulate neuroblastoma differentiation. Oncogene 23: 213–225.
Reya T, Morrison SJ, Clarke MF, Weissman IL . (2001). Stem cells, cancer, and cancer stem cells. Nature 414: 105–111.
Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C et al. (2007). Identification and expansion of human colon-cancer initiating cells. Nature 445: 111–115.
Shmelkov SV, Jun L, St Clair R, McGarrigle D, Derderian CA, Usenko JK et al. (2004). Alternative promoters regulate transcription of the gene that encodes stem cell surface protein AC133. Blood 103: 2055–2061.
Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T et al. (2004). Identification of human brain tumour initiating cells. Nature 432: 396–401.
Walton JD, Kattan DR, Thomas SK, Spengler BA, Guo HF, Biedler JL et al. (2004). Characteristics of stem cells from human neuroblastoma cell lines and in tumors. Neoplasia 6: 838–845.
Weinberg RA (ed) (2006). The Biology of Cancer. Garland Science: New York.
Yin AH, Miraglia S, Zanjani ED, Almeida-Porada G, Ogawa M, Leary AG et al. (1997). AC133, a novel marker for human hematopoietic stem and progenitor cells. Blood 90: 5002–5012.
Yin S, Li J, Hu C, Chen X, Yao M, Yan M et al. (2007). CD133 positive hepatocellular carcinoma cells possess high capacity for tumorigenicity. Int J Cancer 120: 1444–1450.
Zacchigna S, Oh H, Wilsch-Bräuninger M, Missol-Kolka E, Jászai J, Jansen S et al. (2009). Loss of the cholesterol-binding protein prominin-1/CD133 causes disk dysmorphogenesis and photoreceptor degeneration. J Neurosci 29: 2297–2308.
Acknowledgements
We thank K Sakurai and S Matsushita for technical assistance, Dr Hiroyuki Miyoshi (BioResource Center, RIKEN) for the gift of CSII-CMV-MCS-IRES2-Bsd plasmid and Daniel Mrozek, Medical English Service, for editorial assistance. This work was supported in part by a grant-in-aid from JSPS for Young Scientists (B) (number: 19790274), a grant-in-aid from the Ministry of Health, Labor, and Welfare for Third Term Comprehensive Control Research for Cancer, a grant-in-aid for Cancer Research (20–13) from the Ministry of Health, Labor, and Welfare of Japan and a grant-in-aid from the Ministry of Education, Culture, Sports, Science and Technology, Japan (number: 21591377).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies the paper on the Oncogene website
Rights and permissions
About this article
Cite this article
Takenobu, H., Shimozato, O., Nakamura, T. et al. CD133 suppresses neuroblastoma cell differentiation via signal pathway modification. Oncogene 30, 97–105 (2011). https://doi.org/10.1038/onc.2010.383
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/onc.2010.383
Keywords
This article is cited by
-
Emerging roles of prominin-1 (CD133) in the dynamics of plasma membrane architecture and cell signaling pathways in health and disease
Cellular & Molecular Biology Letters (2024)
-
Neural crest-related NXPH1/α-NRXN signaling opposes neuroblastoma malignancy by inhibiting organotropic metastasis
Oncogene (2023)
-
HNF4A-AS1-encoded small peptide promotes self-renewal and aggressiveness of neuroblastoma stem cells via eEF1A1-repressed SMAD4 transactivation
Oncogene (2022)
-
Transition to a mesenchymal state in neuroblastoma confers resistance to anti-GD2 antibody via reduced expression of ST8SIA1
Nature Cancer (2022)
-
Combination of a synthetic retinoid and a DNA demethylating agent induced differentiation of neuroblastoma through retinoic acid signal reprogramming
British Journal of Cancer (2021)