Skip to main content

Advertisement

SpringerLink
Log in

The stem cell marker prominin-1/CD133 interacts with vascular endothelial growth factor and potentiates its action

  • Original Paper
  • Published:
Angiogenesis Aims and scope Submit manuscript

Abstract

Prominin-1, a pentaspan transmembrane protein, is a unique cell surface marker commonly used to identify stem cells, including endothelial progenitor cells and cancer stem cells. However, recent studies have shown that prominin-1 expression is not restricted to stem cells but also occurs in modified forms in many mature adult human cells. Although prominin-1 has been studied extensively as a stem cell marker, its physiological function of the protein has not been elucidated. We investigated prominin-1 function in two cell lines, primary human endothelial cells and B16-F10 melanoma cells, both of which express high levels of prominin-1. We found that prominin-1 directly interacts with the angiogenic and tumor survival factor vascular endothelial growth factor (VEGF) in both the primary endothelial cells and the melanoma cells. Knocking down prominin-1 in the endothelial cells disrupted capillary formation in vitro and decreased angiogenesis in vivo. Similarly, tumors derived from prominin-1 knockdown melanoma cells had a reduced growth rate in vivo. Further, melanoma cells with knocked down prominin-1 had diminished ability to interact with VEGF, which was associated with decreased bcl-2 protein levels and increased apoptosis. In vitro studies with soluble prominin-1 showed that it stabilized dimer formation of VEGF164, but not VEGF121. Taken together, our findings support the notion that prominin-1 plays an active role in cell growth through its ability to interact and potentiate the anti-apoptotic and pro-angiogenic activities of VEGF. Additionally, prominin-1 promotes tumor growth by supporting angiogenesis and inhibiting tumor cell apoptosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Corbeil D, Roper K, Weigmann A, Huttner WB (1998) AC133 hematopoietic stem cell antigen: human homologue of mouse kidney prominin or distinct member of a novel protein family? Blood 91:2625–2626

    PubMed  CAS  Google Scholar 

  2. Miraglia S, Godfrey W, Yin AH, Atkins K, Warnke R, Holden JT, Bray RA, Waller EK, Buck DW (1997) A novel five-transmembrane hematopoietic stem cell antigen: isolation, characterization, and molecular cloning. Blood 90:5013–5021

    PubMed  CAS  Google Scholar 

  3. Yin AH, Miraglia S, Zanjani ED, Almeida-Porada G, Ogawa M, Leary AG, Olweus J, Kearney J, Buck DW (1997) AC133, a novel marker for human hematopoietic stem and progenitor cells. Blood 90:5002–5012

    PubMed  CAS  Google Scholar 

  4. Weigmann A, Corbeil D, Hellwig A, Huttner WB (1997) 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 U S A 94:12425–12430

    Article  PubMed  CAS  Google Scholar 

  5. Lardon J, Corbeil D, Huttner WB, Ling Z, Bouwens L (2008) Stem cell marker prominin-1/AC133 is expressed in duct cells of the adult human pancreas. Pancreas 36:e1–e6

    Article  PubMed  Google Scholar 

  6. Corbeil D, Roper K, Fargeas CA, Joester A, Huttner WB (2001) Prominin: a story of cholesterol, plasma membrane protrusions and human pathology. Traffic 2:82–91

    Article  PubMed  CAS  Google Scholar 

  7. Huttner HB, Janich P, Kohrmann M, Jaszai J, Siebzehnrubl F, Blumcke I, Suttorp M, Gahr M, Kuhnt D, Nimsky C, Krex D, Schackert G, Lowenbruck K, Reichmann H, Juttler E, Hacke W, Schellinger PD, Schwab S, Wilsch-Brauninger M, Marzesco AM, Corbeil D (2007) The Stem Cell Marker Prominin-1/CD133 On Membrane Particles In Human Cerebrospinal Fluid Offers Novel Approaches For Studying CNS Disease. Stem Cells 26(3):698–705

    Google Scholar 

  8. Jaszai J, Fargeas CA, Florek M, Huttner WB, Corbeil D (2006) Focus on Molecules: Prominin-1 (CD133). Exp Eye Res 85(5):585–586

    Google Scholar 

  9. Marzesco AM, Janich P, Wilsch-Brauninger M, Dubreuil V, Langenfeld K, Corbeil D, Huttner WB (2005) Release of extracellular membrane particles carrying the stem cell marker prominin-1 (CD133) from neural progenitors and other epithelial cells. J Cell Sci 118:2849–2858

    Article  PubMed  CAS  Google Scholar 

  10. Lee A, Kessler JD, Read TA, Kaiser C, Corbeil D, Huttner WB, Johnson JE, Wechsler-Reya RJ (2005) Isolation of neural stem cells from the postnatal cerebellum. Nat Neurosci 8:723–729

    Article  PubMed  CAS  Google Scholar 

  11. Missol-Kolka E, Karbanova J, Janich P, Haase M, Fargeas CA, Huttner WB, Corbeil D (2011) Prominin-1 (CD133) is not restricted to stem cells located in the basal compartment of murine and human prostate. Prostate 71, 254–267

    Google Scholar 

  12. Bauer N, Fonseca AV, Florek M, Freund D, Jaszai J, Bornhauser M, Fargeas CA, Corbeil D (2008) New insights into the cell biology of hematopoietic progenitors by studying prominin-1 (CD133). Cells Tissues Organs 188:127–138

    Article  PubMed  CAS  Google Scholar 

  13. Shmelkov SV, Jun L, St Clair R, McGarrigle D, Derderian CA, Usenko JK, Costa C, Zhang F, Guo X, Rafii S (2004) Alternative promoters regulate transcription of the gene that encodes stem cell surface protein AC133. Blood 103:2055–2061

    Article  PubMed  CAS  Google Scholar 

  14. Ria R, Piccoli C, Cirulli T, Falzetti F, Mangialardi G, Guidolin D, Tabilio A, Di Renzo N, Guarini A, Ribatti D, Dammacco F, Vacca A (2008) Endothelial differentiation of hematopoietic stem and progenitor cells from patients with multiple myeloma. Clin Cancer Res 14:1678–1685

    Article  PubMed  CAS  Google Scholar 

  15. Toren A, Bielorai B, Jacob-Hirsch J, Fisher T, Kreiser D, Moran O, Zeligson S, Givol D, Yitzhaky A, Itskovitz-Eldor J, Kventsel I, Rosenthal E, Amariglio N, Rechavi G (2005) CD133-positive hematopoietic stem cell “stemness” genes contain many genes mutated or abnormally expressed in leukemia. Stem Cells 23:1142–1153

    Article  PubMed  CAS  Google Scholar 

  16. Lee ST, Jang JH, Min YH, Hahn JS, Ko YW (2001) AC133 antigen as a prognostic factor in acute leukemia. Leuk Res 25:757–767

    Article  PubMed  CAS  Google Scholar 

  17. Isidori A, Motta MR, Tani M, Terragna C, Zinzani P, Curti A, Rizzi S, Taioli S, Giudice V, D’Addio A, Gugliotta G, Conte R, Baccarani M, Lemoli RM (2007) Positive selection and transplantation of autologous highly purified CD133(+) stem cells in resistant/relapsed chronic lymphocytic leukemia patients results in rapid hematopoietic reconstitution without an adequate leukemic cell purging. Biol Blood Marrow Transplant 13:1224–1232

    Article  PubMed  CAS  Google Scholar 

  18. Crescenzi B, Chase A, Starza RL, Beacci D, Rosti V, Galli A, Specchia G, Martelli MF, Vandenberghe P, Cools J, Jones AV, Cross NC, Marynen P, Mecucci C (2007) FIP1L1-PDGFRA in chronic eosinophilic leukemia and BCR-ABL1 in chronic myeloid leukemia affect different leukemic cells. Leukemia 21:397–402

    Article  PubMed  CAS  Google Scholar 

  19. Lazaridou A, Miraxtsi C, Tokmaktsis A, Hatjiharissi E, Christakis J (2000) Detection of genetic markers on different populations of hematopoietic progenitor cells in B-cell chronic lymphocytic leukemia. Blood 95:3634–3635

    PubMed  CAS  Google Scholar 

  20. Green CL, Loken M, Buck D, Deeg HJ (2000) Discordant expression of AC133 and AC141 in patients with myelodysplastic syndrome (MDS) and acute myelogeneous leukemia (AML). Leukemia 14:770–772

    Article  PubMed  CAS  Google Scholar 

  21. Feller N, Kelder A, Westra G, Ossenkoppele GJ, Schuurhuis GJ (2008) Positive selection for CD90 as a purging option in acute myeloid leukemia stem cell transplants. Cytometry B Clin Cytom 74:9–16

    PubMed  Google Scholar 

  22. Seigel GM, Hackam AS, Ganguly A, Mandell LM, Gonzalez-Fernandez F (2007) Human embryonic and neuronal stem cell markers in retinoblastoma. Mol Vis 13:823–832

    PubMed  CAS  Google Scholar 

  23. Zhong X, Li Y, Peng F, Huang B, Lin J, Zhang W, Zheng J, Jiang R, Song G, Ge J (2007) Identification of tumorigenic retinal stem-like cells in human solid retinoblastomas. Int J Cancer 121:2125–2131

    Article  PubMed  CAS  Google Scholar 

  24. Murat A, Migliavacca E, Gorlia T, Lambiv WL, Shay T, Hamou MF, de Tribolet N, Regli L, Wick W, Kouwenhoven MC, Hainfellner JA, Heppner FL, Dietrich PY, Zimmer Y, Cairncross JG, Janzer RC, Domany E, Delorenzi M, Stupp R, Hegi ME (2008) Stem cell-related “self-renewal” signature and high epidermal growth factor receptor expression associated with resistance to concomitant chemoradiotherapy in glioblastoma. J Clin Oncol 26:3015–3024

    Article  PubMed  CAS  Google Scholar 

  25. Huttner HB, Janich P, Kohrmann M, Jaszai J, Siebzehnrubl F, Blumcke I, Suttorp M, Gahr M, Kuhnt D, Nimsky C, Krex D, Schackert G, Lowenbruck K, Reichmann H, Juttler E, Hacke W, Schellinger PD, Schwab S, Wilsch-Brauninger M, Marzesco AM, Corbeil D (2008) The stem cell marker prominin-1/CD133 on membrane particles in human cerebrospinal fluid offers novel approaches for studying central nervous system disease. Stem Cells 26:698–705

    Article  PubMed  CAS  Google Scholar 

  26. Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J, Dirks PB (2003) Identification of a cancer stem cell in human brain tumors. Cancer Res 63:5821–5828

    PubMed  CAS  Google Scholar 

  27. Yin S, Li J, Hu C, Chen X, Yao M, Yan M, Jiang G, Ge C, Xie H, Wan D, Yang S, Zheng S, Gu J (2007) CD133 positive hepatocellular carcinoma cells possess high capacity for tumorigenicity. Int J Cancer 120:1444–1450

    Article  PubMed  CAS  Google Scholar 

  28. Zabierowski SE, Herlyn M (2008) Melanoma stem cells: the dark seed of melanoma. J Clin Oncol 26:2890–2894

    Article  PubMed  Google Scholar 

  29. Bruno S, Bussolati B, Grange C, Collino F, Graziano ME, Ferrando U, Camussi G (2006) CD133 + renal progenitor cells contribute to tumor angiogenesis. Am J Pathol 169:2223–2235

    Article  PubMed  CAS  Google Scholar 

  30. Suetsugu A, Nagaki M, Aoki H, Motohashi T, Kunisada T, Moriwaki H (2006) Characterization of CD133 + hepatocellular carcinoma cells as cancer stem/progenitor cells. Biochem Biophys Res Commun 351:820–824

    Article  PubMed  CAS  Google Scholar 

  31. Florek M, Haase M, Marzesco AM, Freund D, Ehninger G, Huttner WB, Corbeil D (2005) Prominin-1/CD133, a neural and hematopoietic stem cell marker, is expressed in adult human differentiated cells and certain types of kidney cancer. Cell Tissue Res 319:15–26

    Article  PubMed  CAS  Google Scholar 

  32. Kleinman ME, Ambati J (2008) Fifty years later: the disk goes to the prom. J Clin Invest 118:2681–2684

    PubMed  CAS  Google Scholar 

  33. Yang Z, Chen Y, Lillo C, Chien J, Yu Z, Michaelides M, Klein M, Howes KA, Li Y, Kaminoh Y, Chen H, Zhao C, Chen Y, Al-Sheikh YT, Karan G, Corbeil D, Escher P, Kamaya S, Li C, Johnson S, Frederick JM, Zhao Y, Wang C, Cameron DJ, Huttner WB, Schorderet DF, Munier FL, Moore AT, Birch DG, Baehr W, Hunt DM, Williams DS, Zhang K (2008) Mutant prominin 1 found in patients with macular degeneration disrupts photoreceptor disk morphogenesis in mice. J Clin Invest 118:2908–2916

    Article  PubMed  CAS  Google Scholar 

  34. Zhang Q, Zulfiqar F, Xiao X, Riazuddin SA, Ahmad Z, Caruso R, MacDonald I, Sieving P, Riazuddin S, Hejtmancik JF (2007) Severe retinitis pigmentosa mapped to 4p15 and associated with a novel mutation in the PROM1 gene. Hum Genet 122:293–299

    Article  PubMed  CAS  Google Scholar 

  35. Maw MA, Corbeil D, Koch J, Hellwig A, Wilson-Wheeler JC, Bridges RJ, Kumaramanickavel G, John S, Nancarrow D, Roper K, Weigmann A, Huttner WB, Denton MJ (2000) A frameshift mutation in prominin (mouse)-like 1 causes human retinal degeneration. Hum Mol Genet 9:27–34

    Article  PubMed  CAS  Google Scholar 

  36. Pidgeon GP, Barr MP, Harmey JH, Foley DA, Bouchier-Hayes DJ (2001) Vascular endothelial growth factor (VEGF) upregulates BCL-2 and inhibits apoptosis in human and murine mammary adenocarcinoma cells. Br J Cancer 85:273–278

    Article  PubMed  CAS  Google Scholar 

  37. Fernandez A, Udagawa T, Schwesinger C, Beecken W, Achilles-Gerte E, McDonnell T, D’Amato R (2001) Angiogenic potential of prostate carcinoma cells overexpressing bcl-2. J Natl Cancer Inst 93:208–213

    Article  PubMed  CAS  Google Scholar 

  38. Potgens AJ, Lubsen NH, van Altena MC, Vermeulen R, Bakker A, Schoenmakers JG, Ruiter DJ, de Waal RM (1994) Covalent dimerization of vascular permeability factor/vascular endothelial growth factor is essential for its biological activity. Evidence from Cys to Ser mutations. J Biol Chem 269:32879–32885

    PubMed  CAS  Google Scholar 

  39. Melero-Martin JM, De Obaldia ME, Allen P, Dudley AC, Klagsbrun M, Bischoff J (2010) Host myeloid cells are necessary for creating bioengineered human vascular networks in vivo. Tissue Eng Part A 16, 2457–2466

    Google Scholar 

  40. Ma S, Lee TK, Zheng BJ, Chan KW, Guan XY (2008) CD133 + HCC cancer stem cells confer chemoresistance by preferential expression of the Akt/PKB survival pathway. Oncogene 27:1749–1758

    Article  PubMed  CAS  Google Scholar 

  41. Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD, Dirks PB (2004) Identification of human brain tumour initiating cells. Nature 432:396–401

    Article  PubMed  CAS  Google Scholar 

  42. Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, Dewhirst MW, Bigner DD, Rich JN (2006) Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444:756–760

    Article  PubMed  CAS  Google Scholar 

  43. Collins AT, Berry PA, Hyde C, Stower MJ, Maitland NJ (2005) Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res 65:10946–10951

    Article  PubMed  CAS  Google Scholar 

  44. Bao S, Wu Q, Sathornsumetee S, Hao Y, Li Z, Hjelmeland AB, Shi Q, McLendon RE, Bigner DD, Rich JN (2006) Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer Res 66:7843–7848

    Article  PubMed  CAS  Google Scholar 

  45. Maeda S, Shinchi H, Kurahara H, Mataki Y, Maemura K, Sato M, Natsugoe S, Aikou T, Takao S (2008) CD133 expression is correlated with lymph node metastasis and vascular endothelial growth factor-C expression in pancreatic cancer. Br J Cancer 98:1389–1397

    Article  PubMed  CAS  Google Scholar 

  46. Mamluk R, Gechtman Z, Kutcher ME, Gasiunas N, Gallagher J, Klagsbrun M (2002) Neuropilin-1 binds vascular endothelial growth factor 165, placenta growth factor-2, and heparin via its b1b2 domain. J Biol Chem 277:24818–24825

    Article  PubMed  CAS  Google Scholar 

  47. Saint-Geniez M, Maharaj AS, Walshe TE, Tucker BA, Sekiyama E, Kurihara T, Darland DC, Young MJ, D’Amore PA (2008) Endogenous VEGF is required for visual function: evidence for a survival role on muller cells and photoreceptors. PLoS ONE 3:e3554

    Article  PubMed  Google Scholar 

  48. Arrigoni FI, Matarin M, Thompson PJ, Michaelides M, McClements ME, Redmond E, Clarke L, Ellins E, Mohamed S, Pavord I, Hunt DM, Moore AT, Halcox J (2011) Sisodiya SM Extended extraocular phenotype of PROM1 mutation in kindreds with known autosomal dominant macular dystrophy. Eur J Hum Genet 19, 131–137

    Google Scholar 

  49. Michaelides M, Gaillard MC, Escher P, Tiab L, Bedell M, Borruat FX, Barthelmes D, Carmona R, Zhang K, White E, McClements M, Robson AG, Holder GE, Bradshaw K, Hunt DM, Webster AR, Moore AT, Schorderet DF, Munier FL (2010) The PROM1 mutation p.R373C causes an autosomal dominant bull’s eye maculopathy associated with rod, rod-cone, and macular dystrophy. Invest Ophthalmol Vis Sci 51, 4771–4780

    Google Scholar 

  50. Anderson LH, Boulanger CA, Smith GH, Carmeliet P, Watson CJ (2011) Stem cell marker prominin-1 regulates branching morphogenesis, but not regenerative capacity, in the mammary gland. Dev Dyn 240, 674–681

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Vascular Biology Program, Department of Surgery, Children’s Hospital, Harvard Medical School, Boston, MA, 02115, USA

    Avner Adini, Irit Adini, Ofra Benny, Elke Pravda, Ron Hu, Dema Luyindula & Robert J. D’Amato

  2. Department of Ophthalmology, Harvard Medical School, Boston, MA, USA

    Robert J. D’Amato

  3. Department of Bioengineering, University of California-Riverside, Riverside, CA, 92521, USA

    Kaustabh Ghosh

Authors
  1. Avner Adini
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Irit Adini
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kaustabh Ghosh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ofra Benny
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Elke Pravda
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ron Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Dema Luyindula
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Robert J. D’Amato
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Avner Adini.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Adini, A., Adini, I., Ghosh, K. et al. The stem cell marker prominin-1/CD133 interacts with vascular endothelial growth factor and potentiates its action. Angiogenesis 16, 405–416 (2013). https://doi.org/10.1007/s10456-012-9323-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10456-012-9323-8

Keywords

Search

Navigation