Skip to main content
SpringerLink
Log in

Calreticulin and Tumor Suppression

  • Chapter
Calreticulin

Part of the book series: Molecular Biology Intelligence Unit ((MBIU))

  • 216 Accesses

Abstract

Lymphoblastic cell lines derived by Epstein-Barr virus (EBV) immortalization of normal B lymphocytes can reproducibly inhibit tumor growth in nude mice. This anti-tumor activity is due, in part, to a mediator present in the culture supernatant of EBV-immortalized lymphoblastic cells identified as a fragment of calreticulin encompassing the NH2 terminal domain. Recombinant calreticulin NH2 domain (amino acids 1–180), but not calreticulin P domain (amino acids 181–189), can inhibit endothelial cell proliferation in vitro and angiogenesis in vivo. Calreticulin NH2 domain can bind specifically to the extracellular matrix protein laminin and through this binding can interfere with endothelial cell attachment and spread on laminin-coated surfaces. It can also bind directly to endothelial cell membranes. When inoculated subcutanously into nude mice, recombinant calreticulin NH2 domain prevents the development of subcutaneous tumors and reduces the growth of established tumors of various lineages. The capillary vascular network of tumor tissues from mice treated with calreticulin NH2 domain is reduced compared to controls and scattered tumor cell apoptosis is noted, but tumor histology is otherwise similar. Thus, the NH2 domain of calreticulin is detected in the culture supernatant of lymphoblastoid cells and can exert anti-tumor activities acting as an inhibitor of endothelial cell growth and neovascularization.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Folkman J. Anti-angiogenesis: new concept for therapy of solid tumors. Ann Surg 1972; 175(3):409–416.

    Article  PubMed  CAS  Google Scholar 

  2. Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 1999; 86(3):353-364.

    Google Scholar 

  3. Asahara T, Murohara T, Sullivan A et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 1997; 275(5302):964–967.

    Article  PubMed  CAS  Google Scholar 

  4. Holash J, Maisonpierre PC, Compton D et al. Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science 1999; 284(5422):1994–1998.

    Article  PubMed  CAS  Google Scholar 

  5. Lyden D, Young AZ, Zagzag D et al. Id1 and Id3 are required for neurogenesis, angiogenesis and vascularization of tumour xenografts [see comments]. Nature 1999; 401(6754):670–677.

    Article  PubMed  CAS  Google Scholar 

  6. Gullino PM. Angiogenesis and oncogenesis. J Natl Cancer Inst 1978; 61(3):639–643.

    PubMed  CAS  Google Scholar 

  7. Fukumura D, Xavier R, Sugiura T et al. Tumor induction of VEGF promoter activity in stromal cells. Cell 1998; 94(6):715–725.

    Article  PubMed  CAS  Google Scholar 

  8. Carmeliet P. Mechanisms of angiogenesis and arteriogenesis. Nat Med 2000; 6(4):389–395.

    Article  PubMed  CAS  Google Scholar 

  9. Carmeliet P, Lampugnani MG, Moons L et al. Targeted deficiency or cytosolic truncation of the VE-cadherin gene in mice impairs VEGF-mediated endothelial survival and angiogenesis. Cell 1999; 98(2):147–157.

    Article  PubMed  CAS  Google Scholar 

  10. Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature 2000; 407(6801):249–257.

    Article  PubMed  CAS  Google Scholar 

  11. Yancopoulos GD, Davis S, Gale NW et al. Vascular-specific growth factors and blood vessel formation. Nature 2000; 407(6801):242–248.

    Article  PubMed  CAS  Google Scholar 

  12. Kim KJ, Li B, Winer J et al. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 1993; 362(6423):841–844.

    Article  PubMed  CAS  Google Scholar 

  13. Ferrara N, Alitalo K. Clinical applications of angiogenic growth factors and their inhibitors. Nat Med 1999; 5(12):1359–1364.

    Article  PubMed  CAS  Google Scholar 

  14. Rastinejad F, Polverini PJ, Bouck NP. Regulation of the activity of a new inhibitor of angiogenesis by a cancer suppressor gene. Cell 1989; 56(3):345–355.

    Article  PubMed  CAS  Google Scholar 

  15. Dameron KM, Volpert OV, Tainsky MA et al. Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1. Science 1994; 265(5178):1582–1584.

    Article  PubMed  CAS  Google Scholar 

  16. O'Reilly MS, Holmgren L, Shing Y et al. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma [see comments]. Cell 1994; 79(2):315–328.

    Article  PubMed  Google Scholar 

  17. O'Reilly MS, Boehm T, Shing Y et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 1997; 88(2):277–285.

    Article  PubMed  Google Scholar 

  18. Dong Z, Greene G, Pettaway C et al. Suppression of angiogenesis, tumorigenicity, and metastasis by human prostate cancer cells engineered to produce interferon-beta. Cancer Res 1999; 59(4):872–879.

    PubMed  CAS  Google Scholar 

  19. Gohongi T, Fukumura D, Boucher Y et al. Tumor-host interactions in the gallbladder suppress distal angiogenesis and tumor growth: involvement of transforming growth factor betal. Nat Med 1999; 5(10):1203–1208.

    Article  PubMed  CAS  Google Scholar 

  20. Zhang M, Volpert O, Shi YH et al. Maspin is an angiogenesis inhibitor. Nat Med 2000; 6(2):196–199.

    Article  PubMed  Google Scholar 

  21. Tosato G, Sgadari C, Taga K et al. Regression of experimental Burkitt’s lymphoma induced by Epstein-Barr virus-immortalized human B cells. Blood 1994; 83(3):776–784.

    PubMed  CAS  Google Scholar 

  22. Angiolillo AL, Sgadari C, Sheikh N et al. Regression of experimental human leukemias and solid tumors induced by Epstein-Barr virus-immortalized B cells. Leuk Lymphoma 1995; 19(3-4):267–276.

    Article  PubMed  CAS  Google Scholar 

  23. Cherney BW, Sgadari C, Kanegane C et al. Expression of the Epstein-Barr virus protein LMP1 mediates tumor regression in vivo. Blood 1998; 91(7):2491–2500.

    PubMed  CAS  Google Scholar 

  24. Angiolillo AL, Sgadari C, Taub DD et al. Human interferon-inducible protein 10 is a potent inhibitor of angiogenesis in vivo. J Exp Med 1995; 182(1):155–162.

    Article  PubMed  CAS  Google Scholar 

  25. Angiolillo AL, Sgadari C, Tosato G. A role for the interferon-inducible protein 10 in inhibition of angiogenesis by interleukin-12. Ann N Y Acad Sci 1996; 795:158–167.

    Article  PubMed  CAS  Google Scholar 

  26. Sgadari C, Angiolillo AL, Cherney BW et al. Interferon-inducible protein-10 identified as a mediator of tumor necrosis in vivo. Proc Natl Acad Sci USA 1996; 93(24):13791–13796.

    Article  PubMed  CAS  Google Scholar 

  27. Sgadari C, Angiolillo AL, Tosato G. Inhibition of angiogenesis by interleukin-12 is mediated by the interferon-inducible protein 10. Blood 1996; 87(9):3877–3882.

    PubMed  CAS  Google Scholar 

  28. Sgadari C, Farber JM, Angiolillo AL et al. Mig, the monokine induced by interferon-gamma, promotes tumor necrosis in vivo. Blood 1997; 89(8):2635–2643.

    PubMed  CAS  Google Scholar 

  29. Urbe S, Page LJ, Tooze SA. Homotypic fusion of immature secretory granules during maturation in a cell-free assay. J Cell Biol 1998; 143(7):1831–1844.

    Article  PubMed  CAS  Google Scholar 

  30. Zhu Q, Zelinka P, White T et al. Calreticulin-integrin bidirectional signaling complex. Biochem Biophys Res Commun 1997; 232(2):354–358.

    Article  PubMed  CAS  Google Scholar 

  31. Borisjuk N, Sitailo L, Adler K et al. Calreticulin expression in plant cells: developmental regulation, tissue specificity and intracellular distribution. Planta 1998; 206(4):504–514.

    Article  PubMed  CAS  Google Scholar 

  32. Zuber C, Spiro MJ, Guhl B et al. Golgi apparatus immunolocalization of endomannosidase suggests post-endoplasmic reticulum glucose trimming: implications for quality control. Mol Biol Cell 2000; 11(12):4227–4240.

    PubMed  CAS  Google Scholar 

  33. Day PJ, Owens SR, Wesche J et al. An interaction between ricin and calreticulin that may have implications for toxin trafficking. J Biol Chem 2001; 276(10):7202–7208.

    Article  PubMed  CAS  Google Scholar 

  34. Corbett EF, Michalak KM, Oikawa K et al. The conformation of calreticulin is influenced by the endoplasmic reticulum luminal environment. J Biol Chem 2000; 275(35):27177–27185.

    PubMed  CAS  Google Scholar 

  35. Pike SE, Yao L, Jones KD et al. Vasostatin, a calreticulin fragment, inhibits angiogenesis and suppresses tumor growth. J Exp Med 1998; 188(12):2349–2356.

    Article  PubMed  CAS  Google Scholar 

  36. Pike SE, Yao L, Setsuda J et al. Calreticulin and calreticulin fragments are endothelial cell inhibitors that suppress tumor growth. Blood 1999; 94(7):2461–2468.

    PubMed  CAS  Google Scholar 

  37. McDonnell JM, Jones GE, White TK et al. Calreticulin binding affinity for glycosylated Iaminin. J Biol Chem 1996; 271(14):7891–7894.

    Article  PubMed  CAS  Google Scholar 

  38. Burgeson RE, Chiquer M, Deutzmann R et al. A new nomenclature for the laminins. Matrix Biol 1994; 14(3):2O9–211.

    Article  Google Scholar 

  39. Timpl R, Brown JC. The laminins. Matrix Biol. Aug 1994; 14(4):275–281.

    CAS  Google Scholar 

  40. Kleinman HK, Cannon FB, Laurie GW et al. Biological activities of Iaminin. J Cell Biochem 1985; 27(4):317–325.

    Article  PubMed  CAS  Google Scholar 

  41. Grant DS, Tashiro K, Segui-Real B et al. Two different Iaminin domains mediate the differentiation of human endothelial cells into capillary-like structures in vitro. Cell 1989; 58(5):933–943.

    Article  PubMed  CAS  Google Scholar 

  42. Kanemoto T, Reich R, Royce L et al. Identification of an amino acid sequence from the Iaminin A chain that stimulates metastasis and collagenase IV production. Proc Natl Acad Sci USA. Mar 1990; 87(6):2279–2283.

    CAS  Google Scholar 

  43. Sanes JR, Engvall E, Butkowski R et al. Molecular heterogeneity of basal laminae: isoforms of lammin and collagen IV at the neuromuscular junction and elsewhere. J Cell Biol 1990; 111(4):1685–1699.

    Article  PubMed  CAS  Google Scholar 

  44. Alitalo K. Production of both interstitial and basement membrane procollagens by fibroblastic WI-38 cells from human embryonic lung. Biochem Biophys Res Commun 1980; 93(3):873–880.

    Article  PubMed  CAS  Google Scholar 

  45. Tokida Y, Aratani Y, Morita A et al. Production of two variant Iaminin forms by endothelial cells and shift of their relative levels by angiostatic steroids. J Biol Chem 1990; 265(30):18123–18129.

    PubMed  CAS  Google Scholar 

  46. Yao Lei PSE, Tosato G. Laminin Binding to the Calreticulin Fragment Vasostatin Regulates Endothelial cell Functin. Journal of Leukocyte Biology 2002; 71(1):47–53.

    PubMed  CAS  Google Scholar 

  47. Hynes RO. Integrins: versatility, modulation, and signaling in cell adhesion. Cell 1992; 69(1):11–25.

    Article  PubMed  CAS  Google Scholar 

  48. Malinoff HL, Wicha MS. Isolation of a cell surface receptor protein for laminin from murine fibrosarcoma cells. J Cell Biol 1983; 96(5):1475–1479.

    Article  PubMed  CAS  Google Scholar 

  49. Mecham RP. Receptors for laminin on mammalian cells. Faseb J 1991; 5(11):2538–2546.

    PubMed  CAS  Google Scholar 

  50. Montanaro F, Lindenbaum M, Carbonetto S. alpha-Dystroglycan is a laminin receptor involved in extracellular matrix assembly on myotubes and muscle cell viability. J Cell Biol 1999; 145(6):1325–1340.

    Article  PubMed  CAS  Google Scholar 

  51. Kuwabara K, Pinsky DJ, Schmidt AM et al. Calreticulin, an antithrombotic agent which binds to vitamin K-dependent coagulation factors, stimulates endothelial nitric oxide production, and limits thrombosis in canine coronary arteries. J Biol Chem 1995; 270(l4):8179–8187.

    PubMed  CAS  Google Scholar 

  52. Basu S, Binder RJ, Ramalingam T et al. CD91 is a common receptor for heat shock proteins gp96, hsp90, hsp70, and calreticulin. Immunity 2001; 14(3):303–313.

    Article  PubMed  CAS  Google Scholar 

  53. Yao L, Sgadari C, Furuke K et al. Contribution of natural killer cells to inhibition of angiogenesis by interleukin-12. Blood 1999; 93(5):1612–1621.

    PubMed  CAS  Google Scholar 

  54. Troyanovsky B, Levchenko T, Mansson G et al. Angiomotin: an angiostatin binding protein that regulates endothelial cell migration and tube formation. J Cell Biol 2001; 152(6):1247–1254.

    Article  PubMed  CAS  Google Scholar 

  55. Yao L, Pike SE, Setsuda J et al. Effective Targeting of Tumor Vasculature by the Angiogenesis Inhibitors Vasostatin and Interleukin-12. BLOOD 2000; 96(5):1900–1905.

    PubMed  CAS  Google Scholar 

  56. Cheng WF, Hung CF, Chai CY et al. Tumor-specific immunity and antiangiogenesis generated by a DNA vaccine encoding calreticulin linked to a tumor antigen, J Clin Invest 2001; 108(5):669–678.

    PubMed  CAS  Google Scholar 

  57. Sadasivan B, Lehner PJ, Ortmann B et al. Roles for calreticulin and a novel glycoprotein, tapasin, in the interaction of MHC class I molecules with TAP. Immunity 1996; 5(2):103–114.

    Article  PubMed  CAS  Google Scholar 

  58. Spee P, Neefjes J. TAP-translocated peptides specifically bind proteins in the endoplasmic reticulum, including gp96, protein disulfide isomerase and calreticulin. Eur J Immunol 1997; 27(9):2441–2449.

    Article  PubMed  CAS  Google Scholar 

  59. Basu S, Srivastava PK. Calreticulin, a peptide-binding chaperone of the endoplasmic reticulum, elicits tumor-and peptide-specific immunity. J Exp Med 1999; 189(5):797–802.

    Article  PubMed  CAS  Google Scholar 

Download references

Authors
  1. Giovanna Tosato
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lei Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sandra E. Pike
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Peninsula Medical School, Devon, U.K. MRC Immunochemistry Unit Department of Biochemistry, University of Oxford, Oxford, UK

    Paul Eggleton Ph.D.

  2. CIHR Membrane Protein Research Group Department of Biochemistry, University of Alberta Edmonton, Alberta, Canada

    Marek Michalak Ph.D.

Rights and permissions

Reprints and permissions

Copyright information

© 2003 Springer Science+Business Media New York

About this chapter

Cite this chapter

Tosato, G., Yao, L., Pike, S.E. (2003). Calreticulin and Tumor Suppression. In: Eggleton, P., Michalak, M. (eds) Calreticulin. Molecular Biology Intelligence Unit. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-9258-1_16

Download citation

  • DOI: https://doi.org/10.1007/978-1-4419-9258-1_16

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4613-4862-7

  • Online ISBN: 978-1-4419-9258-1

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation