Skip to main content

Advertisement

SpringerLink
Log in

Antitumor effects of combined therapy of recombinant heat shock protein 70 and hyperthermia using magnetic nanoparticles in an experimental subcutaneous murine melanoma

  • Original Article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Heat shock proteins (HSPs) are recognized as significant participants in cancer immunity. We previously reported that HSP70 expression following hyperthermia using magnetic nanoparticles induces antitumor immunity. In the present study, we examine whether the antitumor immunity induced by hyperthermia is enhanced by administration of recombinant HSP70 protein into the tumor in situ. Hyperthermia was conducted using our original magnetite cationic liposomes (MCLs), which have a positive surface charge and generate heat in an alternating magnetic field (AMF) due to hysteresis loss. MCLs and recombinant mouse HSP70 (rmHSP70) were injected into melanoma nodules in C57BL/6 mice, which were subjected to AMF for 30 min. Temperature within the tumor reached 43°C and was maintained by controlling the magnetic field intensity. The combined treatment strongly inhibited tumor growth over a 30-day period and complete regression of tumors was observed in 20% (2/10) of mice. It was also found that systemic antitumor immunity was induced in the cured mice. This study suggests that novel combined therapy using exogenous HSP70 and hyperthermia has great potential in cancer treatment.

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. 2A–F
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Abe M, Hiraoka M, Takahashi M, Egawa S, Matsuda C, Onoyama Y, Morita K, Kakehi M, Sugahara T (1986) Multi-institutional studies on hyperthermia using an 8-MHz radiofrequency capacitive heating device (Thermotron RF-8) in combination with radiation for cancer therapy. Cancer 58:1589

    PubMed  Google Scholar 

  2. Asea A, Kraeft SK, Kurt-Jones EA, Stevenson MA, Chen LB, Finberg RW, Koo GC, Calderwood SK (2000) HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine. Nat Med 6:435

    CAS  PubMed  Google Scholar 

  3. Basu S, Srivastava PK (2000) Heat shock proteins: the fountainhead of innate and adaptive immune responses. Cell Stress Chaperones 5:443

    PubMed  Google Scholar 

  4. Basu S, Binder RJ, Suto R, Anderson KM, Srivastava PK (2000) Necrotic but not apoptotic cell death releases heat shock proteins, which deliver a partial maturation signal to dendritic cells and activate the NF-kappa B pathway. Int Immunol 12:1539

    CAS  PubMed  Google Scholar 

  5. Basu S, Binder RJ, Ramalingam T, Srivastava PK (2001) CD91 is a common receptor for heat shock proteins gp96, hsp90, hsp70, and calreticulin. Immunity 14:303

    CAS  PubMed  Google Scholar 

  6. Chen CH, Wang TL, Hung CF, Yang Y, Young RA, Pardoll DM, Wu TC (2000) Enhancement of DNA vaccine potency by linkage of antigen gene to an HSP70 gene. Cancer Res 60:1035

    CAS  PubMed  Google Scholar 

  7. Ishii T, Udono H, Yamano T, Ohta H, Uenaka A, Ono T, Hizuta A, Tanaka N, Srivastava PK, Nakayama E (1999) Isolation of MHC class I-restricted tumor antigen peptide and its precursors associated with heat shock proteins hsp70, hsp90, and gp96. J Immunol 162:1303

    CAS  PubMed  Google Scholar 

  8. Ito A, Shinkai M, Honda H, Wakabayashi T, Yoshida J, Kobayashi T (2001) Augmentation of MHC class I antigen presentation via heat shock protein expression by hyperthermia. Cancer Immunol Immunother 50:515

    Article  CAS  PubMed  Google Scholar 

  9. Ito A, Shinkai M, Honda H, Yoshikawa K, Saga S, Wakabayashi T, Yoshida J, Kobayashi T (2003) Heat shock protein 70 expression induces antitumor immunity during intracellular hyperthermia using magnetite nanoparticles. Cancer Immunol Immunother 52:80

    CAS  PubMed  Google Scholar 

  10. Ito A, Tanaka K, Kondo K, Shinkai M, Honda H, Matsumoto K, Saida T, Kobayashi T (2003) Tumor regression by combined immunotherapy and hyperthermia using magnetic nanoparticles in an experimental subcutaneous murine melanoma. Cancer Sci 94:308

    CAS  PubMed  Google Scholar 

  11. Jordan A, Wust P, Fahling H, John W, Hinz A, Felix R (1993) Inductive heating of ferrimagnetic particles and magnetic fluids: physical evaluation of their potential for hyperthermia. Int J Hyperthermia 9:51

    CAS  PubMed  Google Scholar 

  12. Kubista B, Trieb K, Blahovec H, Kotz R, Micksche M (2002) Hyperthermia increases the susceptibility of chondro- and osteosarcoma cells to natural killer cell-mediated lysis. Anticancer Res 22:789

    CAS  PubMed  Google Scholar 

  13. Li Z, Menoret A, Srivastava P (2002) Roles of heat-shock proteins in antigen presentation and cross-presentation. Curr Opin Immunol 14:45

    Article  CAS  PubMed  Google Scholar 

  14. Melcher A, Todryk S, Hardwick N, Ford M, Jacobson M, Vile RG (1998) Tumor immunogenicity is determined by the mechanism of cell death via induction of heat shock protein expression. Nat Med 4:581

    PubMed  Google Scholar 

  15. Ménoret A, Chandawarkar R (1998) Heat-shock protein-based anticancer immunotherapy: an idea whose time has come. Sem Immunol 25:654

    Google Scholar 

  16. Ménoret A, Patry Y, Burg C, Le Pendu J (1995) Co-segregation of tumor immunogenicity with expression of inducible but not constitutive hsp70 in rat colon carcinomas. J Immunol 155:740

    CAS  PubMed  Google Scholar 

  17. Ménoret A, Chaillot D, Callahan M, Jacquin C (2002) Hsp70, an immunological actor playing with the intracellular self under oxidative stress. Int J Hyperthermia 18:490

    Article  PubMed  Google Scholar 

  18. Minamimura T, Sato H, Kasaoka S, Saito T, Ishizawa S, Takemori S, Tazawa K, Tsukada K (2000) Tumor regression by inductive hyperthermia combined with hepatic embolization using dextran magnetite-incorporated microspheres in rats. Int J Oncol 16:1153

    PubMed  Google Scholar 

  19. Mise K, Kan N, Okino T, Nakanishi M, Satoh K, Teramura Y, Yamasaki S, Ohgaki K, Tobe T (1990) Effect of heat treatment on tumor cells and antitumor effector cells. Cancer Res 50:6199

    CAS  PubMed  Google Scholar 

  20. Mondovi B, Santoro AS, Strom R, Faiola R, Fanelli AR (1972) Increased immunogenicity of Ehrlich ascites cells after heat treatment. Cancer 30:885

    CAS  PubMed  Google Scholar 

  21. Moroz P, Jones SK, Gray BN (2002) Magnetically mediated hyperthermia: current status and future directions. Int J Hyperthermia 18:267

    Article  CAS  PubMed  Google Scholar 

  22. Mosser DD, Caron AW, Bourget L, Meriin AB, Sherman MY, Morimoto RI, Massie B (2000) The chaperon function of hsp70 is required for protection against stress-induced apoptosis. Mol Cell Biol 20:7146

    Article  CAS  PubMed  Google Scholar 

  23. Ozdemirli M, Akdeniz H, el-Khatib M, Ju ST (1991) A novel cytotoxicity of CD4+ T h 1 clones on heat-shocked tumor targets, I: implications for internal disintegration model for target death and hyperthermia treatment of cancers. J Immunol 147:4027

    CAS  PubMed  Google Scholar 

  24. Parmiani G, Castelli C, Dalerba P, Mortarini R, Rivoltini L, Marincola FM, Anichini A (2002) Cancer immunotherapy with peptide-based vaccines: what have we achieved? Where are we going? J Natl Cancer Inst 94:805

    Article  CAS  PubMed  Google Scholar 

  25. Schlesinger MJ (1990) Heat shock proteins. J Biol Chem 265:12111

    CAS  PubMed  Google Scholar 

  26. Shinkai M, Matsui M, Kobayashi T (1994) Heat properties of magnetoliposomes for local hyperthermia. Jpn J Hyperthermic Oncol 10:168

    Google Scholar 

  27. Shinkai M, Yanase M, Honda H, Wakabayashi T, Yoshida J, Kobayashi T (1996) Intracellular hyperthermia for cancer using magnetite cationic liposomes: in vitro study. Jpn J Cancer Res 87:1179

    CAS  PubMed  Google Scholar 

  28. Srivastava PK, Menoret A, Basu S, Binder RJ, McQuade KL (1998) Heat shock proteins come of age: primitive functions acquired new roles in an adaptive world. Immunity 8:657

    CAS  PubMed  Google Scholar 

  29. Suzuki M, Shinkai M, Honda H, Kobayashi T (2003) Anti-cancer effect and immune induction by hyperthermia of malignant melanoma using magnetite cationic liposomes. Melanoma Res 13:129

    Article  PubMed  Google Scholar 

  30. Tamura Y, Peng P, Liu K, Daou M, Srivastava PK (1997) Immunotherapy of tumors with autologous tumor-derived heat shock protein preparations. Science 278:117

    CAS  PubMed  Google Scholar 

  31. Todryk S, Melcher AA, Hardwick N, Linardakis E, Bateman A, Colombo MP, Stoppacciaro A, Vile RG (1999) Heat shock protein 70 induced during tumor cell killing induces Th1 cytokines and targets immature dendritic cell precursors to enhance antigen uptake. J Immunol 163:1398

    CAS  PubMed  Google Scholar 

  32. Udono H, Srivastava PK (1993) Heat shock protein 70-associated peptides elicit specific cancer immunity. J Exp Med 178:1391

    CAS  PubMed  Google Scholar 

  33. Udono H, Srivastava PK (1994) Comparison of tumor-specific immunogenicities of stress-induced protein gp96, hsp90, and hsp70. J Immunol 152:5398

    CAS  PubMed  Google Scholar 

  34. Van der Zee J (2002) Heating the patient: a promising approach? Annu Oncol 13:1173

    Article  Google Scholar 

  35. Wallen ES, Buettner GR, Moseley PL (1997) Oxidants differentially regulate the heat shock response. Int J Hyperthermia 13:517

    PubMed  Google Scholar 

  36. Wells AD, Rai SK, Salvato MS, Band H, Malkovsky M (1998) Hsp72-mediated augmentation of MHC class I surface expression and endogenous antigen presentation. Int Immunol 10:609

    CAS  PubMed  Google Scholar 

  37. Yanase M, Shinkai M, Honda H, Wakabayashi T, Yoshida J, Kobayashi T (1997) Intracellular hyperthermia for cancer using magnetite cationic liposomes: ex vivo study. Jpn J Cancer Res 88:630

    CAS  PubMed  Google Scholar 

  38. Yanase M, Shinkai M, Honda H, Wakabayashi T, Yoshida J, Kobayashi T (1998) Intracellular hyperthermia for cancer using magnetite cationic liposomes: an in vivo study. Jpn J Cancer Res 89:463

    CAS  PubMed  Google Scholar 

  39. Yanase M, Shinkai M, Honda H, Wakabayashi T, Yoshida J, Kobayashi T (1998) Antitumor immunity induction by intracellular hyperthermia using magnetite cationic liposomes. Jpn J Cancer Res 89:775

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Toda Kogyo Co. for supplying the magnetite. This work was partially supported by a Grant-in-Aid for Scientific Research (No. 13853005 and 15760587), the University Start-Up Creation Support System and the 21st Century COE Program “Nature-Guided Materials Processing” from the Ministry of Education, Science, Sports and Culture of Japan.

Author information

Authors and Affiliations

  1. Department of Biotechnology, School of Engineering, Nagoya University, 464-8603, Nagoya, Japan

    Akira Ito, Fumiko Matsuoka, Hiroyuki Honda & Takeshi Kobayashi

Authors
  1. Akira Ito
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fumiko Matsuoka
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hiroyuki Honda
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Takeshi Kobayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Takeshi Kobayashi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ito, A., Matsuoka, F., Honda, H. et al. Antitumor effects of combined therapy of recombinant heat shock protein 70 and hyperthermia using magnetic nanoparticles in an experimental subcutaneous murine melanoma. Cancer Immunol Immunother 53, 26–32 (2004). https://doi.org/10.1007/s00262-003-0416-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-003-0416-5

Keywords

Search

Navigation