Abstract
The recent advances in designing Hsp70-based anti-cancer vaccines and the ability of the chaperone to penetrate inside a living cell prompted us to develop a non-invasive method for the treatment of surface tumors. We designed hydrogel-containing gel-forming substances and human recombinant Hsp70 and applied them on the surface of a 7-day-old B16F10 melanoma tumor. According to the results of histochemistry, Hsp70 diffused through skin layer inside the B16 tumor, and this transport was proved by biochemical data. The application of Hsp70 gel reduced the rate of tumor growth by 64 % and prolonged the life of animals by 46 %. Increased survival was correlated with the enhancement of B16-specific cytotoxicity and up-regulation of gamma–interferon production. Taken together, the data confirm the anti-tumor effect of pure recombinant Hsp70 delivered intratumorally and demonstrate the relevance of a novel non-invasive technology of Hsp70-based therapy.
References
Calderwood SK, Ciocca DR (2008) Heat shock proteins: stress proteins with Janus-like properties in cancer. Int J Hyperthermia 24:31–39. doi:10.1080/02656730701858305
Chang CL, Tsai YC, He L, Wu TC, Hung CF (2007) Cancer immunotherapy using irradiated tumor cells secreting heat shock protein 70. Cancer Res 67(20):10047–10057. doi:10.1158/0008-5472
Dressel R, Grzeszik C, Kreiss M, Lindemann D, Herrmann T, Walter L, Gunther E (2003) Differential effect of acute and permanent heat shock protein 70 overexpression in tumor cells on lysability by cytotoxic T lymphocytes. Cancer Res 63(23):8212–8120
Ekimova IV, Nitsinskaya LE, Romanova IV, Pastukhov YF, Margulis BA, Guzhova IV (2010) Exogenous protein Hsp70/Hsc70 can penetrate into brain structures and attenuate the severity of chemically-induced seizures. J Neurochem 115(4):1035–1044. doi:10.1111/j.1471-4159.2010.06989.x
Gastpar R, Gehrmann M, Bausero MA, Asea A, Gross C, Schroeder JA, Multhoff G (2005) Heat shock protein 70 surface-positive tumor exosomes stimulate migratory and cytolytic activity of natural killer cells. Cancer Res 65:5238–5247. doi:10.1158/0008-5472
Gastpar R, Gross C, Rossbacher L, Ellwart J, Riegger J, Multhoff G (2004) The cell surface-localized heat shock protein 70 epitope TKD induces migration and cytolytic activity selectively in human NK-cells. J Immunol 172:972–980
Gehrmann M, Stangl S, Kirshner A, Foulds GA, Sievert W, Doss BT, Walch A, Pockley AG, Multhoff G (2012) Immunotherapeutic targeting of membrane Hsp70-expressing tumors using recombinant human granzyme B. PLoS One 7(7):e41341. doi:10.1371/journal.pone.0041341
Geng H, Zhang GM, Xiao H, Yuan Y, Li D, Zhang H, Qiu H, He YF, Feng ZH (2006) HSP70 vaccine in combination with gene therapy with plasmid DNA encoding sPD-1 overcomes immune resistance and suppresses the progression of pulmonary metastatic melanoma. Int J Cancer 118:2657–2664
Guo Q-Y, Yuan M, Peng J, Cui X-M, Song G, Sui X, Lu S-B (2011) Antitumor activity of mixed heat shock protein/peptide vaccine and cyclophosphamide plus interleukin-12 in mice sarcoma. J Exp Clin Cancer Res 30:24. doi:10.1186/1756-9966-30-24
Guzhova I, Kislyakova K, Moskaliova O, Fridlanskaya I, Tytell M, Cheetham M, Margulis B (2001) In vitro studies show that Hsp70 can be released by glia and that exogenous Hsp70 can enhance neuronal stress tolerance. Brain Res 914:66–73
Guzhova IV, Komarova EI, Pimenova AA, Bakhtin IB, Kaminskaia EV, Margulis BA (2008) The role of extracellular chaperone Hsp70 in creating antitumor immunity in rat rhabdomyosarcoma RA-2 model. Vopr Onkol 54:611–617
Guzhova IV, Lazarev VF, Kaznacheeva AV, Ippolitova MV, Muronetz VI, Kinev AV, Margulis BA (2011) Novel mechanism of Hsp70 chaperone-mediated prevention of polyglutamine aggregates in a cellular model of huntington disease. Hum Mol Genet 20:3953–3963
Ito A, Matsuoka F, Honda H, Kobayashi T (2004) 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
Kumar S, Deepak P, Acharya A (2009) Autologous Hsp70 immunization induces anti-tumor immunity and increases longevity and survival of tumor-bearing mice. Neoplasma 56:259–268. doi:10.4149/neo_2009_03_259
Lazarev VF, Onokhin KV, Antimonova OI, Polonik SG, Guzhova IV, Margulis BA (2011) Kinetics of chaperone activity of proteins Hsp70 and Hdj1 in human leukemia U-937 cells after preconditioning with thermal shock or compound u-133. Biochemistry (Mosc) 76(5):590–595. doi:10.1134/s0006297911050099
Murshid A, Theriault J, Gong J, Calderwood SK (2011) Investigating receptors for extracellular heat shock proteins. Methods Mol Biol 787:289–302. doi:10.1007/978-1-61779-295-3_22
Nishikawa M, Takemoto S, Takakura Y (2008) Heat shock protein derivatives for delivery of antigens to antigen presenting cells. Int J Pharm 354(1–2):23–27
Srivastava P (2002) Interaction of heat shock proteins with peptides and antigen presenting cells: chaperoning of the innate and adaptive immune responses. Annu Rev Immunol 20:395–425. doi:10.1038/nri749
Udono H, Srivatsava PK (1993) Heat shock protein 70-associated peptides elicit specific cancer immunity. J Exp Med 178:1391–1396
Acknowledgments
The authors thank Dr. Irina V. Romanova for the histological analysis and Dr. Maxim A. Shevtsov for fruitful discussions. The work was supported by grants from the Russian Foundation for Basic Research 10-04-01049, 11-08-00445 and the Program of Russian Academy of Sciences “Molecular and Cellular Biology.”
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Sergey V. Abkin and Katerina M. Pankratova contributed equally to this work.
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Abkin, S.V., Pankratova, K.M., Komarova, E.Y. et al. Hsp70 chaperone-based gel composition as a novel immunotherapeutic anti-tumor tool. Cell Stress and Chaperones 18, 391–396 (2013). https://doi.org/10.1007/s12192-012-0391-x
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DOI: https://doi.org/10.1007/s12192-012-0391-x