Abstract
The history of immunizing animals with fetal tissues to generate an antitumor response dates back a century ago. Subsequent reports supported the idea that vaccination with embryonic materials could generate cancer-specific immunity and protect animals from transplantable and chemically induced tumors. In our study, we found C57 BL/6 mice vaccinated with embryonic stem cells (ESCs) received obvious antitumor immunity, which protected them from the formation and development of lung cancer. Furthermore, we investigated the antitumor effects of administration of ESCs in mice with minor and/or heavy tumor load. The tumor growth was monitored, the proliferation of lymphocytes and secretion of cytokines were examined, and finally the tissue sections were approached by immunohistochemical and apoptosis staining. The results suggested that mice injected with ESCs received obvious tumor inhibition and retardation due to significant lymphocyte proliferation and cytokine secretion, which help to rebuild the host’s immunity against cancer to some extent and comprise the main part of antitumor immunity. Moreover, mice with minor tumor load received stronger antitumor effect compared with mice with heavy tumor load, may be due to relatively intact immune system. Thus, besides their function as prophylactic vaccines, administration of ESCs could be a potential treatment for cancer, which obviously prevent and control the proliferation and development of malignant tumors.
Similar content being viewed by others
References
Reya T, Morrison SJ, Clarke MF, Weissman IL (2001) Stem cells, cancer, and cancer stem cells. Nature 414:105–111
Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 100:3983–3988
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
Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, Adsay V, Wicha M, Clarke MF, Simeone DM (2007) Identification of pancreatic cancer stem cells. Cancer Res 67:1030–1037
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
Wang S, Garcia AJ, Wu M, Lawson DA, Witte ON, Wu H (2006) Pten deletion leads to the expansion of a prostatic stem/progenitor cell subpopulation and tumor initiation. Proc Natl Acad Sci USA 103:1480–1485
Gibbs CP, Kukekov VG, Reith JD, Tchigrinova O, Suslov ON, Scott EW, Ghivizzani SC, Ignatova TN, Steindler DA (2005) Stem-like cells in bone sarcomas: implications for tumorigenesis. Neoplasia 7:967–976
Prince ME, Sivanandan R, Kaczorowski A, Wolf GT, Kaplan MJ, Dalerba P, Weissman IL, Clarke MF, Ailles LE (2007) Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc Natl Acad Sci USA 104:973–978
Pardal R, Clarke MF, Morrison SJ (2003) Applying the principles of stem-cell biology to cancer. Nat Rev Cancer 3:895–902
Cabanillas R, Llorente JL (2009) The Stem Cell Network model: clinical implications in cancer. Eur Arch Otorhinolaryngol 266:161–170
Reya T, Clevers H (2005) Wnt signalling in stem cells and cancer. Nature 434:843–850
Li L, Neaves WB (2006) Normal stem cells and cancer stem cells: the niche matters. Cancer Res 66:4553–4557
Huang EH, Heidt DG, Li CW, Simeone DM (2007) Cancer stem cells: a new paradigm for understanding tumor progression and therapeutic resistance. Surgery 141:415–419
Okamoto OK (2009) Cancer stem cell genomics: the quest for early markers of malignant progression. Expert Rev Mol Diagn 9:545–554
Rubio D, Garcia-Castro J, Martin MC, de la Fuente R, Cigudosa JC, Lloyd AC, Bernad A (2005) Spontaneous human adult stem cell transformation. Cancer Res 65:3035–3039
Li Y, Zeng H, Xu RH, Liu B, Li Z (2009) Vaccination with human pluripotent stem cells generates a broad spectrum of immunological and clinical responses against colon cancer. Stem Cells 27:3103–3111
Brewer BG, Mitchell RA, Harandi A, Eaton JW (2009) Embryonic vaccines against cancer: an early history. Exp Mol Pathol 86:192–197
LeMevel BP, Wells SA Jr (1973) Foetal antigens cross-reactive with tumour-specific transplantation antigens. Nat New Biol 244:183–184
Sikora K, Stern P, Lennox E (1977) Immunoprotection by embryonal carcinoma cells for methylcholanthrene-induced murine sarcomas. Nature 269:813–815
Coggin JH Jr, Adkinson L, Anderson NG (1980) Fetal antigens shared as transplantation rejection antigens on chemically induced mouse and hamster sarcomas. Cancer Res 40:1568–1573
Bertram JS, Janik P (1980) Establishment of a cloned line of Lewis Lung Carcinoma cells adapted to cell culture. Cancer Lett 11:63–73
Wang Z, Tang X, Li Y, Leu C, Guo L, Zheng X, Zhu D (2008) 20-Hydroxyeicosatetraenoic acid inhibits the apoptotic responses in pulmonary artery smooth muscle cells. Eur J Pharmacol 588:9–17
Rosato A, Zoso A, Dalla Santa S, Milan G, Del Bianco P, De Salvo GL, Zanovello P (2006) Predicting tumor outcome following cancer vaccination by monitoring quantitative and qualitative CD8+ T cell parameters. J Immunol 176:1999–2006
van Herck H, Baumans V, Brandt CJ, Hesp AP, Sturkenboom JH, van Lith HA, van Tintelen G, Beynen AC (1998) Orbital sinus blood sampling in rats as performed by different animal technicians: the influence of technique and expertise. Lab Anim 32:377–386
Mayo JG (1972) Biologic characterization of the subcutaneously implanted Lewis lung tumor. Cancer Chemother Rep 23:325–330
Jaffee EM (2006) Immunotherapy of Cancer. Ann NY Acad Sci 67–72
Al-Hajj M, Becker MW, Wicha M, Weissman I, Clarke MF (2004) Therapeutic implications of cancer stem cells. Curr Opin Genet Dev 14:43–47
Jordan CT (2005) Targeting the most critical cells: approaching leukemia therapy as a problem in stem cell biology. Nat Clin Pract Oncol 2:224–225
Copland M, Fraser AR, Harrison SJ, Holyoake TL (2005) Targeting the silent minority: emerging immunotherapeutic strategies for eradication of malignant stem cells in chronic myeloid leukaemia. Cancer Immunol Immunother 54:297–306
Hirschowitz EA, Yannelli JR (2009) Immunotherapy for lung cancer. Proc Am Thorac Soc 6:224–232
Whiteside TL (2006) Immune suppression in cancer: effects on immune cells, mechanisms and future therapeutic intervention. Semin Cancer Biol 16:3–15
Sioud M (2009) Does our current understanding of immune tolerance, autoimmunity, and immunosuppressive mechanisms facilitate the design of efficient cancer vaccines? Scand J Immunol 70:516–525
Xiong G, Husseiny MI, Song L, Erdreich-Epstein A, Shackleford GM, Seeger RC, Jackel D, Hensel M, Metelitsa LS. Novel cancer vaccine based on genes of Salmonella pathogenicity island 2. Int J Cancer 126:2622–2634
Johnsen A, France J, Sy MS, Harding CV (1998) Down-regulation of the transporter for antigen presentation, proteasome subunits, and class I major histocompatibility complex in tumor cell lines. Cancer Res 58:3660–3667
Drukker M, Katchman H, Katz G, Even-Tov Friedman S, Shezen E, Hornstein E, Mandelboim O, Reisner Y, Benvenisty N (2006) Human embryonic stem cells and their differentiated derivatives are less susceptible to immune rejection than adult cells. Stem Cells 24:221–229
Drukker M, Benvenisty N (2004) The immunogenicity of human embryonic stem-derived cells. Trends Biotechnol 22:136–141
Fairchild PJ, Cartland S, Nolan KF, Waldmann H (2004) Embryonic stem cells and the challenge of transplantation tolerance. Trends Immunol 25:465–470
Boyd AS, Higashi Y, Wood KJ (2005) Transplanting stem cells: potential targets for immune attack. Modulating the immune response against embryonic stem cell transplantation. Adv Drug Deliv Rev 57:1944–1969
Begley J, Ribas A (2008) Targeted therapies to improve tumor immunotherapy. Clin Cancer Res 14:4385–4391
Rosenberg SA, Yang JC, Restifo NP (2004) Cancer immunotherapy: moving beyond current vaccines. Nat Med 10:909–915
Ikeda H, Chamoto K, Tsuji T, Suzuki Y, Wakita D, Takeshima T, Nishimura T (2004) The critical role of type-1 innate and acquired immunity in tumor immunotherapy. Cancer Sci 95:697–703
Shurin MR, Lu L, Kalinski P, Stewart-Akers AM, Lotze MT (1999) Th1/Th2 balance in cancer, transplantation and pregnancy. Springer Semin Immunopathol 21:339–359
Koestenbauer S, Zech NH, Juch H, Vanderzwalmen P, Schoonjans L, Dohr G (2006) Embryonic stem cells: similarities and differences between human and murine embryonic stem cells. Am J Reprod Immunol 55:169–180
Acknowledgments
This study was supported by the National High-Tech Research and Development Programme of China (Programme 863) (Grant Number 2007AA021802). We would like to thank Professor Liu of Department of Pathology for her assistance in the processing of tissue sections.
Conflict of interest
None.
Author information
Authors and Affiliations
Corresponding author
Additional information
W. Dong and J. Du contributed equally to this work.
Rights and permissions
About this article
Cite this article
Dong, W., Du, J., Shen, H. et al. Administration of embryonic stem cells generates effective antitumor immunity in mice with minor and heavy tumor load. Cancer Immunol Immunother 59, 1697–1705 (2010). https://doi.org/10.1007/s00262-010-0899-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00262-010-0899-9