Skip to main content
SpringerLink
Log in

Immunostimulation exacerbates the biological effects of chemical carcinogens

  • Regeneration
  • Published:
Biology Bulletin Aims and scope Submit manuscript

Abstract

The reciprocal relation between the high regenerative ability of various animal species and the low incidence of haphazard or experimentally induced malignant tumours in these animal species is well documented. Equally well documented is the repeated observation that the decline in regenerative potential coincides with an increase in the incidence of cancers, a fact which, on an evolutionary scale, parallels with the development of a sophisticated immune system. The combination of the above observations led to the hypothesis that at least parts of an immune reaction might promote tumour development, and indeed, many experiments specifically designed to answer this question support this prediction. However, this “immunostimulation theory of tumour development” is neither explained in a satisfactory fashion nor universally adopted. The aim of the present investigation was to approach this issue by exploiting the dual, spectacular ability of urodele amphibians to regenerate a lot of organs and to make a stand to carcinogenesis. To this end, urodele amphibians of the species Triturus cristatus were immunologically challenged by intra-abdominal injections of sheep serum, they had then both their hind limbs amputated, and crystals of MNNG (N-Methyl-N″-nitro-N-nitrosoguanidine) were implanted into the stumps. The results show that the effects of MNNG on the immunostimulated animals display significant quantitative augmentation with respect to non-immunized controls. This augmentation consists in higher animal mortality, extension of the dedifferentiating stump tissue and concomitant retardation of limb restoration, and increase in the incidence of abnormal regenerates.

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

Similar content being viewed by others

References

  • Balls, M. and Ruben, I.K., A Review of the Chemical Induction of Neoplasms in Amphibian, Experientia, 1964, vol. 20, pp. 241–247.

    Article  PubMed  CAS  Google Scholar 

  • Barski, G. and Young, J.K., Evolution of Cell-Mediated Immunity in Mice Bearing an Antigenic Tumor. Influence of Tumor Growth and Surgical Removal, J. Natl. Cancer Inst., 1969, vol. 43, pp. 111–121.

    PubMed  CAS  Google Scholar 

  • Brockes, J., Regeneration and Cancer, Biochim. Biophys. Acta, 1998, vol. 1377, pp. 1–11.

    Google Scholar 

  • Burwell, R.G., The Role of Lymphoid Tissue in Morphostasis, Lancet, 1963, vol. 2, pp. 69–70.

    Article  PubMed  CAS  Google Scholar 

  • Doll, R., An Epidemiological Perspective of the Biology of Cancer, Cancer Res., 1978, vol. 38, no. 11, pt. 1, pp. 3573–3583.

    PubMed  CAS  Google Scholar 

  • Donaldson, D.J. and Mason, J.M., Cancer-Related Aspects of Regeneration Research. A Review, Growth, 1975, vol. 39, pp. 475–496.

    PubMed  CAS  Google Scholar 

  • Eguchi, G. and Watanabe, K., Elicitation of Lens Formation from the “Ventral Iris” Epithelium of the Newt by a Carcinogen, N-Methyl-N′-Nitro-N-Nitrosoguanidine, J. Embryol. Exp. Morphol., 1973, vol. 30, no. 1, pp. 63–71.

    PubMed  CAS  Google Scholar 

  • Frangioni, G. and Borgioli, G., Effect of Spleen Congestion and Decongestion on Newt Blood, J. Zool., 1991, vol. 223, pp. 15–25.

    Google Scholar 

  • Goding, J.W., Monoclonal Antibodies: Principles and Practice, New York: Academic, 1996.

    Google Scholar 

  • Hansen, J.D. and Zapata, A.G., Lymphocyte Development in Fish and Amphibians, Immunol. Rev., 1998, vol. 166, pp. 199–220.

    Article  PubMed  CAS  Google Scholar 

  • Hersey, P., Impediments to Successful Immunotherapy, Pharmacol. Ther., 1999, vol. 81, no. 2, pp. 111–119.

    Article  PubMed  CAS  Google Scholar 

  • Hudson, L. and Hay, F.C., Practical Immunology, 3rd Ed., Oxford: Blackwell Scientific, 1989.

    Google Scholar 

  • Humphreys, T. and Reichert, E.L., Invertebrate Immune Recognition, Natural Immunity and the Evolution of Positive Selection, Immunol. Today, 1999, vol. 15, pp. 316–320.

    Article  Google Scholar 

  • Ichim, C.V., Revisiting Immunosurveillance and Immunostimulation: Implications for Cancer Immunotherapy, J. Transl. Med, 2005, vol. 3, no. 1, pp. 1–34.

    Article  CAS  Google Scholar 

  • Iten, L.E. and Bryant, S.V., Forelimb Regeneration from Different Levels of Amputation in the Newt Notophthalmus Viridescens: Length, Rate and Stages, Wilh. Roux’s Arch, 1973, vol. 173, pp. 263–282.

    Article  Google Scholar 

  • Kadhim, S.A. and Rees, R.C., Enhancement of Tumor Growth in Mice: Evidence for the Involvement of Host Macrophages, Cell Immunol., 1984, vol. 87, no. 1, pp. 259–269.

    Article  PubMed  CAS  Google Scholar 

  • Keramitsoglou, T., Grispou, E., Margaritis, L.H., and Koussoulakos, S., Implantation of MNNG Crystals into a Triturus Intact Limb Affects Mitotic and Labeling Indices, Regeneration Rate and Morphogenesis in the Contralateral, Regenerating Limb, Teratog. Carcinog. Mutagen., 2002, vol. 22, no. 6, pp. 473–483.

    Article  PubMed  CAS  Google Scholar 

  • Kim, W.-J., Beardsley, D.I., Adamson, A.W., and Brown, K.D., The Monofunctional Alkylating Agent N-Methyl-N′-Nitro-N-Nitrosoguanidine Triggers Apoptosis through p53-Dependent and-Independent Pathways, Toxicol. Appl. Pharmacol., 2005, vol. 202, no. 1, pp. 84–98.

    Article  PubMed  CAS  Google Scholar 

  • Koussoulakos, S. and Kiortsis, V., Regeneration: Birth of Experimental Zoology. Physiology. Recent Research Trends, Trends Compar. Biochem. Physiol., 1993, vol. 1, pp. 210–218.

    Google Scholar 

  • Koussoulakos, S. and Mitashov, V., N-Methyl-N-Nitro-N-Nitrosoguanidine (MNNG) May Induce Accessory Out-growth on Triturus cristatus Hind Limbs Even away from the Level of Its Administration, Biol. Bull., 1998, vol. 25, no. 6, pp. 540–544.

    Google Scholar 

  • Krakowski, L., Krzyzanowski, J., Wrona, Z., et al., The Influence of Nonspecific Immunostimulation of Pregnant Sows on the Immunological Value of Colostrums, Vet. Immunol. Immunopathol., 2002, vol. 87, nos. 1–2, pp. 89–95.

    Article  PubMed  CAS  Google Scholar 

  • McBrearty, B.A., Clark, L.D., Zhang, X.M., et al., Genetic Analysis of Mammalian Wound-Healing Trait, Proc. Natl. Acad. Sci. USA, 1998, vol. 95, no. 20, pp. 11792–11797.

    Article  PubMed  CAS  Google Scholar 

  • Mescher, A.L. and Neff, A.W., Regenerative Capacity and the Developing Immune System, Adv. Biochem. Eng. Biotechnol., 2005, vol. 93, pp. 39–66.

    PubMed  CAS  Google Scholar 

  • Milulska, J.B., Smith, C., and Alexander, P., Evidence for An Immunological Reaction of the Host Directed Against Its Own Actively Growing Primary Tumor, J. Natl. Cancer Inst., 1966, vol. 36, no. 1, pp. 29–35.

    Google Scholar 

  • Needham, J., New Advances in the Chemistry and Biology of Organized Growth, Proc. Roy. Soc., 1936, vol. 29, pp. 1577–1626.

    CAS  Google Scholar 

  • Pfeiffer, C.J., Nagai, T., Fujimura, M., and Tobe, T., Teratogenic Effects of Carcinogenic Agents on Limb Regeneration in the Japanese Newt Cynops Pyrrhogaster, Teratog. Carcinog. Mutagen., 1985, vol. 5, no. 3, pp. 137–147.

    Article  PubMed  CAS  Google Scholar 

  • Pierce, G.B. and Speers, W.C., Tumors as Caricatures of the Process of Tissue Renewal: Prospects for Therapy by Directing Differentiation, Cancer Res., 1988, vol. 48, no. 8, pp. 1996–2004.

    PubMed  CAS  Google Scholar 

  • Prehn, R.T. and Lappe, M.A., An Immunostimulation Theory of Tumor Development, Transplant. Rev., 1971, vol. 7, pp. 26–54.

    PubMed  CAS  Google Scholar 

  • Prehn, R.T., Stimulatory Effects of Immune Reactions upon the Growth of Untransplanted Tumors, Cancer Res., 1994, vol. 54, no. 4, pp. 908–914.

    PubMed  CAS  Google Scholar 

  • Prehn, R.T., The Immune Reaction as a Stimulator of Tumor Growth, Science, 1972, vol. 176, pp. 170–171.

    Article  PubMed  CAS  Google Scholar 

  • Rao, V.P., Poutahidis, T., Ge, Z., et al., Proinflammatory CD4 + CD45RB(hi) Lymphocytes Promote Mammary and Intestinal Carcinogenesis in Apc(Min/+) Mice, Cancer Res., 2006, vol. 66, no. 1, pp. 57–61.

    Article  PubMed  CAS  Google Scholar 

  • Rose, S.M., The Effect of NaCl in Stimulating Regeneration of Limbs of Frogs, J. Morphol., 1945, vol. 77, pp. 119–139.

    Article  Google Scholar 

  • Ruben, L.N and Edwards, B.F, The Influence of Lymphoid Cell Heterogeneity in the Newt, Triturus viridescens, from Hapten-Carrier Antigen Binding Studies, in Phylogeny of Thymus and Bone Marrow-Bursa Cells, Wright, R.K. and Cooper, E.I., Eds., Amsterdam: Elsevier, 1975, pp. 161–168.

    Google Scholar 

  • Ruben, L.N., Balls, M., and Stevens, J., Cancer and Super-Regeneration in Triturus viridescens Limbs, Experientia, 1996, vol. 22, no. 4, pp. 260–261.

    Article  Google Scholar 

  • Ruben, L.N., IgM Memory: Long-Lived Hapten-Specific Memory in the Newt, Notophthalmus Viridescens, Immunology, 1983, vol. 48, pp. 385–392.

    PubMed  CAS  Google Scholar 

  • Schwartz, M. and Cohen, I.R., Autoimmunity Can Benefit Self-Maintenance, Immunol. Today, 2000, vol. 21, no. 6, pp. 265–268.

    Article  PubMed  CAS  Google Scholar 

  • Seilern-Aspang, F., Experimentelle Beitrage zur Frage der Zusammenhange: Regenerationsfahigkeit-Geschwulstbildung, Wilh. Roux’s Arch, 1960, vol. 152, pp. 491–516.

    Article  Google Scholar 

  • Sharova, L.V., Gogal, R.M. Jr., Sharov, A.A., et al., Immune Stimulation in Urethane-Exposed Pregnant Mice Increases Expression Level of Spleen Leukocyte Genes for TGFbeta3 GM-CSF and Other Cytokines That May Play a Role in Reduced Chemical-Induced Birth Defects, Int. Immunopharmacol., 2002, vol. 2, no. 10, pp. 1477–1489.

    Article  PubMed  CAS  Google Scholar 

  • Sicard, R.E. and Laffond, W.T., Putative Immunological Influence upon Amphibian Forelimb Regeneration. I. Effects of Several Immunoreactive Agents on Regeneration Rate and Gross Morphology, Exp. Cell Biol., 1983, vol. 51, pp. 337–344.

    CAS  Google Scholar 

  • Stewart, T.H., Evidence for Immune Facilitation of Breast Cancer Growth and for the Immune Promotion of Oncogenesis in Breast Cancer, Medicina, 1996, vol. 56, suppl. 1, pp. 13–24.

    PubMed  Google Scholar 

  • Taban, C.-H., Charolais, P., and Bersier, F., Controle Immunologique De La Regeneration (II), C.R. Seances Soc. Phys. Hist. Nat. (Geneve), 1996, vol. 1, pp. 32–44.

    Google Scholar 

  • Torchinsky, A., Toder, V., Savion, S., et al., Immunostimulation Increases the Resistance of Mouse Embryos to the Teratogenic Effect of Diabetes Mellitus, Diabetologia, 1997, vol. 40, no. 6, pp. 635–640.

    Article  PubMed  CAS  Google Scholar 

  • Tournefier, A., Incomplete Antibodies and Immunoglobulin Characterization in Adult Urodeles, Pleurodeles waltlii Michah and Triturus alpestris Laur., Immunology, 1975, vol. 29, no. 1, pp. 209–217.

    PubMed  CAS  Google Scholar 

  • Tsonis, P.A. and Del Rio-Tsonis, K., Spontaneous Neoplasms in Amphibian, Tumor Biol., 1988, vol. 9, pp. 221–234.

    Article  CAS  Google Scholar 

  • Tsonis, P.A. and Eguchi, G., Carcinogens on Regeneration. Effects of N-Methyl-N′-Nitro-N-Nitrosoguanidine and 4-Nitro-Quinoline-1-Oxide on Limb Regeneration in Adult Newts, Differentiation, 1981, vol. 20, pp. 52–60.

    Article  PubMed  CAS  Google Scholar 

  • Wahl, S.M. and Wahl, L.H., Lymphokine Modulation of Connective Tissue Metabolism, Ann. New York Acad. Sci., 1979, vol. 332, pp. 411–432.

    Article  CAS  Google Scholar 

  • Washabaugh, C.H. and Tsonis, P.A., Mononuclear Leukocytes in the Newt Limb Blastema: in Vitro Behaviour, Int. J. Dev. Biol., 1994, vol. 38, no. 4, pp. 745–749.

    PubMed  CAS  Google Scholar 

  • Winn, H.J., Immune Mechanisms in Homotransplantations: II. Quantitative Assay of the Immunologic Activity of Lymphoid Cells Stimulated by Tumour Homografts, J. Immunol., 1961, vol. 86, pp. 228–239.

    PubMed  CAS  Google Scholar 

  • Wohlrab, F., Victoria Blue: Staining Properties in Orthology and Pathology, Acta Histochem., 1991, vol. 91, no. 1, pp. 51–57.

    PubMed  CAS  Google Scholar 

  • Zilakos, N.P., Tsonis, P.A., Del Rio-Tsonis, K., and Parchment, R.E., Newt Squamous Carcinoma Proves Phylogenetic Conservation of Tumors as Caricatures of Tissue Renewal, Cancer Res., 1992, vol. 52, no. 18, pp. 4858–4865.

    PubMed  CAS  Google Scholar 

  • Zitvogel, L., Tesniere, A., and Kroemer, G., Cancer Despite Immunosurveillance: Immunoselection and Immunosubversion, Nat. Rev. Immunol., 2006, vol. 6, no. 10, pp. 715–727.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Faculty of Biology, Department of Cell Biology and Biophysics, University of Athens, Athens, Greece

    V. Skourou, Th. Keramitsoglou, D. Koussoulakou & S. Koussoulakos

  2. Kol’tsov Institute of Developmental Biology, Russian Academy of Science, ul. Vavilova 26, Moscow, 119991, Russia

    V. Mitashov

Authors
  1. V. Skourou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Th. Keramitsoglou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D. Koussoulakou
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. V. Mitashov
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S. Koussoulakos
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Skourou, V., Keramitsoglou, T., Koussoulakou, D. et al. Immunostimulation exacerbates the biological effects of chemical carcinogens. Biol Bull Russ Acad Sci 34, 333–339 (2007). https://doi.org/10.1134/S1062359007040048

Download citation

  • Received:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S1062359007040048

Keywords

Search

Navigation