Skip to main content
SpringerLink
Log in
Book cover

Cytokines in the Genesis and Treatment of Cancer pp 199–209Cite as

In Vivo Murine Cytokine Models and the Genesis of Cancer

  • Chapter

  • 902 Accesses

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Abstract

Cytokines and their receptors comprise a critical communication pathway among the various cell types of the immune system that regulate cell growth, survival, differentiation, activation, and trafficking. As such, dysregulation of cytokine expression or secretion, cytokine-receptor expression, and their linked intracellular signaling pathways can result in undesired cell growth, survival, and ultimately malignant transformation. Use of transgenic mouse technology provides a powerful tool to better understand the physiologic sequelae resulting from unregulated activation of a cytokine/receptor pair at the level of the whole organism. In addition to altered expression of cytokine/receptor pairs leading directly to malignancy, indirect effects may also be elucidated using carcinogen models. Although other chapters in this book provide in depth review of individual cytokines’ role in the genesis or therapy of cancer, here we generally discuss transgenic and knock-out mouse models that lead to malignant transformation. When relevant, studies from patients with cancer are also mentioned to provide some correlation with human disease, in addition to other chapters in this volume. One common theme that emerges from these models is the importance of chronic cytokine-induced growth, survival, or inflammatory signals as a background leading to malignant transformation. Ultimately, better understanding of the cellular and molecular events that lead to the development of cancer will help provide novel targets for therapeutic intervention.

This is a preview of subscription content, 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   169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   219.99
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

Learn about institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Palmiter RD, Brinster RL, Hammer RE, et al. Dramatic growth of mice that develop from eggs microinjected with metallothionein-growth hormone fusion genes. Nature. 1982;300:611–615.

    Article  CAS  PubMed  Google Scholar 

  2. Hofker MH, VanDeursen J. Transgenic mouse methods and protocols. In: Walker JM ed. Methods in Molecular Biology, Vol. 209. Humana Press, Totowa, New Jersey, p. 374, 2003.

    Google Scholar 

  3. Pasparakis M, Alexopoulou L, Episkopou V, Kollias G. Immune and inflammatory responses in TNF alpha-deficient mice: A critical requirement for TNF alpha in the formation of primary B cell follicles, follicular dendritic cell networks and germinal centers, and in the maturation of the humoral immune response. J Exp Med. 1996;184:1397–1411.

    Article  CAS  PubMed  Google Scholar 

  4. Kishimoto T, Akira S, Narazaki M, Taga T. Interleukin-6 family of cytokines and gpl30. Blood. 1995;86:1243–1254.

    CAS  PubMed  Google Scholar 

  5. Naka T, Nishimoto N, Kishimoto T. The paradigm of IL-6: From basic science to medicine. Arthritis Res. 2002;4:S233–242.

    Article  PubMed  Google Scholar 

  6. Kawano M, Hirano T, Matsuda T, et al. Autocrine generation and requirement of BSF-2/IL-6 for human multiple myelomas. Nature. 1988;332:83–85.

    Article  CAS  PubMed  Google Scholar 

  7. Zhang XG, Klein B, Bataille R. Interleukin-6 is a potent myeloma-cell growth factor in patients with aggressive multiple myeloma. Blood. 1989;74:11–13.

    CAS  PubMed  Google Scholar 

  8. Klein B, Zhang XG, Lu ZY, Bataille R. Interleukin-6 in human multiple myeloma. Blood. 1995; 85:863–872.

    CAS  PubMed  Google Scholar 

  9. Tosato G, Jones K, Breinig MK, McWilliams HP, McKnight JL. Interleukin-6 production in posttransplant lymphoproliferative disease. J Clin Invest. 1993;91:2806–2814.

    Article  CAS  PubMed  Google Scholar 

  10. Yoshizaki K, Matsuda T, Nishimoto N, et al. Pathogenic significance of interleukin-6 (IL-6/BSF-2) in Castleman’s disease. Blood. 1989;74:1360–1367.

    CAS  PubMed  Google Scholar 

  11. Suematsu S, Matsuda T, Aozasa K, et al. IgGl plasmacytosis in interleukin 6 transgenic mice. Proc Natl Acad Sci USA. 1989;86:7547–7551.

    Article  CAS  PubMed  Google Scholar 

  12. Suematsu S, Matsusaka T, Matsuda T, et al. Generation of plasmacytomas with the chromosomal translocation t(12;15) in interleukin 6 transgenic mice. Proc Natl Acad Sci USA. 1992;89:232–235.

    Article  CAS  PubMed  Google Scholar 

  13. Kovalchuk AL, Kim JS, Park SS, et al. IL-6 transgenic mouse model for extraosseous plasmacytoma. Proc Natl Acad Sci USA. 2002;99:1509–1514.

    Article  CAS  PubMed  Google Scholar 

  14. Woodroofe C, Muller W, Ruther U. Long-term consequences of interleukin-6 overexpression in transgenic mice. DNA Cell Biol 1992;11:587–592.

    Article  CAS  PubMed  Google Scholar 

  15. Fattori E, Delia Rocca C, Costa P, et al. Development of progressive kidney damage and myeloma kidney in interleukin-6 transgenic mice. Blood 1994;83:2570–2579.

    CAS  PubMed  Google Scholar 

  16. Peters M, Jacobs S, Ehlers M, et al. The function of the soluble interleukin 6 (IL-6) receptor in vivo: Sensitization of human soluble IL-6 receptor transgenic mice towards IL-6 and prolongation of the plasma half-life of IL-6. J Exp Med 1996;183:1399–1406.

    Article  CAS  PubMed  Google Scholar 

  17. Schirmacher P, Peters M, Ciliberto G, et al. Hepatocellular hyperplasia, plasmacytoma formation, and extramedullary hematopoiesis in interleukin (IL)-6/soluble IL-6 receptor double-transgenic mice. Am J Pathol. 1998;153:639–648.

    CAS  PubMed  Google Scholar 

  18. Hilbert DM, Kopf M, Mock BA, Kohler G, Rudikoff S. Interleukin 6 is essential for in vivo development of B lineage neoplasms. J Exp Med 1995;182:243–248.

    Article  CAS  PubMed  Google Scholar 

  19. Maione D, Di Carlo E, Li W, et al. Coexpression of IL-6 and soluble IL-6R causes nodular regenerative hyperplasia and adenomas of the liver. EMBO J 1998;17:5588–5597.

    Article  CAS  PubMed  Google Scholar 

  20. Fry TJ, Mackall CL. Interleukin-7: From bench to clinic. Blood 2002;99:3892–3904.

    Article  CAS  PubMed  Google Scholar 

  21. Qin, JZ, Dummer, R, Burg, G, and Dobbeling, U. Constitutive and interleukin-7/interleukin-15 stimulated DNA binding of Myc, Jun, and novel Myc-like proteins in cutaneous T-cell lymphoma cells. Blood 1999;93:260–267.

    CAS  PubMed  Google Scholar 

  22. Rich BE, Campos-Torres J, Tepper RI, Moreadith RW, Leder P. Cutaneous lymphoproliferation and lymphomas in interleukin 7 transgenic mice. J Exp Med 1993;177:305–316.

    Article  CAS  PubMed  Google Scholar 

  23. Fisher AG, Burdet C, Bunce C, Merkenschlager M, Ceredig R. Lymphoproliferative disorders in IL-7 transgenic mice: Expansion of immature B cells which retain macrophage potential. Int Immunol 1995;7:415–423.

    Article  CAS  PubMed  Google Scholar 

  24. Valenzona HO, Pointer R, Ceredig R, Osmond DG. Prelymphomatous B cell hyperplasia in the bone marrow of interleukin-7 transgenic mice: Precursor B cell dynamics, microenvironmental organization and osteolysis. Exp Hematol 1996;24:1521–1529.

    CAS  PubMed  Google Scholar 

  25. Demoulin JB, Renauld JC. Interleukin 9 and its receptor: An overview of structure and function. Int Rev Immunol 1998; 16:345–364.

    CAS  PubMed  Google Scholar 

  26. Merz H, Houssiau FA, Orscheschek K, et al. Interleukin-9 expression in human malignant lymphomas: Unique association with Hodgkin’s disease and large cell anaplastic lymphoma. Blood 1991;78:1311–1317.

    CAS  PubMed  Google Scholar 

  27. Fischer M, Bijman M, Molin D, et al. Increased serum levels of interleukin-9 correlate to negative prognostic factors in Hodgkin’s lymphoma. Leukemia 2003;17:2513–2516.

    Article  CAS  PubMed  Google Scholar 

  28. Renauld JC, van der Lugt N, Vink A, et al. Thymic lymphomas in interleukin 9 transgenic mice. Oncogene 1994;9:1327–1332.

    CAS  PubMed  Google Scholar 

  29. Renauld JC, Vink A, Louahed J, Van Snick J. Interleukin-9 is a major anti-apoptotic factor for thymic lymphomas. Blood 1995;85:1300–1305.

    CAS  PubMed  Google Scholar 

  30. Morris SW, Kirstein MN, Valentine MB, et al. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin’s lymphoma. Science 1994;263:1281–1284.

    Article  CAS  PubMed  Google Scholar 

  31. Morris SW, Xue L, Ma Z, Kinney MC. Alk+ CD30+ lymphomas: A distinct molecular genetic subtype of non-Hodgkin’s lymphoma. Br J Haematol 2001; 113:275–295.

    Article  CAS  PubMed  Google Scholar 

  32. Lange K, Uckert W, Blankenstein T, et al. Overexpression of NPM-ALK induces different types of malignant lymphomas in IL-9 transgenic mice. Oncogene 2003;22:517–527.

    Article  CAS  PubMed  Google Scholar 

  33. Pestka S, Krause CD, Sarkar D, Walter MR, Shi Y, Fisher PB. Interleukin-10 and related cytokines and receptors. Annu Rev Immunol 2004;22:929–979.

    Article  CAS  PubMed  Google Scholar 

  34. Hagenbaugh A, Sharma S, Dubinett SM, et al. Altered immune responses in interleukin 10 transgenic mice. J Exp Med 1997;185:2101–2110.

    Article  CAS  PubMed  Google Scholar 

  35. Huang M, Sharma S, Mao JT, Dubinett SM. Non-small cell lung cancer-derived soluble mediators and prostaglandin E2 enhance peripheral blood lymphocyte IL-10 transcription and protein production. J Immunol 1996;157:5512–5520.

    CAS  PubMed  Google Scholar 

  36. Sharma S, Stolina M, Lin Y, et al. T cell-derived IL-10 promotes lung cancer growth by suppressing both T cell and APC function. J Immunol 1999;163:5020–5028.

    CAS  PubMed  Google Scholar 

  37. Fehniger TA, Caligiuri MA. Interleukin 15: Biology and relevance to human disease. Blood 2001;97:14–32.

    Article  CAS  PubMed  Google Scholar 

  38. Leroy S, Dubois S, Tenaud I, et al. Interleukin-15 expression in cutaneous T-cell lymphoma (mycosis fungoides and Sezary syndrome). Br J Dermatol 2001;144:1016–1023.

    Article  CAS  PubMed  Google Scholar 

  39. Dobbeling U, Dummer R, Lainez E, Potoczna N, Qin JZ, Burg G. Interleukin-15 is an autocrine/paracrine viability factor for cutaneous T-cell lymphoma cells. Blood 1998;92:252–258.

    CAS  PubMed  Google Scholar 

  40. Zambello R, Facco M, Trentin L, et al. Interleukin-15 triggers the proliferation and cytotoxicity of granular lymphocytes in patients with lymphoproliferative disease of granular lymphocytes. Blood 1997;89:201–211.

    CAS  PubMed  Google Scholar 

  41. Tinhofer I, Marschitz I, Henn T, Egle A, Greil R. Expression of functional interleukin-15 receptor and autocrine production of interleukin-15 as mechanisms of tumor propagation in multiple myeloma. Blood 2000;95:610–618.

    CAS  PubMed  Google Scholar 

  42. Fehniger TA, Suzuki K, Ponnappan A, et al. Fatal leukemia in interleukin 15 transgenic mice follows early expansions in natural killer and memory phenotype CD8+ T cells. J Exp Med 2001;193: 219–231.

    Article  CAS  PubMed  Google Scholar 

  43. Fehniger TA, Suzuki K, VanDeusen JB, Cooper MA, Freud AG, Caligiuri MA. Fatal leukemia in interleukin-15 transgenic mice. Blood Cells Mol Dis 2001;27:223–230.

    Article  CAS  PubMed  Google Scholar 

  44. Battista S, Fidanza V, Fedele M, et al. The expression of a truncated HMGI-C gene induces gigantism associated with lipomatosis. Cancer Res 1999;59:4793–4797.

    CAS  PubMed  Google Scholar 

  45. Baldassarre G, Fedele M, Battista S, et al. Onset of natural killer cell lymphomas in transgenic mice carrying a truncated HMGI-C gene by the chronic stimulation of the IL-2 and IL-15 pathway. Proc Natl Acad Sci USA. 2001;98:7970–7975.

    Article  CAS  PubMed  Google Scholar 

  46. Yu L, Liu C, Vandeusen J, et al. Global assessment of promoter methylation in a murine model of cancer identifies ID4 as a putative tumor suppressor gene in human leukemia. Nat Genet 2005; 37: 265–274.

    Article  CAS  PubMed  Google Scholar 

  47. Yu L, Liu C, Bennett K, et al. A Notl-EcoRV promoter library for studies of genetic and epigenetic alterations in mouse models of human malignancies. Genomics 2004;84:647–660.

    Article  CAS  PubMed  Google Scholar 

  48. Moore RJ, Owens DM, Stamp G, et al. Mice deficient in tumor necrosis factor-alpha are resistant to skin carcinogenesis. Nat Med 1999;5:828–831.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Hematology and Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO

    Todd A. Fehniger MD, PHD

  2. The Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA

    Megan A. Cooper MD, PHD

  3. The Ohio State University Comprehensive Cancer Center, Columbus, OH

    Michael A. Caligiuri MD

Authors
  1. Todd A. Fehniger MD, PHD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Megan A. Cooper MD, PHD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael A. Caligiuri MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. The Ohio State University Comprehensive Cancer Center, Columbus, OH

    Michael A. Caligiuri MD

  2. University of Pittsburgh Cancer Center, Pittsburgh, PA

    Michael T. Lotze MD (Director) (Director)

Rights and permissions

Reprints and permissions

Copyright information

© 2007 Humana Press Inc.

About this chapter

Cite this chapter

Fehniger, T.A., Cooper, M.A., Caligiuri, M.A. (2007). In Vivo Murine Cytokine Models and the Genesis of Cancer. In: Caligiuri, M.A., Lotze, M.T. (eds) Cytokines in the Genesis and Treatment of Cancer. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1007/978-1-59745-455-1_11

Download citation

  • DOI: https://doi.org/10.1007/978-1-59745-455-1_11

  • Publisher Name: Humana Press

  • Print ISBN: 978-0-89603-820-2

  • Online ISBN: 978-1-59745-455-1

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation