Skip to main content

Advertisement

SpringerLink
Log in

Role of tumor-derived transforming growth factor-β1 (TGF-β1) in site-dependent tumorigenicity of murine ascitic lymphosarcoma

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

Abstract

An ascitic lymphosarcoma (LS-A) of Swiss mice that regressed spontaneously on subcutaneous (s.c.) transplantation was investigated for the mechanism of its progressive growth and host mortality on intraperitoneal (i.p.) transplantation. In vitro studies indicated significant inhibition of LS-A proliferation seeded at higher cell density (>104/ml). Culture supernatants of LS-A caused bi-modal growth effects, the early supernatants (24 h) caused stimulation and the late (72 h) supernatants inhibited LS-A proliferation. The 72-h supernatants also suppressed T and B cell response to mitogens in a dose-dependent manner. Pan anti-transforming growth factor-β antibody abrogated the inhibitory effects of supernatants. The supernatants contained both latent as well as bio-active form of transforming growth factor-β1 (TGF-β1) as determined by ELISA. Mice bearing i.p. ascites tumor had elevated serum TGF-β1, hemoglobulinemia, splenic lymphopenia, impaired response of the T cells to mitogen and reduced expression of transferrin receptor (CD71) on the bone marrow cells. However, mice which rejected s.c. transplants, did not show significant changes in these parameters. Our studies indicated profound influence of site of tumor growth on tumor progression and host immune system mediated by tumor-derived TGF-β1. It is possible that human tumors which secrete TGF-β1 may exhibit similar patho-physiological effects in the host depending on the anatomical site of the tumor.

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. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Akhurst RJ, Derynck R (2001) TGF-β signaling in cancer—a double-edged sword. Trends Cell Biol 11:S44–S51

    Google Scholar 

  2. Balasubramaniam P, Malathi A (1992) Comparative study of hemoglobin estimated by Drabkin’s and Sahli’s methods. J Post Grad Med 38:8–9

    Google Scholar 

  3. Bodmer S, Srommer K, Frei K, Siepl C, de,Tribolet N, Heid I, Fontana A (1989) Immunosuppression and transforming growth factor beta in glioblastoma. Preferential production of transforming growth factor beta2. J Immunol 143:3222–3229

    Google Scholar 

  4. Burbridge MF, Kraus-Berthier L, Naze M, Pierre A, Atassi G, Guilbaud N (1999) Biological and pharmacological characterization of three models of human ovarian carcinoma established in nude mice: use of the CA 125 tumor marker to predict antitumor activity. Int J Oncol 15:1155–1162

    Google Scholar 

  5. Chouaib S, Asselin-Paturel C, Mami-Chouaib F, Caignard A, Blay JY (1997) The host-tumor immune conflict: from immnosuppression to resistance and destruction. Immunol Today 18:493–497

    Article  Google Scholar 

  6. Czarniecki W, Chiu HH, Wong GH, Mc Cabe SM, Palladino MA (1988) Transforming growth factor beta 1 modulates the expression of class II histocompatibility antigens on human cells. J Immunol 140:4217–4223

    Google Scholar 

  7. De Coteau JF, Knaus PI, Yankelev H, Reis MD, Lowsky R, Lodish HF, Kadin ME (1997) Loss of functional cell surface transforming growth factor beta (TGF-β) type I receptor correlate with insensitivity to TGF-β in chronic lymphocyte leukemia. Proc Natl Acad Sci USA 94:5877–5881

    Article  Google Scholar 

  8. Donelli MG, Russo R, Garattini S (1975) Selective chemotherapy in relation to the site of tumor transplantation. Int J Cancer 32:78–88

    Google Scholar 

  9. Fischer JR, Darjes H, Schindel M, Drings P, Krammer PH (1994) Constitutive secretion of bioactive transforming growth factor beta1 by small cell lung cancer cell lines. Eur J Cancer 30A:2125–2129

    Article  Google Scholar 

  10. Garba L, Frelinger JA (2001) Intracellular cytokine staining for TGF-beta. J Immunol Methods 258:193–198

    Article  Google Scholar 

  11. Hamilton TC, Young RC, Louie KG, Behrens BC, McKoy WM, Grotzinger KR (1984) Characterization of a xenografts model of human ovarian carcinoma which produces ascites and intraabdominal carcinomatosis in mice. Cancer Res 44:5286–5290

    Google Scholar 

  12. Hentze MW, Kuhn LC (1996) Molecular control of vertebrate iron metabolism: mRNA-based regulatory circuits operated by iron, nitric oxide and oxidative stress Proc Natl Acad Sci USA 93:8175–8182

    Article  CAS  PubMed  Google Scholar 

  13. Kehrl JH, Wakefield LM, Roberts AB, Jakowlew S, Alvarez-Mon M, Derynck R, Sporn MB, Fauci AS (1986) Production of transforming growth factor β by human T lymphocytes and its potential role in the regulation of T cell growth. J Exp Med 163:1037–1050

    Article  Google Scholar 

  14. Keyes KA, Mann L, Teicher B, Alvarez E (2003) Site-dependent angiogenic cytokine production in human tumor xenografts. Cytokine 21:98–104

    Article  Google Scholar 

  15. Khar A (1993) Characterization of spontaneous immunological rejection in a histiocytoma. I. Role of NK cell and anti tumor antibodies. Int J Oncol 3:393–398

    Google Scholar 

  16. Kloen P, Jennings CL, Gebhardt MC, Springfield DS, Mankin HJ (1994) Expression of transforming growth factor beta (TGF-β) receptors. TGF-β1 and TGF-β2 production and autocrine growth control in osteosarcoma cells. Int J Cancer 58:440–445

    Google Scholar 

  17. Kumar M, Seshadri M, Poduval TB, Chauhan PS, Sundaram K (1987) Cytogenetic studies on murine lymphosarcoma. Adv Biosci 6:35–44

    Google Scholar 

  18. Liaw FD, Denkins YM, Collins JH, Van Arsdall M, Chang JL, Chakrabarty S, Nguyen D, Kruzel E, Fidler IJ (2002) Type-1 transforming growth factor-beta differentially modulates tumoricidal activity of murine peritoneal macrophages against metastatic variants of the B16 murine melanoma. J Exp Ther Oncol 2:286–297

    Article  CAS  PubMed  Google Scholar 

  19. Mesiano S, Ferrara N, Jaffe RB (1998) Role of vascular endothelial growth factor in ovarian cancer: Inhibition of ascites formation by neutralization. Am J Pathol 153:1249–1256

    Google Scholar 

  20. Morikane K, Tempero R, Sivinski CL, Kitajima S, Gendler SJ, Hollingsworth MA (2001) Influence of organ site and tumor cell type on MUC1-specific tumor immunity. Int Immunol 13:233–240

    Article  CAS  PubMed  Google Scholar 

  21. Morris PC, Scholten V (1996) Osmotic lysis of tumor spill in ovarian cancer: a murine model. Am J Obstet Gynecol 175:1489–1492

    Google Scholar 

  22. Nakajima M, Morikawa K, Fabra A, Bucana CD, Fidler IJ (1990) Influence of organ environment on extracellular matrix degradative activity and metastasis of human colon carcinoma cells. J Natl Cancer Inst 82:1890–1898

    Google Scholar 

  23. Oklu R, Hasketh R (2000) The latent transforming growth factor beta binding protein (LTBP) family. Biochem. J 352:601–610

    Article  Google Scholar 

  24. Papac RJ (1996) Spontaneous regression of cancer. Cancer Treat Rev 22:395–423

    Article  Google Scholar 

  25. Paterson C, Davies M, Stone A, Huntley S, Smith E, Pring M, Eveson JW, Robinson CM, Parkinson EK, Prime SS (2002) TGF-beta 1 acts as a tumor suppressor of human malignant keratinocytes independently of Smad 4 expression and ligand-induced G(1) arrest. Oncogene 21:1616–1624

    Article  Google Scholar 

  26. Roberts B, Flanders KC, Kondaiah P, Thompson NL, Obberghen- Schilling E, Wakfield L, Rossi P, de Cambrugghe B, Heine U, Sporn MB (1988)Transforming growth factor beta: biochemistry and roles in embriogenesis, tissue repair and remodeling and carcinogenesis. Recent Prog Horm Res 44:157–168

    Google Scholar 

  27. Roberts B, Flanders KC, Heine UI, Jakowlew S, Kondaiah P, Kim SJ, Sporn MB (1990) Transforming growth factor-beta: multifunctional regulator of differentiation and development. Philos Trans R Soc Lond B Biol Sci 327:145–154

    Google Scholar 

  28. Rodeck U, Bosller A, Graeven U, Fox FE, Nowell PC, Knabbe K, Kari C (1994) Transforming growth factor beta production and responsiveness in normal human melanocytes and melanoma cells. Cancer Res 54:575–581

    Google Scholar 

  29. Saharinen J, Hyytiainen M, Taipale J, Keski-Oja J (1999) Latent transforming growth factor beta binding proteins (LTBPs)– structural extracellular matrix proteins for targeting TGF beta action. Cytokine Growth Factor Rev 10:99–117

    Article  CAS  PubMed  Google Scholar 

  30. Schomaker SJ, Clemo FA, Amacher DE(2002) Analysis of rat bone marrow by flow cytometry following in vivo exposure to cyclohexanone oxime or daunomycin HCl. Toxicol Appl Pharmacol 185:48–54

    Article  Google Scholar 

  31. Schwarz RE, McCarty TM, Peralta EA, Diamond DJ, Ellenhorn JD (1999) An orthotopic in vivo model of human pancreatic cancer. Surgery 126:562–567

    Article  CAS  PubMed  Google Scholar 

  32. Shim KS, Kim KH, Han WS, Park EB (1999) Elevated serum levels of transforming growth factor-beta1 in patients with colorectal carcinoma: its association with tumor progression and its significant decrease after curative surgical resection. Cancer 85:554–561

    Article  Google Scholar 

  33. Staroselsky N, Fan D, O’Brian CA, Bucana CD, Gupta KP, Fidler IJ (1990) Site-dependent differences in response of the UV-2237 murine fibrosarcoma to systemic therapy with adriamycin. Cancer Res 50:7775–7782

    Google Scholar 

  34. Tan MH, Chu TM (1985) Characterization of the mouse tumorigenic and metastatic properties of a human pancreatic tumor cell line (AsPC-1) implanted orthotopically into nude mice. Tumor Biol 6:89–98

    Google Scholar 

  35. Thakur VS, Seshadri M, Shah DH, Poduval TB (1997) Adoptive immunotherapy of murine lymphosaroma: comparative study using allo-immune or tumor-immune T cells. Ind J Exp Biol 35:581–588

    Google Scholar 

  36. Vanky F, Nagy N, Hising C, Sjovall K, Larson B, Klein E (1997) Human ex vivo carcinoma cells produce transforming growth factor-β and thereby can inhibit lymphocyte function in vitro. Cancer Immnol Immunother 43:317–323

    Article  Google Scholar 

  37. Wilmanns C, Fan D, O’Brian CA, Bucana CD, Fidler IJ (1992) Orthotopic and ectopic organ environments differentially influence the sensitivity of murine colon carcinoma cells to doxorubicin and 5-fluorouracil. Int J Cancer 52:98–104

    Google Scholar 

Download references

Acknowledgements

The authors, thank Shri S. Santosh Kumar for critically going through the manuscript and Shri N.S. Sidnalkar, also, Shri K.S. Munankar for their expert technical help in animal experiments.

Author information

Authors and Affiliations

  1. Radiation Biology & Health Sciences Division, Bioscience Group, Modular Laboratories, Bhabha Atomic Research Centre, Trombay, Mumbai, 400 085, India

    V. S. Thakur, B. Shankar, S. Chatterjee, S. Premachandran & K. B. Sainis

Authors
  1. V. S. Thakur
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. B. Shankar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S. Chatterjee
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S. Premachandran
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. K. B. Sainis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to K. B. Sainis.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Thakur, V.S., Shankar, B., Chatterjee, S. et al. Role of tumor-derived transforming growth factor-β1 (TGF-β1) in site-dependent tumorigenicity of murine ascitic lymphosarcoma. Cancer Immunol Immunother 54, 837–847 (2005). https://doi.org/10.1007/s00262-004-0656-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-004-0656-z

Keywords

Search

Navigation