Skip to main content

Advertisement

SpringerLink
Log in

Regulation of galectin-1 expression by transforming growth factor β1 in metastatic mammary adenocarcinoma cells: implications for tumor-immune escape

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

Abstract

Tumors escape from immune surveillance by producing immunosuppressive cytokines and proapototic factors, including TGF-β and galectin-1 (Gal-1). Since immunosuppressive mechanisms might act in concert to confer tumor-immune privilege, we investigated the potential cross talk between TGF-β and Gal-1 in highly metastatic mammary adenocarcinoma (LM3) cells. While Gal-1 treatment was not capable of regulating TGF-β synthesis, a pronounced and dose-dependent increase in Gal-1 expression was observed when tumor cells were treated with TGF-β1. This effect was also observed in the murine lung adenocarcinoma LP07 and in the human breast adenocarcinoma MCF-7 cell lines. TGF-β1-mediated upregulation of Gal-1 expression was specifically mediated by TβRI and TβRII, since it was abrogated when LM3 cells were infected with retroviral vectors expressing the dominant negative forms of these receptors. In addition, gal-1 gene sequence analysis revealed the presence of three putative binding sites for Smad4 and Smad3 transcription factors, consistent with the ability of TGF-β1 to trigger a Smad-dependent signaling pathway in these cells. Thus, TGF-β1 may trigger a Smad-dependent pathway to control Gal-1 expression, suggesting that distinct mechanisms might cooperate in tilting the balance toward an immunosuppressive environment at the tumor site.

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

Similar content being viewed by others

References

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

    PubMed  CAS  Google Scholar 

  2. Bakin AV, Rinehart C, Tomlinson AK, Arteaga CL (2002) p38 mitogen-activated protein kinase is required for TGF β-mediated fibroblastic transdifferentiation and cell migration. J Cell Sci 115:3193–3206

    PubMed  CAS  Google Scholar 

  3. Brooks SC, Locke ER, Soule HD (1973) Estrogen receptor in a human cell line (MCF-7) from breast carcinoma. J Biol Chem 248:6251–6253

    PubMed  CAS  Google Scholar 

  4. Camby I, Belot N, Lefranc F, Sadeghi N, de Launoit Y, Kaltner H, Musette S, Darro F, Danguy A, Salmon I, Gabius HJ, Kiss R (2002) Galectin-1 modulates human glioblastoma cell migration into the brain through modifications to the actin cytoskeleton and levels of expression of small GTPases. J Neuropathol Exp Neurol 61:585–596

    PubMed  CAS  Google Scholar 

  5. Camby I, Decaestecker C, Lefranc F, Kaltner H, Gabius HJ, Kiss R (2005) Galectin-1 knocking down in human U87 glioblastoma cells alters their gene expression pattern. Biochem Biophys Res Commun 335:27–35

    Article  PubMed  CAS  Google Scholar 

  6. Chiariotti L, Benvenuto G, Salvatore P, Veneziani BM, Villone G, Fusco A, Russo T, Bruni CB (1994) Expression of the soluble lectin L-14 gene is induced by TSH in thyroid cells and suppressed by retinoic acid in transformed neural cells. Biochem Biophys Res Commun 199:540–546

    Article  PubMed  CAS  Google Scholar 

  7. Chiariotti L, Salvatore P, Frunzio R, Bruni CB (2004) Galectin genes: regulation of expression. Glycoconj J 19:441–449

    Article  PubMed  Google Scholar 

  8. Cooper DN (2002) Galectinomics: finding themes in complexity. Biochim Biophys Acta 1572:209–231

    PubMed  CAS  Google Scholar 

  9. Danguy A, Camby I, Kiss R (2002) Galectins and cancer. Biochim Biophys Acta 1572:285–293

    PubMed  CAS  Google Scholar 

  10. Daroqui MC, Puricelli LI, Urtreger AJ, Elizalde PV, Lanuza GM, Bal de Kier Joffe E (2003) Involvement of TGF-beta(s)/T(beta)Rs system in tumor progression of murine mammary adenocarcinomas. Breast Cancer Res Treat 80:287–301

    Article  PubMed  CAS  Google Scholar 

  11. Dunn GP, Old LJ, Schreiber RD (2004) The immunobiology of cancer immunosurveillance and immunoediting. Immunity 21:137–148

    Article  PubMed  CAS  Google Scholar 

  12. Gabrilovich D, Pisarev V (2003) Tumor escape from immune response: mechanisms and targets of activity. Curr Drug Targets 4:525–536

    Article  PubMed  CAS  Google Scholar 

  13. Gillenwater A, Xu XC, Estrov Y, Sacks PG, Lotan D, Lotan R (1998) Modulation of galectin-1 content in human head and neck squamous carcinoma cells by sodium butyrate. Int J Cancer 75:217–224

    Article  PubMed  CAS  Google Scholar 

  14. Gorelik L, Flavell RA (2001) Immune-mediated eradication of tumors through the blockade of transforming growth factor-beta signaling in T cells. Nat Med 7:1118–1122

    Article  PubMed  CAS  Google Scholar 

  15. Hirabayashi J, Hashidate T, Arata Y, Nishi N, Nakamura T, Hirashima M, Urashima T, Oka T, Futai M, Muller WE, Yagi F, Kasai K (2002) Oligosaccharide specificity of galectins: a search by frontal affinity chromatography. Biochim Biophys Acta 1572:232–254

    PubMed  CAS  Google Scholar 

  16. Kaklamani VG, Pasche B (2004) Role of TGF-beta in cancer and the potential for therapy and prevention. Expert Rev Anticancer Ther 4:649–661

    Article  PubMed  CAS  Google Scholar 

  17. Kloth JN, Fleuren GJ, Oosting J, de Menezes RX, Eilers PH, Kenter GG, Gorter A (2005) Substantial changes in gene expression of Wnt, MAPK and TNFalpha pathways induced by TGF-beta1 in cervical cancer cell lines. Carcinogenesis 26:1493–1502

    Article  PubMed  CAS  Google Scholar 

  18. Kopitz J, von Reitzenstein C, Andre S, Kaltner H, Uhl J, Ehemann V, Cantz M, Gabius HJ (2001) Negative regulation of neuroblastoma cell growth by carbohydrate-dependent surface binding of galectin-1 and functional divergence from galectin-3. J Biol Chem 276:35917–35923

    Article  PubMed  CAS  Google Scholar 

  19. Lahm H, Andre S, Hoeflich A, Kaltner H, Siebert HC, Sordat B, von der Lieth CW, Wolf E, Gabius HJ (2004) Tumor galectinology: insights into the complex network of a family of endogenous lectins. Glycoconj J 20:227–238

    Article  PubMed  CAS  Google Scholar 

  20. Laping NJ, Grygielko E, Mathur A, Butter S, Bomberger J, Tweed C, Martin W, Fornwald J, Lehr R, Harling J, Gaster L, Callahan JF, Olson BA (2002) Inhibition of transforming growth factor (TGF)-beta1-induced extracellular matrix with a novel inhibitor of the TGF-beta type I receptor kinase activity: SB-431542. Mol Pharmacol 62:58–64

    Article  PubMed  CAS  Google Scholar 

  21. Le QT, Shi G, Cao H, Nelson DW, Wang Y, Chen EY, Zhao S, Kong C, Richardson D, O’Byrne KJ, Giaccia AJ, Koong AC (2005) Galectin-1: a link between tumor hypoxia and tumor immune privilege. J Clin Oncol 23:8932–8941

    Article  PubMed  CAS  Google Scholar 

  22. Levy L, Hill CS (2005) Smad4 dependency defines two classes of transforming growth factor {beta} (TGF-{beta}) target genes and distinguishes TGF-{beta}-induced epithelial-mesenchymal transition from its antiproliferative and migratory responses. Mol Cell Biol 25:8108–8125

    Article  PubMed  CAS  Google Scholar 

  23. Liu F, Rabinovich G (2005) Galectins as modulators of tumour progression. Nature Rev Cancer 5:29–41

    Article  CAS  Google Scholar 

  24. Lu Y, Lotan D, Lotan R (2000) Differential regulation of constitutive and retinoic acid-induced galectin-1 gene transcription in murine embryonal carcinoma and myoblastic cells. Biochim Biophys Acta 1491:13–9

    PubMed  CAS  Google Scholar 

  25. Massague J (1998) TGF-beta signal transduction. Annu Rev Biochem 67:753–791

    Article  PubMed  CAS  Google Scholar 

  26. Mendez R, Ruiz-Cabello F, Rodriguez T, Del Campo A, Paschen A, Schadendorf D, Garrido F (2006) Identification of different tumor escape mechanisms in several metastases from a melanoma patient undergoing immunotherapy. Cancer Immunol Immunother (Epub ahead of print)

  27. Michl P, Ramjaun AR, Pardo OE, Warne PH, Wagner M, Poulsom R, D’Arrigo C, Ryder K, Menke A, Gress T, Downward J (2005) CUTL1 is a target of TGF(beta) signaling that enhances cancer cell motility and invasiveness. Cancer Cell 7:521–532

    Article  PubMed  CAS  Google Scholar 

  28. Moiseeva EP, Javed Q, Spring EL, de Bono DP (2000) Galectin-1 is involved in vascular smooth muscle cell proliferation. Cardiovasc Res 45:493–502

    Article  PubMed  CAS  Google Scholar 

  29. Oft M, Heider KH, Beug H (1998) TGFbeta signaling is necessary for carcinoma cell invasiveness and metastasis. Curr Biol 8:1243–52

    Article  PubMed  CAS  Google Scholar 

  30. Pantel K, Brakenhoff RH (2004) Dissecting the metastatic cascade. Nat Rev Cancer 4:448–456

    Article  PubMed  CAS  Google Scholar 

  31. Pardoll D, Allison J (2004) Cancer immunotherapy: breaking the barriers to harvest the crop. Nat Med 10:887–892

    Article  PubMed  CAS  Google Scholar 

  32. Pawelec G (1999) Tumour escape from the immune response: the last hurdle for successful immunotherapy of cancer? Cancer Immunol Immunother 48:343–345

    Article  PubMed  CAS  Google Scholar 

  33. Paz A, Haklai R, Elad-Sfadia G, Ballan E, Kloog Y (2001) Galectin-1 binds oncogenic H-Ras to mediate Ras membrane anchorage and cell transformation. Oncogene 20:7486–7493

    Article  PubMed  CAS  Google Scholar 

  34. Rabinovich GA, Daly G, Dreja H, Tailor H, Riera CM, Hirabayashi J, Chernajovsky Y (1999) Recombinant galectin-1 and its genetic delivery suppress collagen-induced arthritis via T cell apoptosis. J Exp Med 190:385–398

    Article  PubMed  CAS  Google Scholar 

  35. Rabinovich GA, Baum LG, Tinari N, Paganelli R, Natoli C, Liu FT, Iacobelli S (2002) Galectins and their ligands: amplifiers, silencers or tuners of the inflammatory response? Trends Immunol 23:313–320

    Article  PubMed  CAS  Google Scholar 

  36. Rabinovich GA, Rubinstein N, Matar P, Rozados V, Gervasoni S, Scharovsky GO (2002) The antimetastatic effect of a single low dose of cyclophosphamide involves modulation of galectin-1 and Bcl-2 expression. Cancer Immunol Immunother 50:597–603

    Article  PubMed  CAS  Google Scholar 

  37. Rabinovich GA, Rubinstein N, Toscano MA (2002) Role of galectins in inflammatory and immunomodulatory processes. Biochim Biophys Acta 1572:274–284

    PubMed  CAS  Google Scholar 

  38. Rabinovich GA, Cumashi A, Bianco GA, Ciavardelli D, Iurisci I, D’Egidio M, Piccolo E, Tinari N, Nifantiev N, Iacobelli S (2006) Synthetic lactulose amines: novel class of anticancer agents that induce tumor-cell apoptosis and inhibit galectin-mediated homotypic cell aggregation and endothelial cell morphogenesis. Glycobiology 16:210–220

    Article  PubMed  CAS  Google Scholar 

  39. Real LM, Jimenez P, Kirkin A, Serrano A, Garcia A, Canton J, Zeuthen J, Garrido F, Ruiz-Cabello F (2001) Multiple mechanisms of immune evasion can coexist in melanoma tumor cell lines derived from the same patient. Cancer Immunol Immunother 49:621–628

    Article  PubMed  CAS  Google Scholar 

  40. Rubinstein N, Alvarez M, Zwirner NW, Toscano MA, Ilarregui JM, Bravo A, Mordoh J, Fainboim L, Podhajcer OL, Rabinovich GA (2004) Targeted inhibition of galectin-1 gene expression in tumor cells results in heightened T cell-mediated rejection; A potential mechanism of tumor-immune privilege. Cancer Cell 5:241–251

    Article  PubMed  CAS  Google Scholar 

  41. Satterwhite DJ, Matsunami N, White RL (2000) TGF-beta1 inhibits BRCA1 expression through a pathway that requires pRb. Biochem Biophys Res Commun 276:686–692

    Article  PubMed  CAS  Google Scholar 

  42. Sorme P, Kahl-Knutsson B, Wellmar U, Magnusson BG, Leffler H, Nilsson UJ (2003) Design and synthesis of galectin inhibitors. Methods Enzymol 363: 157–169

    Article  PubMed  Google Scholar 

  43. ten Dijke P, Hill CS (2004) New insights into TGF-beta-Smad signalling. Trends Biochem Sci 29:265–273

    Article  PubMed  CAS  Google Scholar 

  44. Thomas DA, Massague J (2005) TGF-beta directly targets cytotoxic T cell functions during tumor evasion of immune surveillance. Cancer Cell 8:369–380

    Article  PubMed  CAS  Google Scholar 

  45. Tinari N, Kuwabara I, Huflejt ME, Shen PF, Iacobelli S, Liu FT (2001) Glycoprotein 90K/MAC-2BP interacts with galectin-1 and mediates galectin-1-induced cell aggregation. Int J Cancer 91:167–172

    Article  PubMed  CAS  Google Scholar 

  46. Urtreger AJ, Diament MJ, Ranuncolo SM, Del C Vidal M, Puricelli LI, Klein SM, Bal de Kier Joffe ED (2001) New murine cell line derived from a spontaneous lung tumor induces paraneoplastic syndromes. Int J Oncol 18:639–647

    PubMed  CAS  Google Scholar 

  47. Urtreger A, Ladeda V, Puricelli L, Rivelli A, Vidal MC, Lustig ES, Bal de Kier Joffé E (1997) Modulation of fibronectin expression and proteolytic activity associated with the invasive and metastatic phenotype in two murine mammary cell lines. Int J Oncol 11:489–496

    CAS  Google Scholar 

  48. van den Brule F, Califice S, Castronovo V (2004) Expression of galectins in cancer: a critical review. Glycoconj J 19:537–542

    Article  PubMed  Google Scholar 

  49. van den Brule FA, Buicu C, Baldet M, Sobel ME, Cooper DN, Marschal P, Castronovo V (1995) Galectin-1 modulates human melanoma cell adhesion to laminin. Biochem Biophys Res Commun 209:760–767

    Article  PubMed  Google Scholar 

  50. Zacarias-Fluck MF, Rico MJ, Gervasoni SI, Ilarregui JM, Toscano MA, Rabinovich GA, Scharovsky GO (2006) Low dose cyclophosphamide modulates galectin-1 expression and function in an experimental rat lymphoma model. Cancer Immunol Immunother (Epub ahead of print)

Download references

Acknowledgments

The authors wish to thank Drs. J. Hirabayashi and K.I. Kasai for providing the plasmid pET21a/Gal1. This work was supported in part by grants from Mizutani Foundation for Glycoscience (Japan), University of Buenos Aires (UBACYT-M091), Agencia de Promoción Científica y Tecnológica (PICT 2003-05-13787) and Fundación Sales to G.A.R., and by grants from the University of Buenos Aires (UBACYT-M068) Agencia de Promoción Científica y Tecnológica (PICT 2003-05-14088) to E.B.K.J. G.A.R, L.P. and E.B.K.J. are researchers of CONICET. J.M.I., N.R., MS and M.A.T. thank CONICET and M.C.D. and P.V. thanks ANPCyT and Fundación Bunge & Born for the fellowships granted.

Author information

Author notes

  1. Cecilia M. Daroqui

    Present address: Department of Oncology, Montefiore Medical Center, Albert Einstein Cancer Center, Bronx, NY, USA

Authors and Affiliations

  1. Research Area, Institute of Oncology “Angel H. Roffo”, University of Buenos Aires, San Martin Avenue 5481, Buenos Aires, Argentina

    Cecilia M. Daroqui, Paula Vazquez, Lydia Puricelli & Elisa Bal de Kier Joffé

  2. Division of Immunogenetics, Hospital de Clínicas “José de San Martín”, Faculty of Medicine, University of Buenos Aires, Avenue Córdoba 2351. 3er Piso. (1120) Ciudad de Buenos Aires, Buenos Aires, Argentina

    Juan M. Ilarregui, Natalia Rubinstein, Mariana Salatino, Marta A. Toscano & Gabriel A. Rabinovich

  3. Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA

    Andrei Bakin

Authors
  1. Cecilia M. Daroqui
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Juan M. Ilarregui
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Natalia Rubinstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mariana Salatino
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Marta A. Toscano
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Paula Vazquez
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Andrei Bakin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Lydia Puricelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Elisa Bal de Kier Joffé
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Gabriel A. Rabinovich
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gabriel A. Rabinovich.

Additional information

C. M. Daroqui, Juan M. Ilarregui, Natalia Rubinstein, and Mariana Salatino contributed equally to this work. E. Bal de Kier Joffé and, Gabriel A. Rabinovich jointly supervised this study and should be considered as senior authors.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Daroqui, C.M., Ilarregui, J.M., Rubinstein, N. et al. Regulation of galectin-1 expression by transforming growth factor β1 in metastatic mammary adenocarcinoma cells: implications for tumor-immune escape. Cancer Immunol Immunother 56, 491–499 (2007). https://doi.org/10.1007/s00262-006-0208-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-006-0208-9

Keywords

Search

Navigation