Skip to main content

Oncofetal antigen/immature laminin receptor protein in pregnancy and cancer

Abstract

The 37-kDa immature laminin receptor protein (iLRP) is a speciesconserved, universal immunogenic protein that is expressed in all thus-far examined embryonic and early fetal cells of inbred and outbred rodents. It has also been identified in human concepti. It is altered through normal maturation processes to become a non-immunogenic 67-kDa dimeric mature laminin receptor protein (mLRP) in mid-to late gestation in the mammalian fetus. This antigen ceases to be expressed as an active autoimmunogen in the full-term fetus and in the normal differentiating tissues and organs of the neonate or adult organism, apparently due to dimerization, but it is re-expressed as an immunogenic monomer in tumor cells. In this review, we highlight the known mechanisms of immune responses with particular emphasis on the possible role of the 37-kDa oncofetal antigen/immature laminin receptor (OFA/iLRP) in both pregnancy and cancer.

Abbreviations

APC:

antigen processing cell

CTL:

cytotoxic T lymphocyte

DC:

dendritic cell

DMBA:

2,4-dimethoxybenzaldehyde

FasL:

Fas ligand

Gal:

galectin

IFN:

interferon

IL:

interleuken

iLRP:

immature laminin receptor protein

MHC:

major histocompatibility complex

mLRP:

mature laminin receptor protein

NK:

natural killer

OFA:

oncofetal antigen

Tc:

T cytotoxic

TCR:

T-cell receptor

TGF:

transforming growth factor

Th:

T helper

TNF:

tumor necrosis factor

Treg:

regulatory T cells

Ts:

T suppressor

TSTA:

tumor-specific transplantation antigen

References

  1. Billingham, R.E., Brent, L. and Medawar, P.B. ‘Actively acquired tolerance’ of foreign cells. 1953. J. Immunol. 184 (2010) 5–8.

    PubMed  Article  CAS  Google Scholar 

  2. Billington, W.D. The immunological problem of pregnancy: 50 years with the hope of progress. A tribute to Peter Medawar. J. Reprod. Immunol. 60 (2003) 1–11.

    PubMed  Article  Google Scholar 

  3. Smith, T.R. and Kumar, V. Revival of CD8+ Treg-mediated suppression. Trends Immunol. 29 (2008) 337–342. DOI: 10.1016/j.it.2008.04.002.

    PubMed  Article  CAS  Google Scholar 

  4. Saito, S., Shiozaki, A., Sasaki, Y., Nakashima, A., Shima, T. and Ito, M. Regulatory T cells and regulatory natural killer (NK) cells play important roles in feto-maternal tolerance. Semin. Immunopathol. 29 (2007) 115–122. DOI: 10.1007/s00281-007-0067-2.

    PubMed  Article  CAS  Google Scholar 

  5. Wegmann, T.G, Lin, H., Guilbert, L. and Mosmann, T.R. Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a TH2 phenomenon? Immunol. Today 14 (1993) 353–356.

    PubMed  Article  CAS  Google Scholar 

  6. Liu, F., Guo, J., Tian, T., Wang, H., Dong, F., Huang, H. and Dong, M. Placental trophoblasts shifted Th1/Th2 balance toward Th2 and inhibited Th17 immunity at fetomaternal interface. APMIS 119 (2011) 597–604. DOI: 10.1111/j.1600-0463. 2011. 02774.x.

    PubMed  Article  CAS  Google Scholar 

  7. Van Mourik, M.S., Macklon, N.S. and Heijnen, C.J. Embryonic implantation: cytokines, adhesion molecules, and immune cells in establishing an implantation environment. J. Leukoc. Biol. 85 (2009) 4–19.

    PubMed  Article  Google Scholar 

  8. Knutson, K.L. and Disis, M.L. Tumor antigen-specific T helper cells in cancer immunity and immunotherapy. Cancer Immunol. Immunother. 54 (2005) 721–728.

    PubMed  Article  CAS  Google Scholar 

  9. Blois, S.M., Kammerer, U., Alba Soto, C., Tometten, M.C., Shaikly, V., Barrientos, G., Jurd, R., Rukavina, D., Thomson, A.W., Klapp, B.F., Fernandez, N. and Arck, P.C. Dendritic cells: key to fetal tolerance? Biol. Reprod. 77 (2007) 590–598. DOI: 10.1095/biolreprod.107.060632.

    PubMed  Article  CAS  Google Scholar 

  10. Geissmann, F., Manz, M.G., Jung, S., Sieweke, M.H., Merad, M. and Ley, K. Development of monocytes, macrophages, and dendritic cells. Science 327 (2010) 656–661.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  11. Nelson, D. and Ganss, R. Tumor growth or regression: powered by inflammation. J. Leukoc. Biol. 80 (2006) 685–690.

    PubMed  Article  CAS  Google Scholar 

  12. Zamarron, B. F. and Chen, W. Dual roles of immune cells and their factors in cancer development and progression. Int. J. Biol. Sci. 7 (2011) 651–658.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  13. Steinman, R.M., Hawiger, D. and Nussenzweig, M.C. Tolerogenic dendritic cells. Annu Rev. Immunol. 21 (2003) 685–711.

    PubMed  Article  CAS  Google Scholar 

  14. Walker, M.R., Kasprowicz, D.J., Gersuk, V.H., Benard, A., Van Landeghen, M., Buckner, J.H. and Ziegler, S.F. Induction of FoxP3 and acquisition of T regulatory activity by stimulated human CD4+CD25-T cells. J. Clin. Invest. 112 (2003) 1437–1443.

    PubMed  Article  CAS  Google Scholar 

  15. Aluvihare, V.R., Kallikourdis, M. and Betz, A.G. Regulatory T cells mediate maternal tolerance to the fetus. Nat. Immunol. 5 (2004) 266–271. DOI: 10.1038/ni1037.

    PubMed  Article  CAS  Google Scholar 

  16. Zhao, J.X., Zeng, Y.Y. and Liu, Y. Fetal alloantigen is responsible for the expansion of the CD4(+)CD25(+) regulatory T-cell pool during pregnancy. J. Reprod. Immunol. 75 (2007) 71–81. DOI: 10.1016/j.jri.2007.06.05217.

    PubMed  Article  CAS  Google Scholar 

  17. Blois, S.M., Joachim, R., Kandil, J., Margni, R., Tometten, M., Klapp, B.F. and Arck, P.C. Depletion of CD8+ cells abolishes the pregnancy protective effect of progesterone substitution with dydrogesterone in mice by altering the Th1/Th2 cytokine profile. J. Immunol. 172 (2004) 5893–5899.

    PubMed  Article  CAS  Google Scholar 

  18. Wang, H.Y. and Wang, R.F. Regulatory T cells and cancer. Curr. Opin. Immunol. 19 (2007) 217–223.

    PubMed  Article  CAS  Google Scholar 

  19. Rohrer, J.W. and Coggin, J.H., Jr. CD8 T-cell clones inhibit antitumor T-cell function by secreting IL-10. J. Immunol. 155 (1995) 5719–5727.

    PubMed  CAS  Google Scholar 

  20. Rohrer, J.W., Culpepper, C., Barsoum A.L. and Coggin, J.H., Jr. Characterization of RFM mouse T lymphocyte anti-oncofetal antigen immunity in apparent tumor-free, long-term survivors of sublethal X-irradiation by limiting dilution T lymphocyte cloning. J. Immunol. 154 (1995) 2266–2280.

    PubMed  CAS  Google Scholar 

  21. Rabinovich, G.A., Baum, L.G., Tinari, N., Paganelli, R., Natoli, C., Liu, F.T. and Iacobelli, S. Galectins and their ligands: amplifiers, silencers or tuners of the inflammatory response? Trends Immunol. 23 (2002) 313–220.

    PubMed  Article  CAS  Google Scholar 

  22. Cooper, D., Ilarregui, J.M., Pesoa, S,A., Croci, D.O., Perretti, M. and Rabinovich, G.A. Multiple functional targets of the immunoregulatory activity of galectin-1: Control of immune cell trafficking, dendritic cell physiology, and T-cell fate. Methods Enzymol. 480 (2010) 199–244. DOI: 10.1016/s0076-6879(10)80011-423.

    PubMed  Article  CAS  Google Scholar 

  23. Peng, W., Wang, H.Y., Miyahara, Y., Peng, G. and Wang, R.F. Tumorassociated galectin-3 modulates the function of tumor-reactive T cells. Cancer Res. 68 (2008) 7228–7236. DOI: 10.1158/0008-5472.can-08-124524.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  24. Coggin, J.H. Jr., Barsoum, A.L. and Rohrer, J.W. 37-kiloDalton oncofetal antigen protein and immature laminin receptor protein are identical, universal T-cell inducing immunogens on primary rodent and human cancers. Anticancer Res. 19 (1999) 5535–5542.

    PubMed  CAS  Google Scholar 

  25. Barsoum, A.L., Rohrer, J.W., Coggin, J.H., Jr. 37kDa Oncofetal antigen is an autoimmunogenic homologue of the 37kDa laminin receptor precursor. Cell. Mol. Biol. Lett. 5 (2000) 207–230.

    CAS  Google Scholar 

  26. Castronovo, V. Laminin receptors and laminin-binding proteins during tumor invasion and metastasis. Invasion Metastasis 13 (1993) 1–30.

    PubMed  CAS  Google Scholar 

  27. Castronovo, V., Claysmith, A.P., Barker, K.T., Cioce, V., Krutzsch, H.C. and Sobel, M.E. Biosynthesis of the 67 kDa high affinity laminin receptor. Biochem. Biophys. Res. Commun. 177 (1991) 177–183.

    PubMed  Article  CAS  Google Scholar 

  28. Castronovo, V., Taraboletti, G. and Sobel, M.E. Functional domains of the 67-kDa laminin receptor precursor. J. Biol. Chem. 266 (1991) 20440–20446.

    PubMed  CAS  Google Scholar 

  29. Coggin, J.H., Jr., Adkinson, L. and Anderson, N.G. Fetal antigens shared as transplantation rejection antigens on chemically induced mouse and hamster sarcomas. Cancer Res. 40 (1980) 1568–1573.

    PubMed  Google Scholar 

  30. Rohrer, J.W., Rohrer, S.D., Barsoum, A. and Coggin, J.H., Jr. Differential recognition of murine tumor-associated oncofetal transplantation antigen and individually specific tumor transplantation antigens by syngeneic cloned BALB/c and RFM mouse T cells. J. Immunol. 152 (1994) 754–764.

    PubMed  CAS  Google Scholar 

  31. Rohrer, J.W., Barsoum, A.L., Dyess, D.L., Tucker, J.A. and Coggin, J.H., Jr. Human breast carcinoma patients develop clonable oncofetal antigenspecific effector and regulatory T lymphocytes. J. Immunol. 162 (1999) 6880–6892.

    PubMed  CAS  Google Scholar 

  32. Holtl, L., Zelle-Rieser, C., Gander, H., Papesh, C., Ramoner, R., Bartsch, G., Rogatsch, H., Barsoum, A.L., Coggin, J.H., Jr. and Thurnher, M. Immunotherapy of metastatic renal cell carcinoma with tumor lysate-pulsed autologous dendritic cells. Clin. Cancer Res. 8 (2002) 3369–3376.

    PubMed  CAS  Google Scholar 

  33. Friedrichs, B., Siegel, S., Kloess, M., Barsoum, A., Coggin, J., Jr., Rohrer, J., Jakob, I., Tiemann, M., Heidorn, K., Schulte, C., Kabelitz, D., Steinmann, J., Schmitz, N. and Zeis, M. Humoral immune responses against the immature laminin receptor protein show prognostic significance in patients with chronic lymphocytic leukemia. J. Immunol. 180 (2008) 6374–6384.

    PubMed  Article  CAS  Google Scholar 

  34. Payne, W.J., Jr. and Coggin, J.H., Jr. Mouse monoclonal antibody to embryonic antigen: development, cross-reactivity with rodent and human tumors, and preliminary polypeptide characterization. J. Nat. Cancer Inst. 75 (1985) 527–544.

    PubMed  CAS  Google Scholar 

  35. Coggin, J.H., Jr. and Anderson, N.G. Cancer, differentiation and embryonic antigens: some central problems. Adv. Cancer Res. 19 (1974) 105–165.

    PubMed  Article  CAS  Google Scholar 

  36. Coggin, J.H., Jr., Rohrer, S.D., Hester, R.D., Barsoum, A.L., Rashid, H.U. and Gussack, G.S. 44-kd oncofetal transplantation antigen in rodent and human fetal cells. Implications of recrudescence in human and rodent cancers. Arch. Otolaryngol. Head Neck Surg. 119 (1993) 1257–1266.

    PubMed  Article  Google Scholar 

  37. Coggin, J.H., Jr. Embryonic antigens in malignancy and pregnancy: common denominators in immune regulation. Ciba Found. Symp. 96 (1983) 28–54.

    PubMed  Google Scholar 

  38. Zhang, C., Duan, E., Cao, Y., Jiang, G. and Zeng, G. Effect of 32/67 kDa laminin-binding protein antibody on mouse embryo implantation. J. Reprod. Fertil. 119 (2000) 137–142.

    PubMed  Article  CAS  Google Scholar 

  39. Coggin, J.H., Jr. The implications of embryonic gene expression in neoplasia. Crit. Rev. Oncol. Hematol. 5 (1986) 37–55.

    PubMed  Article  Google Scholar 

  40. Chakravarty, P.K. and Sinha, D.K. Pregnancy induced mammary tumor specific effector cells are present long after parturition in a breast cancer model in rats. Cancer Letts. 154 (2000) 1–7.

    Article  CAS  Google Scholar 

  41. Janerich, D.T. The fetal antigen hypothesis: cancers and beyond. Medical Hypotheses 56 (2001) 101–103. DOI: 10.1054/mehy.2000.1119.

    PubMed  Article  CAS  Google Scholar 

  42. Rohrer, S.D, Sarli, R.N., Barsoum, A.L, Hester, R.B. and Coggin, J.H., Jr. Expression of 44-kilodalton oncofetal antigen as a premalignancy marker in X irradiation-induced murine T-cell lymphoma. J. Nat. Cancer Inst. 84 (1992) 602–609.

    PubMed  Article  CAS  Google Scholar 

  43. Menard, S., Castronovo, V., Tagliabue, E. and Sobel, M.E. New insights into the metastasis-associated 67 kD laminin receptor. J. Cell. Biochem. 67 (1997) 155–165.

    PubMed  Article  CAS  Google Scholar 

  44. Gussack, G.S., Rohrer, S.D., Hester, R.B., Liu, P.I. and Coggin, J.H., Jr. Human squamous cell carcinoma lines express oncofetal 44-kD polypeptide defined by monoclonal antibody to mouse fetus. Cancer 62 (1988) 283–290.

    PubMed  Article  CAS  Google Scholar 

  45. Zelle-Rieser, C., Barsoum, A.L., Sallusto, F., Ramoner, R., Rohrer, J.W., Holtl, L., Bartsch, G., Coggin, J.H., Jr. and Thurnher, M. Expression and immunogenicity of oncofetal antigen-immature laminin receptor in human renal cell carcinoma. J. Urol. 165 (2001) 1705–1709.

    PubMed  Article  CAS  Google Scholar 

  46. Siegel, S., Wagner, A., Kabelitz, D., Marget, M., Coggin, J., Jr., Barsoum, A., Rohrer, J., Schmitz, N. and Zeis, M. Induction of cytotoxic T-cell responses against the oncofetal antigen-immature laminin receptor for the treatment of hematologic malignancies. Blood 102 (2003) 4416–4423. DOI: 10.1182/blood-2003-01-0198.

    PubMed  Article  CAS  Google Scholar 

  47. Siegel, S., Wagner, A., Friedrichs, B., Wendeler, A., Wendel, L., Kabelitz, D., Steinmann, J., Barsoum, A., Coggin, J., Rohrer, J., Dreger, P., Schmitz, N. and Zeis, M. Identification of HLA-A*0201-presented T-cell epitopes derived from the oncofetal antigen-immature laminin receptor protein in patients with hematological malignancies. J. Immunol. 176 (2006) 6935–6944.

    PubMed  Article  CAS  Google Scholar 

  48. Friedrichs, B., Siegel, S., Reimer, R., Barsoum, A., Coggin J., Jr., Kabelitz D., Heidorn, K., Schulte, C., Schmitz, N. and Zeis, M. High expression of the immature laminin receptor protein correlates with mutated IGVH status and predicts a favorable prognosis in chronic lymphocytic leukemia. Leuk. Res. 35 (2011) 721–729. DOI: 10.1016/j.leukres.2010.10.002.

    PubMed  Article  CAS  Google Scholar 

  49. Rohrer, J.W., Barsoum, A.L. and Coggin, J.H., Jr. Identification of oncofetal antigen/immature laminin receptor protein epitopes that activate BALB/c mouse OFA/iLRP-specific effector and regulatory T-cell clones. J. Immunol. 176 (2006) 2844–2856.

    PubMed  Article  CAS  Google Scholar 

  50. Barsoum, A.L., Liu, B., Rohrer, J.W., Coggin, J.H., Jr., Tucker, J.A., Pannell, L.K. and Schwarzenberger, P.O. Production, safety and antitumor efficacy of recombinant Oncofetal Antigen/immature laminin receptor protein. Biomaterials 30 (2009) 3091–3099. DOI: 10.1016/j.biomaterials.2009.02.022.

    PubMed  Article  CAS  Google Scholar 

  51. Coggin, J.H., Jr., Barsoum, A.L. and Rohrer, J.W. Tumors express both unique TSTA and crossprotective 44 kDa oncofetal antigen. Immunol. Today 19 (1998) 405–408.

    PubMed  Article  CAS  Google Scholar 

  52. Buto, S., Tagliabue, E., Ardini, E., Magnifico, A., Ghirelli, C., van den Brule, F., Castronovo, V., Colnaghi, M.I. and Sobel, M.E. Formation of the 67-kDa laminin receptor by acylation of the precursor. J. Cell. Biochem. 69 (1998) 244–251.

    PubMed  Article  CAS  Google Scholar 

  53. Karpatova, M., Tagliabue, E., Castronovo, V., Magnifico, A., Ardini, E., Morelli, D., Belotti, D., Colnaghi, M.I. and Menard, S. Shedding of the 67-kD laminin receptor by human cancer cells. J. Cell. Biochem. 60 (1996) 226–234.

    PubMed  Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Adel L. Barsoum.

Additional information

In Memory of Professors Joseph H. Coggin and James W. Rohrer

Invited paper

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Barsoum, A.L., Schwarzenberger, P.O. Oncofetal antigen/immature laminin receptor protein in pregnancy and cancer. Cell Mol Biol Lett 19, 393–406 (2014). https://doi.org/10.2478/s11658-014-0203-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2478/s11658-014-0203-7

Keywords

  • Cancer
  • Galectins
  • Immature laminin receptor
  • Oncofetal antigen
  • Pregnancy