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Recoverin as a cancer-retina antigen

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Abstract

In photoreceptor cells the Ca2+-binding protein recoverin controls phosphorylation of the visual receptor rhodopsin by inhibiting rhodopsin kinase (GRK-1). It can also serve as a paraneoplastic antigen in the development of retinal degeneration in some patients with cancer. The aberrant expression of recoverin in cancer cells and the presence of autoantibodies against recoverin are essential for the occurrence of cancer-associated retinopathy, which finally results in the apoptosis of photoreceptor cells. Noteworthy in cancer patients, the aberrant recoverin expression and the appearance of autoantibodies against recoverin are more frequent than paraneoplastic syndromes. We suggest the term “cancer-retina antigens” for this kind of proteins like recoverin that are solely expressed in retina and tumor tissues and evoke antibodies and/or T cells in patients with cancer. The rare development of a paraneoplastic syndrome is possibly caused by this immune response and probably depends on further events allowing to overcome the blood–retina barrier and the immune privileged status of the retina. It is still unknown whether aberrantly expressed recoverin could have a specific function in cancer cells, though it is suggested that it can be functionally associated with G-protein-coupled receptor kinases. This paper reviews the present knowledge on paraneoplastic syndromes associated with the aberrant expression of recoverin. A possible application of recoverin as a potential target for immunotherapy of cancer is discussed.

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Abbreviations

CAR:

Cancer-associated retinopathy

CTL:

Cytotoxic T cell(s)

MAR:

Melanoma-associated retinopathy

PNA:

Paraneoplastic antigen(s)

PNS:

Paraneoplastic neurological syndrome(s)

SCLC:

Small cell lung cancer

References

  1. Adamus G, Amundson D (1996) Epitope recognition of recoverin in cancer associated retinopathy: evidence for calcium-dependent conformational epitopes. J Neurosci Res 45:863–872

    Article  PubMed  CAS  Google Scholar 

  2. Adamus G, Guy J, Schmied JL, Arendt A, Hargrave PA (1993) Role of anti-recoverin autoantibodies in cancer-associated retinopathy. Invest Ophthalmol Vis Sci 34:2626–2633

    PubMed  CAS  Google Scholar 

  3. Adamus G, Ortega H, Witkowska D, Polans A (1994) Recoverin: a potent uveitogen for the induction of photoreceptor degeneration in Lewis rats. Exp Eye Res 59:447–455

    Article  PubMed  CAS  Google Scholar 

  4. Adamus G, Machnicki M, Seigel GM (1997) Apoptotic retinal cell death induced by antirecoverin autoantibodies of cancer-associated retinopathy. Invest Ophthalmol Vis Sci 38:283–291

    PubMed  CAS  Google Scholar 

  5. Adamus G, Amundson D, MacKay C, Gouras P (1998) Long-term persistence of antirecoverin antibodies in endometrial cancer-associated retinopathy. Arch Ophthalmol 116:251–253

    PubMed  CAS  Google Scholar 

  6. Adamus G, Machnicki M, Elerding H, Sugden B, Blocker YS, Fox DA (1998) Antibodies to recoverin induce apoptosis of photoreceptor and bipolar cells in vivo. J Autoimmun 11:523–533

    Article  PubMed  CAS  Google Scholar 

  7. Adamus G, Ren G, Weleber RG (2004) Autoantibodies against retinal proteins in paraneoplastic and autoimmune retinopathy. BMC Ophthalmol 4:5

    Article  PubMed  Google Scholar 

  8. Bazhin AV, Shifrina ON, Savchenko MS, Tikhomirova NK, Goncharskaia MA, Gorbunova VA, Senin II, Chuchalin AG, Philippov PP (2001) Low titre autoantibodies against recoverin in sera of patients with small cell lung cancer but without a loss of vision. Lung Cancer 34:99–104

    Article  PubMed  CAS  Google Scholar 

  9. Bazhin AV, Slepova OS, Tikhomirova NK (2001) Retinal degeneration under the effect of antibodies to recoverin. Bull Exp Biol Med 131:350–352

    Article  PubMed  CAS  Google Scholar 

  10. Bazhin AV, Savchenko MS, Belousov EV, Jaques G, Philippov PP (2004) Stimulation of the aberrant expression of a paraneoplastic antigen, recoverin, in small cell lung cancer cell lines. Lung Cancer 45:299–305

    Article  PubMed  Google Scholar 

  11. Bazhin AV, Savchenko MS, Shifrina ON, Demoura SA, Chikina SY, Jaques G, Kogan EA, Chuchalin AG, Philippov PP (2004) Recoverin as a paraneoplastic antigen in lung cancer: the occurrence of anti-recoverin autoantibodies in sera and recoverin in tumors. Lung Cancer 44:193–198

    Article  PubMed  Google Scholar 

  12. Boeck K, Hofmann S, Klopfer M, Ian U, Schmidt T, Engst R, Thirkill CE, Ring J (1997) Melanoma-associated paraneoplastic retinopathy: case report and review of the literature. Br J Dermatol 137:457–460

    Article  PubMed  CAS  Google Scholar 

  13. Borkowski LM, Grover S, Fishman GA, Jampol LM (2001) Retinal findings in melanoma-associated retinopathy. Am J Ophthalmol 132:273–275

    Article  PubMed  CAS  Google Scholar 

  14. Boucher MC, Allaire GS (1997) Cancer-associated retinopathy: a clinicopathological case report. Can J Ophthalmol 32:46–49

    PubMed  CAS  Google Scholar 

  15. Braunewell KH, Gundelfinger ED (1999) Intracellular neuronal calcium sensor proteins: a family of EF-hand calcium-binding proteins in search of a function. Cell Tissue Res 295:1–12

    Article  PubMed  CAS  Google Scholar 

  16. Chan JW (2003) Paraneoplastic retinopathies and optic neuropathies. Surv Ophthalmol 48:12–38

    Article  PubMed  Google Scholar 

  17. Chen CK, Inglese J, Lefkowitz RJ, Hurley JB (1995) Ca(2+)-dependent interaction of recoverin with rhodopsin kinase. J Biol Chem 270:18060–18066

    Article  PubMed  CAS  Google Scholar 

  18. Dalmau J, Furneaux HM, Gralla RJ, Kris MG, Posner JB (1990) Detection of the anti-Hu antibody in the serum of patients with small cell lung cancer—a quantitative western blot analysis. Ann Neurol 27:544–552

    Article  PubMed  CAS  Google Scholar 

  19. Darnell RB, DeAngelis LM (1993) Regression of small-cell lung carcinoma in patients with paraneoplastic neuronal antibodies. Lancet 341:21–22

    Article  PubMed  CAS  Google Scholar 

  20. De Smet C, De Backer O, Faraoni I, Lurquin C, Brasseur F, Boon T (1996) The activation of human gene MAGE-1 in tumor cells is correlated with genome-wide demethylation. Proc Natl Acad Sci USA 93:7149–7153

    Article  PubMed  Google Scholar 

  21. Dizhoor AM, Nekrasova ER, Philippov PP (1991) A novel photoreceptor cell-specific protein with molecular weight 26 kDa capable of binding to immobilized delipidated rhodopsin. Biokhimiya 56:225–229

    Google Scholar 

  22. Dizhoor AM, Ray S, Kumar S, Niemi G, Spencer M, Brolley D, Walsh KA, Philipov PP, Hurley JB, Stryer L (1991) Recoverin: a calcium sensitive activator of retinal rod guanylate cyclase. Science 251:915–918

    Article  PubMed  CAS  Google Scholar 

  23. Eichmüller S, Usener D, Jochim A, Schadendorf D (2002) mRNA expression of tumor-associated antigens in melanoma tissues and cell lines. Exp Dermatol 11:292–301

    Article  PubMed  Google Scholar 

  24. Eltabbakh GH, Hoogerland DL, Kay MC (1995) Paraneoplastic retinopathy associated with uterine sarcoma. Gynecol Oncol 58:120–123

    Article  PubMed  CAS  Google Scholar 

  25. Flaherty KM, Zozulya S, Stryer L, McKay DB (1993) Three-dimensional structure of recoverin, a calcium sensor in vision. Cell 75:709–716

    Article  PubMed  CAS  Google Scholar 

  26. Gery I, Chanaud NP III, Anglade E (1994) Recoverin is highly uveitogenic in Lewis rats. Invest Ophthalmol Vis Sci 35:3342–3345

    PubMed  CAS  Google Scholar 

  27. Gittinger JW Jr, Smith TW (1999) Cutaneous melanoma-associated paraneoplastic retinopathy: histopathologic observations. Am J Ophthalmol 127:612–614

    Article  PubMed  Google Scholar 

  28. Gorodovikova EN, Philippov PP (1993) The presence of a calcium-sensitive p26-containing complex in bovine retina rod cells. FEBS Lett 335:277–279

    Article  PubMed  CAS  Google Scholar 

  29. Graus F, Elkon KB, Cordon-Cardo C, Posner JB (1986) Sensory neuronopathy and small cell lung cancer. Antineuronal antibody that also reacts with the tumor. Am J Med 80:45–52

    Article  PubMed  CAS  Google Scholar 

  30. Grunwald GB, Kornguth SE, Towfighi J, Sassani J, Simmonds MA, Housman CM, Papadopoulos N (1987) Autoimmune basis for visual paraneoplastic syndrome in patients with small cell lung carcinoma. Retinal immune deposits and ablation of retinal ganglion cells. Cancer 60:780–786

    Article  PubMed  CAS  Google Scholar 

  31. Gure AO, Stockert E, Scanlan MJ, Keresztes RS, Jager D, Altorki NK, Old LJ, Chen YT (2000) Serological identification of embryonic neural proteins as highly immunogenic tumor antigens in small cell lung cancer. Proc Natl Acad Sci USA 97:4198–4203

    Article  PubMed  CAS  Google Scholar 

  32. Guy J, Aptsiauri N (1999) Treatment of paraneoplastic visual loss with intravenous immunoglobulin: report of 3 cases. Arch Ophthalmol 117:471–477

    PubMed  CAS  Google Scholar 

  33. Harmon JP, Purvin VA, Guy J, Aptsiauri N, Sutton GP (1999) Cancer-associated retinopathy in a patient with advanced epithelial ovarian carcinoma. Gynecol Oncol 73:430–432

    Article  PubMed  CAS  Google Scholar 

  34. Hartmann TB, Bazhin AV, Schadendorf D, Eichmüller SB (2005) SEREX identification of new tumor antigens linked to melanoma-associated retinopathy. Int J Cancer 114:88–93

    Article  PubMed  CAS  Google Scholar 

  35. Huober J, Holz FG, Schmid H, Nolle B, Bellmann C, Krastel H, Wallwiener D, Bastert G (1997) Paraneoplastic retinopathy in 2 patients with breast carcinoma. Zentralbl Gynakol 119:278–281

    PubMed  CAS  Google Scholar 

  36. Jacobson DM, Thirkill CE, Tipping SJ (1990) A clinical triad to diagnose paraneoplastic retinopathy. Ann Neurol 28:162–167

    Article  PubMed  CAS  Google Scholar 

  37. Kashiwabara K, Nakamura H, Kishi K, Yagyu H, Sarashina G, Kobayashi K, Matsuoka T (1999) Cancer-associated retinopathy during treatment for small-cell lung carcinoma. Intern Med 38:597–601

    PubMed  CAS  Google Scholar 

  38. Katsuta H, Okada M, Nakauchi T, Takahashi Y, Yamao S, Uchida S (2002) Cancer-associated retinopathy associated with invasive thymoma. Am J Ophthalmol 134:383–389

    Article  PubMed  Google Scholar 

  39. Keltner JL, Roth AM, Chang RS (1983) Photoreceptor degeneration. Possible autoimmune disorder. Arch Ophthalmol 101:564–569

    PubMed  CAS  Google Scholar 

  40. Keltner JL, Thirkill CE, Yip PT (2001) Clinical and immunologic characteristics of melanoma-associated retinopathy syndrome: eleven new cases and a review of 51 previously published cases. J Neuroophthalmol 21:173–187

    PubMed  CAS  Google Scholar 

  41. Klenchin VA, Calvert PD, Bownds MD (1995) Inhibition of rhodopsin kinase by recoverin. Further evidence for a negative feedback system in phototransduction. J Biol Chem 270:16147–16152

    Article  PubMed  CAS  Google Scholar 

  42. Kornguth SE, Klein R, Appen R, Choate J (1982) Occurrence of anti-retinal ganglion cell antibodies in patients with small cell carcinoma of the lung. Cancer 50:1289–1293

    Article  PubMed  CAS  Google Scholar 

  43. Kornguth SE, Kalinke T, Grunwald GB, Schutta H, Dahl D (1986) Anti-neurofilament antibodies in the sera of patients with small cell carcinoma of the lung and with visual paraneoplastic syndrome. Cancer Res 46:2588–2595

    PubMed  CAS  Google Scholar 

  44. Lambrecht HG, Koch KW (1991) A 26 kd calcium binding protein from bovine rod outer segments as modulator of photoreceptor guanylate cyclase. EMBO J 10:793–798

    PubMed  CAS  Google Scholar 

  45. Lei B, Bush RA, Milam AH, Sieving PA (2000) Human melanoma-associated retinopathy (MAR) antibodies alter the retinal ON-response of the monkey ERG in vivo. Invest Ophthalmol Vis Sci 41:262–266

    PubMed  CAS  Google Scholar 

  46. Maeda A, Ohguro H, Maeda T, Wada I, Sato N, Kuroki Y, Nakagawa T (2000) Aberrant expression of photoreceptor-specific calcium-binding protein (recoverin) in cancer cell lines. Cancer Res 60:1914–1920

    PubMed  CAS  Google Scholar 

  47. Maeda A, Ohguro H, Nabeta Y, Hirohashi Y, Sahara H, Maeda T, Wada Y, Sato T, Yun C, Nishimura Y, Torigoe T, Kuroki Y, Sato N (2001) Identification of human antitumor cytotoxic T lymphocytes epitopes of recoverin, a cancer-associated retinopathy antigen, possibly related with a better prognosis in a paraneoplastic syndrome. Eur J Immunol 31:563–572

    Article  PubMed  CAS  Google Scholar 

  48. Maeda T, Maeda A, Maruyama I, Ogawa KI, Kuroki Y, Sahara H, Sato N, Ohguro H (2001) Mechanisms of photoreceptor cell death in cancer-associated retinopathy. Invest Ophthalmol Vis Sci 42:705–712

    PubMed  CAS  Google Scholar 

  49. Maeda A, Maeda T, Ohguro H, Palczewski K, Sato N (2002) Vaccination with recoverin, a cancer-associated retinopathy antigen, induces autoimmune retinal dysfunction and tumor cell regression in mice. Eur J Immunol 32:2300–2307

    Article  PubMed  CAS  Google Scholar 

  50. Makino CL, Dodd RL, Chen J, Burns ME, Roca A, Simon MI, Baylor DA (2004) Recoverin regulates light-dependent phosphodiesterase activity in retinal rods. J Gen Physiol 123:729–741

    Article  PubMed  CAS  Google Scholar 

  51. Masaoka N, Emoto Y, Sasaoka A, Fukushima A, Ueno H, Ohguro H (1999) Fluorescein angiographic findings in a case of cancer-associated retinopathy. Retina 19:462–464

    PubMed  CAS  Google Scholar 

  52. Matsubara S, Yamaji Y, Sato M, Fujita J, Takahara J (1996) Expression of a photoreceptor protein, recoverin, as a cancer-associated retinopathy autoantigen in human lung cancer cell lines. Br J Cancer 74:1419–1422

    PubMed  CAS  Google Scholar 

  53. Milam AH, Dacey DM, Dizhoor AM (1993) Recoverin immunoreactivity in mammalian cone bipolar cells. Vis Neurosci 10:1–12

    Article  PubMed  CAS  Google Scholar 

  54. Milam AH, Saari JC, Jacobson SG, Lubinski WP, Feun LG, Alexander KR (1993) Autoantibodies against retinal bipolar cells in cutaneous melanoma-associated retinopathy. Invest Ophthalmol Vis Sci 34:91–100

    PubMed  CAS  Google Scholar 

  55. Miyagawa Y, Ohguro H, Odagiri H, Maruyama I, Maeda T, Maeda A, Sasaki M, Nakazawa M (2003) Aberrantly expressed recoverin is functionally associated with G-protein-coupled receptor kinases in cancer cell lines. Biochem Biophys Res Commun 300:669–673

    Article  PubMed  CAS  Google Scholar 

  56. Old LJ (2001) Cancer/testis (CT) antigens—a new link between gametogenesis and cancer. Cancer Immun 1:1

    PubMed  CAS  Google Scholar 

  57. Polans AS, Buczylko J, Crabb J, Palczewski K (1991) A photoreceptor calcium binding protein is recognized by autoantibodies obtained from patients with cancer-associated retinopathy. J Cell Biol 112:981–989

    Article  PubMed  CAS  Google Scholar 

  58. Polans AS, Witkowska D, Haley TL, Amundson D, Baizer L, Adamus G (1995) Recoverin, a photoreceptor-specific calcium-binding protein, is expressed by the tumor of a patient with cancer-associated retinopathy. Proc Natl Acad Sci USA 92:9176–9180

    Article  PubMed  CAS  Google Scholar 

  59. Posner JB, Furneaux HM (1990) Paraneoplastic syndromes. Res Publ Assoc Res Nerv Ment Dis 68:187–219

    PubMed  CAS  Google Scholar 

  60. Potter MJ, Adamus G, Szabo SM, Lee R, Mohaseb K, Behn D (2002) Autoantibodies to transducin in a patient with melanoma-associated retinopathy. Am J Ophthalmol 134:128–130

    Article  PubMed  Google Scholar 

  61. Rong S, Ikeda H, Sato Y, Hirohashi Y, Takamura Y, Sahara H, Sato T, Maeda A, Ohguro H, Sato N (2002) Frequent detection of anti-recoverin cytotoxic T-lymphocyte precursors in peripheral blood of cancer patients by using an HLA-A24-recoverin tetramer. Cancer Immunol Immunother 51:282–290

    Article  PubMed  CAS  Google Scholar 

  62. Salgia R, Hedges TR, Rizk M, Reimer RH, Skarin AT (1998) Cancer-associated retinopathy in a patient with non-small-cell lung carcinoma. Lung Cancer 22:149–152

    Article  PubMed  CAS  Google Scholar 

  63. Sawyer RA, Selhorst JB, Zimmerman LE, Hoyt WF (1976) Blindness caused by photoreceptor degeneration as a remote effect of cancer. Am J Ophthalmol 81:606–613

    PubMed  CAS  Google Scholar 

  64. Senin II, Zargarov AA, Alekseev AM, Gorodovikova EN, Lipkin VM, Philippov PP (1995) N-myristoylation of recoverin enhances its efficiency as an inhibitor of rhodopsin kinase. FEBS Lett 376:87–90

    Article  PubMed  CAS  Google Scholar 

  65. Senin II, Dean KR, Zargarov AA, Akhtar M, Philippov PP (1997) Recoverin inhibits the phosphorylation of dark-adapted rhodopsin more than it does that of bleached rhodopsin: a possible mechanism through which rhodopsin kinase is prevented from participation in a side reaction. Biochem J 321(Pt 2):551–555

    PubMed  CAS  Google Scholar 

  66. Senin II, Koch KW, Akhtar M, Philippov PP (2002) Ca2+-dependent control of rhodopsin phosphorylation: recoverin and rhodopsin kinase. Adv Exp Med Biol 514:69–99

    PubMed  CAS  Google Scholar 

  67. Sobottka B, Schlote T, Besch D, Djelebova T, Wilhelm H, Zrenner E (2000) Carcinoma-associated retinopathy: a review with clinical examples. Klin Monatsbl Augenheilkd 216:17–24

    Article  PubMed  CAS  Google Scholar 

  68. Thirkill CE (1997) Experimental, cancer-induced retinopathy. Ocul Immunol Inflamm 5:55–65

    Article  PubMed  CAS  Google Scholar 

  69. Thirkill CE, Roth AM, Keltner JL (1987) Cancer-associated retinopathy. Arch Ophthalmol 105:372–375

    PubMed  CAS  Google Scholar 

  70. Thirkill CE, Roth AM, Takemoto DJ, Tyler NK, Keltner JL (1991) Antibody indications of secondary and superimposed retinal hypersensitivity in retinitis pigmentosa. Am J Ophthalmol 112:132–137

    PubMed  CAS  Google Scholar 

  71. Thirkill CE, Tait RC, Tyler NK, Roth AM, Keltner JL (1992) The cancer-associated retinopathy antigen is a recoverin-like protein. Invest Ophthalmol Vis Sci 33:2768–2772

    PubMed  CAS  Google Scholar 

  72. Usener D, Gerhardt A, Schadendorf D, Eichmüller S (2003) Sero-reactivity against MAGE-A and LAGE-1 proteins in melanoma patients. Br J Dermatol 149:282–288

    Article  PubMed  CAS  Google Scholar 

  73. Weinstein JM, Kelman SE, Bresnick GH, Kornguth SE (1994) Paraneoplastic retinopathy associated with antiretinal bipolar cell antibodies in cutaneous malignant melanoma. Ophthalmology 101:1236–1243

    PubMed  CAS  Google Scholar 

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Acknowledgements

This work was supported in parts by grants from the Cancer Research Institute/Elaine R. Shepard Memorial Investigator Award to S.B.E., the Ludwig Institute for Cancer Research and the Russian Foundation for Basic Research NN 04-04-48438 to P.P.Ph.

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Correspondence to Stefan B. Eichmüller.

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This article is a symposium paper from the conference “Progress in Vaccination against Cancer 2005 (PIVAC 5)”, held in Athens, Greece, on 20–21 September 2005.

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Bazhin, A.V., Schadendorf, D., Philippov, P.P. et al. Recoverin as a cancer-retina antigen. Cancer Immunol Immunother 56, 110–116 (2007). https://doi.org/10.1007/s00262-006-0132-z

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