Melanocytes, melanoma and photoreceptor cells are of neuroectodermal origin and have a certain sensitivity to light. In this study, we present evidence for photoreceptor proteins that are responsible for visual transduction and its regulation function as a new class of cancer antigens in melanoma. Visual rhodopsin, transducin, cGMP-phosphodiesterase 6, cGMP-dependent channels, guanylyl cyclase, rhodopsin kinase, recoverin and arrestin are expressed in melanoma and can induce antibody responses in patients. Melanocytes also express mRNA of all photoreceptor genes besides transducin, but were devoid of the corresponding protein, which was tested for rhodopsin, cGMP-phosphodiesterase, guanylyl cyclase and recoverin. Furthermore, we show for the first time that some healthy tissues express mRNA of these genes, but never protein. Expression profiles and autoantibody responses were confirmed in the MT/ret and the HGF tg /Ink4a 2/2 transgenic mouse melanoma models. We propose a molecular transition of cancer-retina antigens from mRNA expression in melanocytes to protein expression in melanoma. Our work provides the basis for analyzing regulation of photoreceptor gene expression in normal and malignant cells as well as possible therapeutic tumor targeting using the newly defined class of cancer-retina antigens. ' 2006 Wiley-Liss, Inc.Key words: tumor antigens; photoreceptor proteins; melanoma; Ret; hepatocyte growth factor/scatter factor; melanocytes Phototransduction is a biochemical process by which the photoreceptor cells generate electrical signals in response to the absorption of photons (reviewed in [1][2][3] ). This process occurs in the outer segments of rod and cone photoreceptor cells. So far in health, the proteins involved in this process have been described to be expressed only in retina and pineal glands. 4 However, in cancer the photoreceptor protein recoverin has also been detected in various types of malignant tumors, most frequently in lung carcinomas. 5 Recoverin is expressed in about 75% of lung cancer tissues, and serum autoantibodies against recoverin were found in about 20% patients with lung cancer. 6 Moreover, recent screening attempts for identifying antigens associated with malignant melanoma have unraveled rhodopsin and arrestin to be transcribed in melanoma cell lines, and autoantibodies against these proteins have been found in sera of melanoma patients by SEREX. 7 By analogy with cancer-testis antigens, we proposed to set off a new group of cancer antigens-cancer-retina antigens with recoverin as the first member of this group. 8 Which proteins involved in phototransduction may be additional candidates for cancer-retina antigens? After photon capture, each molecule of bleached rhodopsin activates hundreds of molecules of the G-protein transducin by catalyzing the GDP/GTPexchange on the transducin molecule. GTP-containing transducin in turn activates the effector enzyme cGMP-phosphodiesterase 6 (PDE6), thus allowing hydrolysis of the photoreceptor secondary messenger, cGMP. The decrease in...
Melanoma-associated retinopathy is a rare paraneoplastic neurological syndrome characterized by retinopathy in melanoma patients. The main photoreceptor proteins have been found to be expressed as cancer-retina antigens in melanoma. Here we present evidence that these can function as paraneoplastic antigens in melanoma-associated retinopathy. Sera and one tumor cell line of such patients were studied and ret-transgenic mice spontaneously developing melanoma were used as a murine model for melanoma-associated retinopathy. Splenocytes and sera were used for adoptive transfer from tumor-bearing or control mice to wildtype mice. Retinopathy was investigated in mice by funduscopy, electroretinography and eye histology. Expression of photoreceptor proteins and autoantibodies against arrestin and transducin were detected in melanoma-associated retinopathy patients. In tumor-bearing ret-transgenic mice, retinopathy was frequently (13/ 15) detected by electroretinogram and eye histology. These pathological changes were manifested in degenerations of photoreceptors, bipolar cells and pigment epithelium as well as retinal detachment. Mostly these defects were combined. Cancer-retina antigens were expressed in tumors of these mice, and autoantibodies against arrestin were revealed in some of their sera. Adoptive transfer of splenocytes and sera from tumor-bearing into wildtype mice led to the induction of retinopathy in 4/16 animals. We suggest that melanoma-associated retinopathy can be mediated by humoral and/or cellular immune responses against a number of cancer-retina antigens which may function as paraneoplastic antigens in melanoma-associated retinopathy. '
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