Photoreceptor proteins as cancer‐retina antigens

Abstract

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...

Autoantibodies against the Ca2+-binding protein recoverin in blood sera of patients with various oncological diseases

“…To generate AAR, tumor cells should express Rc mRNA and recoverin protein. The expression of AAR at the mRNA and/or protein levels has been shown for tumor tissues and/or cell lines in the case of lung tumors (7)(8)(9)(10), malignant melanoma (15,20) and breast, endometrial and cervical carcinomas (14). Recently, the recoverin-positive immune reaction was demonstrated for brain glioma and glioblastoma, squamous cell carcinoma, and carcinomas of the esophagus, stomach, colon, rectum, pancreas, kidney, prostate, ovary, neck of the uterus and breast; in addition, the ability of lung tumors to express recoverin was confirmed (21).…”

“…However, in this case normal tissues were obtained from the brain area adjacent to the malignant tumors, the cells of which may contaminate the specimens obtained for the analysis. It should be added that the recoverin expression at the mRNA level has been detected in normal human lung, brain, thymus, uterus and melanocytes (15).…”

“…Amplified PCR products (394 bp for recoverin and 638 bp for GAPDH) were subjected to electrophoresis on 1.5% agarose gels followed by staining with ethidium bromide. The samples were considered positive if a clear band was visible in the gel in at least 2 out of 3 independent PCR experiments [for primer sequences, see (15)]. …”

Visible Light Modulates the Expression of Cancer-Retina Antigens

“…Furthermore, CRA can be aberrantly expressed in melanoma or lung cancer cells (1,2). This aberrant expression of CRA can generate an autoimmune response (2,3), which, in turn, can eventually lead to development of paraneoplastic retina degeneration (4,5).…”

“…The group of cancer antigens compose the key visual signal proteins: rhodopsin (Rho), transducin (Tr), cyclic guanosine 3 ¶,5 ¶-monophosphate (cGMP) phosphodiesterase 6 (PDE6), cGMP-gated channels, rhodopsin kinase, recoverin (Rec), arrestin (Arr), and photoreceptorspecific guanylyl cyclase 1 (GC1). All CRA are expressed in melanoma (1), which is a highly invasive tumor derived from normal epithelial melanocytes, thus sharing the lineage with retinal cells (6).…”