Characterization of a small-cell-lung-carcinoma cell line from a patient with cancer-associated retinopathy

Abstract

We examined the biologic properties of a small-cell-lungcarcinoma (SCLC) cell line (designated MN-I I 12) established from a patient with SCLC who showed paraneoplastic retinopathy syndrome. Morphologic and immunocytochemical analyses showed that MN-I I I2 cells possess features of the classic type of SCLC. MN-I I I 2 cells grew in suspension forming relatively large clumps of cells with a doubling time of 72 hr. By light-microscope examination, the cells were relatively small and had scanty cytoplasm. The cells produced NSE, ACTH and CK (BB isozyme); they also expressed recoverin, a novel photoreceptor protein, detected by Northern-blot and Westernimmunoblot analysis using human-recoverin-specific DNA probe and anti-bovine-recoverin polyclonal antibody. This report shows that human recoverin is expressed in cultured SCLC cells. Our results support the hypothesis that, in cancer-associated retinopathy (CAR) patients, auto-immune antibody targeting for ectopic recoverin in SCLC is initially produced and cross-reacts with the retinal protein, resulting in the retinal degeneration that occurs in CAR patients.o 1996 Wiley-Liss, Inc.Small-cell lung carcinoma (SCLC) occurs in approximately 15% of total lung carcinoma, which has become the most common cause of cancer deaths among Japanese men. SCLC may originate from the Kultschitzky cells lining the bronchial mucosa and possess characteristics of the APUD series of neuro-endocrine cells. They express neuronal differentiation antigens, including NSE, the BB isozyme of CK, receptors for nerve growth factor, and acetylcholine (Greco et al., 1981). Compared with non-SCLCs, they are more frequently associated with paraneoplastic neuropathy syndromes (PNS), such as Eaton-Lambert myasthenic syndrome (ELMS) and paraneoplastic encephalomyelitis/sensory neuropathy syndrome (PEM/ SNS), which are caused by remote effects of cancer (O'Neill et aL, 1988;Dalmau et al., 1992). The neuronal characteristics of SCLC may provide the antigenic stimulus required for production of a cross-reacting immune response (Kornguth, 1989). Cancer-associated retinopathy (CAR) syndrome is one of such syndromes, and is characterized by degenerative retina without evidence of severe inflammatory processes or metastasis or any known direct effect of the cancer cells (Thirkill et al., 1989). A high percentage of patients reveal a characteristic antibody, which recognizes a 23-kDa antigen (Thirkill et al., 1993). Recoverin, a photoreceptor-specific protein, has been determined as a candidate for the 23-kDa CAR antigen which was screened in human retinal cDNA library using autoantibodies from a CAR patient (Thirkill et al., 1992). According to the auto-immune hypothesis that has been proposed, the process arises as a reaction to the 23-kDa antigen shared by SCLC and the retina; however, such CAR antigen has not yet been clarified in SCLC cells (Thirkill et al., 1989(Thirkill et al., , 1993. In previous studies, however, these cells were usually derived from a tumor of patients without CAR (Thirkill et al.,...

Clinicopathological Features of Gastric Cancer Cases and Aberrantly Expressed Recoverin

“…As a mechanism for the apoptotic cell death of photoreceptor cells observed in CAR, it has been postulated that anti-recoverin antibody generated by unknown mechanisms in some cancer patients penetrates into the photoreceptor cells via the peripheral circulation and causes misregulation of the phototransduction pathway by blocking recoverin function (Adamus et al 1998;Maeda et al 2001b). In the initial step of CAR pathogenesis, several studies suggested that aberrant expression of retina-specific recoverin, serving as a shared antigen between tumor cells and retina, was critical since such aberrant expression of recoverin had been identified in tumor cells in CAR patients but not in non-CAR cancerous patients (Polans et al 1995;Matsubara et al 1996;Yamaji et al 1996). However, in contrast, we have recently found that aberrant expression of retina-specific recoverin occurred in more than 50% of several kinds of cancer cells, and their cell lines obtained from non-CAR cancerous patients (Maeda et al 2000;Maeda et al 2001a).…”

Expression of a photoreceptor protein, recoverin, as a cancer-associated retinopathy autoantigen in human lung cancer cell lines

“…Thirkill et al (1993) previously suggested that recoverin expression could be induced in otherwise quiescent SCLC cell lines. However, the expression of recoverin in an SCLC cell line, MN-1112, was not induced during the establishment and passage of the cell line because, as previously reported, the recoverin expression was immunohistochemically demonstrated in a primary SCLC tumour of the CAR patient from which the cell line was derived (Matsubara et al, 1996).…”

“…An SCLC cell line, designated MN-1112, was established from a tumour of an SCLC patient with CAR (Yamaji et al, 1996). The patient profile had been described previously (Matsubara et al, 1996).…”

Cancer-Associated Retinopathy during Treatment for Small-Cell Lung Carcinoma.

“…This protein is a member of the E-F hand family of calcium-binding proteins involved in the transduction of light by vertebrate photoreceptors and is also identified as an autoantigen in CAR (12,13). It has been reported that this photoreceptor-specific protein is expressed by the tumor in CARpatients (16) and by a human lung cancer cell line (MN-1112), which was established from tumors of small-cell lung carcinoma patients with CAR (17,26). In addition, expression of recoverin was not found in patients with diabetic retinopathy, age-related macular degeneration and in small-cell lung carcinoma patients without CAR (7,17).…”