Presence of Villin, a Tissue-Specific Cytoskeletal Protein, in Sera Of

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Presence of Villin, a Tissue-Specific Cytoskeletal Protein, in Sera Of [CANCER RESEARCH 50, 438-443. January 15, 1990] Presence of Villin, a Tissue-specific Cytoskeletal Protein, in Sera of Patients and an Initial Clinical Evaluation of Its Value for the Diagnosis and Follow-up of Colorectal Cancers1 B. Dudouet, L. Jacob, P. Beuzeboc, H. Magdelenat, S. Robine, Y. Chapuis, B. Christoforov, G. A. Cremer, P. Pmiillanl, P. Bonnichon, F. Pinon, R. J. Salmon, A. Pointereau-Bellanger, J. Bellanger, M. T. Maunoury, and D. Louvard2 DépartementdeMédecineinterne [L. J., B. C., G. A. C.J, Clinique Chirurgicale [Y. C., P. Bo.J, and Poste de Transfusion sanguine ¡F.P.], Hôpital Cochin, 27, rue du Faubourg Saint Jacques, 75674 Paris Cedex 14; DépartementdeMédecineoncologique [P. Be., P. P.], Laboratoire de radiopathologie ¡H.M.], and Service de Chirurgie [R. J. S.], Institut Curie, 26 rue d'Ulm, 75005 Paris; Service de Gastroenterologie, Pr. Y. Le Quintrec, Hôpital Rothschild, 75012 Paris [J. B.]; Pharmacie Hôpital Salpétriére,83bd de l'Hôpital, 75013 Paris [A. P. B.]; Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805 Villejuif Cedex [M. T. M.J; and UnitédeBiologie des Membranes, DépartementdeBiologie Moléculaire,Institut Pasteur, 25 rue du Docteur Roux, 75724 Paris Cedex 15 [B. D., S. R., D. L.], France ABSTRACT This restricted tissue specificity of villin is also conserved during neoplasie processes. In this respect, it is particularly Villin is an actin-binding protein found in a few normal adult epithelia, worth recalling that villin continues to be produced in colorectal namely epithelial cells in the digestive and urogenital tracts. Moreover, tumors at all stages of epithelial cell transformation, but that villin production is maintained in malignant cells. We assumed that cell lysis and necrosis of solid tumors producing villin might result in villin villin is conspicuously absent from tumors arising from cell release into blood. We analyzed the villin content of sera from 788 types in which it is not normally found (5, 6). patients and controls using an enzyme-linked immunosorbent assay. These observations are in contrast with the more generalized Patients and controls were classified into healthy donors, patients with production of CEA,3 a tumor marker that is routinely assayed benign diseases of the gastrointestinal tract, patients with colorectal for screening and follow-up of patients with tumors of the cancers, and patients with malignant nondigestive diseases. In the panel digestive tract. For example, it is now well established that of sera analyzed, the sensitivity of the assay for colorectal cancers was CEA is found in several normal cells of numerous origins (7- 50.5%, and its overall specificity for malignant digestive tumors was 9). 94.5%. Results were statistically analyzed comparing each group of sera The above mentioned properties of villin prompted us to with each other. We conclude that the presence of villin is indicative of a pathological state in the gastrointestinal tract (/' < 0.001). Finally, we determine whether it is released into the blood circulation, due followed villin levels after tumor resections (60 patients). We found that to lysis of malignant cells or by means of another unknown the villin level in sera remains low in remissions but is raised in recur mechanism, which could indicate the existence of a lesion in rences. the digestive tract. We therefore investigated the presence of We suggest that the villin assay may have clinical utility as a diagnostic villin in the sera of 788 patients and controls with an ELISA adjunct for adenocarcinoma of the gastrointestinal tract. It may also have developed for this study in our laboratory. Our initial data some value in monitoring patients with advancing colorectal carcinomas showed that the occurrence of villin in human sera corre after resection of these tumors. sponded to the pathological state of the gastrointestinal tract. Moreover, the presence of villin in sera was very often associ ated with a malignant digestive tumor. This is the first report INTRODUCTION of the presence of villin in human sera. We discuss the value of Enterocytes, the epithelial cells of the intestinal mucosa, villin as a diagnostic adjunct for the diagnosis and follow-up of exhibit a functional and morphological polarity. Their apical patients with colorectal carcinomas. plasma membrane shows an ordered array of microvilli forming the brush border. Each microvillus is supported by a cytoskel- MATERIALS AND METHODS eton based on actin microfilaments. These actin microfilament bundles are associated with a few actin-binding proteins (1). Clinical Specimens. Age- and sex-matched healthy controls were Among them, villin, a M, 95,000 protein, is able to bind actin provided by a serum bank from the Centre National de Transfusion in a calcium-dependent process. Production of villin and its sanguine (HôpitalCochin, Paris, France). The mean age of these donors regulation were previously studied in our laboratory in vivo and was 37 ±15 yr. They included a roughly equal proportion of men and in cell cultures (2-4). During ontogenesis of the human diges women. The mean age of donors from whom sera contained detectable amounts of villin was 39 ±11yr. Coded serum collections from patients tive tract, villin is found in immature intestinal cells as early as bearing gastrointestinal tumors, adenocarcinoma of other organs, or the eight wk of gestation of the human fetus, before the final benign diseases were obtained from three hospitals (Departments of stages of histogenesis. Similarly, villin is found in adult undif- Internal Médecineand Surgery). For this study, the diagnosis and ferentiated crypt cells of the intestinal mucosa. In the adult follow-up of patients bearing digestive tumors were carried out with human, high levels of villin were primarily found in epithelial routine clinical and endoscopie examinations. All specimens (healthy cells with a well-organized brush border, namely the epithelial donors' sera, benign and malignant disease patients' sera) were coded cells in the small and large intestine and in cells lining the and collected during the same period of time. All of them were aliquoted and stored in the same conditions at —¿20°C.Wehave observed that proximal tubules of the kidney. villin is stable in these storage conditions. Provided that the assay was Received 2/27/89; revised 7/13/89; accepted 9/25/89. performed on frozen and thawed samples, there was no significant The costs of publication of this article were defrayed in part by the payment variation in the measured villin concentration. Medical histories of of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. patients were checked to validate this information and to secure addi 1This work was supported by grants from the Institut National de la Santéet tional data about the serum withdrawal date and about the ultimate de la Recherche Médicale(No. 86-7008), by the Fondation pour la Recherche MédicaleFrançaise,by the Association pour la Recherche sur le Cancer (No. 3The abbreviations used are: CEA, carcinocmbryonic antigen; ELISA, enzyme- 6379), théCNRS(UA-1149), and théLigueNationale Françaisecontre le Cancer. linked immunosorbent assay; PBS, phosphate-buffered saline; BSA, bovine serum 1To whom requests for reprints should be addressed. albumin. 438 Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 1990 American Association for Cancer Research. VILLIN, A CYTOSKELETAL PROTEIN IN SERA OF PATIENTS WITH COLORECTAL CANCERS course of the disease. Laboratory assays, such as that for CEA, were RESULTS determined in parallel on the same sample and were available for correlation with the results of the villin assays. Sensitivity and Specificity of the Villin ELISA Assay. The Determination of Villin Levels. Sera were analyzed by an ELISA ELISA assay for villin designed in our laboratory uses a highly using a mouse monoclonal anti-villin (BDID2C3) antibody obtained and specific monoclonal antibody raised against villin and able to characterized as described in Ref. 4. This monoclonal antibody recog recognize a unique epitope found only in villin (4). The assay nizes a well-conserved epitope of villin across species. This epitope is for villin used in this study is a sandwich ELISA (see "Materials located in an actin-binding domain at the COOH-terminal end of the and Methods"). Fig. 1 shows a typical standard curve, made molecule. with villin concentrations ranging from 2 ng/ml to 150 ng/ml. Primary sequence analysis of this domain carried out by our group The slope of the curve depends upon the villin-free medium (10) has revealed that the carbo\>-terminal end of villin is villin specific used for the pure villin dilution. The minimal detectable amount and displays no sequence homologies with other actin-binding proteins is as low as 0.5 ng/ml in PBS and up to 4 ng/ml in some villin- nor with any other known proteins currently listed in a protein data free sera obtained from healthy donors. In all cases, a linear library. response up to 75 ng/ml was obtained. Such differences may In addition, cell extracts prepared with various cell lines established be due to interference by serum proteins and were not investi from cells not expressing villin in viro, when investigated for villin gated further. Specificity was checked on every serum sample content with this ELISA, prove to be negative (2, 11). Moreover, if a known amount of exogenous villin were added to with villin levels above 20 ng/ml by preincubation with an excess of monoclonal antibody against villin as described in these extracts, villin could be quantitatively assayed in these conditions. "Materials and Methods." Only samples exhibiting a total Altogether, these data illustrate the specificity of the antibody for villin and the lack of cross-reactivity for ubiquitous cytoskeletal proteins, inhibition after preincubation with the monoclonal antibody such as gelsolin, tropomyosin, calpactin, actinin, as well as the lack of were considered to contain villin.
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