Abstract 29: Nectin-4 cell-surface oncoprotein in serum and tumor issue as a diagnostic and therapeutic target for lung cancer
Authors: Yataro Daigo, Atsushi Takano, Eiju Tsuchiya, Yusuke Nakamura
Journal: Cancer Research (2010)

Abstract Lung cancer is one of the most serious cancers which has a notably poor prognosis. The number of patients responding well to current standard therapies is still small, and no tumor marker has been sufficiently useful in the detection of curative stage cancers. To identify target molecules which could be useful for the development of diagnostic biomarkers and novel drugs, we have established an effective screening strategy which is as follows; i) Firstly we identified up-regulated genes in lung cancers by genome-wide screening using the cDNA microarray representing 27,648 genes and pure populations of tumor cells taken from 120 lung cancer tissues by laser microdissection, ii) Secondly we confirmed the identification of the candidate genes on the basis of their having a very low level of expression in normal tissues by using northern-blot analysis, iii) We then validated the clinicopathologic significance of its over-expression by means of tissue microarray containing hundreds of archived lung-cancer samples, iv) Next we verified whether the target gene is essential for the growth, survival, or motility of cancer cells by RNA interference and cell growth/invasion assays, and v) Finally we determined its usefulness as a serum diagnostic/prognostic biomarker for lung cancer by ELISA, if it is a tumor-specific transmembrane or secretory protein. As a result of this process, we identified 25 druggable oncoproteins, some of which are being applied as serum biomarkers and cancer vaccines in clinical studies. We further identified the immunoglobulin-like molecule Nectin-4. Immunohistochemical analysis using tumor tissue microarrays demonstrated that strong Nectin-4 expression in tumors was associated with poor prognosis (P&amp;lt;0.0001 by multivariate analysis; N=422). In addition, we established an ELISA to measure serum Nectin-4 and found that the proportion of serum Nectin-4-positive cases was 88 (53.7%) of 164 non-small cell lung cancer (NSCLC) patients, while 3 (2.3%) of 131 healthy volunteers were falsely diagnosed, thereby proving it was superior to CEA and CYFRA21-1 in terms of both sensitivity and specificity. Serum Nectin-4 positivity was an independent prognostic factor for the patients with stage I NSCLC (N=95) after curative surgery or advanced NSCLC treated with an identical protocol of chemotherapy (P=0.0219 and 0.0269, respectively). Treatment of lung cancer cells with siRNAs against Nectin-4 suppressed its expression and growth. In addition, exogenous expression of Nectin-4 increased the lamellipodia formation and the invasive ability of mammalian cells through activation of small GTPase Rac1. Nectin-4 might play a significant role in lung carcinogenesis, and therefore it should be a biomarker for early cancer detection, monitoring, and for the prediction of prognosis, as well as being a suitable therapeutic target. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 29.