Abstract 3729: Prognostication using Hif-1 alpha may require simultaneous nicotine assessment

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Abstract Background: Current cancer diagnosis and treatment increasingly incorporates biomarker expression in the prognostication and therapeutic stratification of cancer patients; however, there is no accurate assessment of exposure to environmental agents such as nicotine that may significantly impact biomarker expression patterns. Methods: Athymic nude mice with human H460 lung cancer cell xenografts were stratified into three treatment groups (n=5 per group) beginning when tumors reached 5 mm in maximal dimension: control (CON), short term nicotine (STN, 60 ug subcutaneously every other day x 6 days), or long term nicotine (LTN, 60 ug SC every other day until tumor explant). All tumors were explanted at endpoint defined when tumors reached 15 mm in maximal dimension. Tumors were analyzed immunohistochemically for hypoxia (using CA-IX expression) and hypoxia-inducible factor 1-alpha (Hif-1) expression. This protocol was approved by the Institutional Animal Care and Use Committee at the University of Kentucky. Results: Nicotine administration had no effect on tumor growth rate and all tumors reached endpoint within a median of 9 days following treatment initiation (range 8-11 days). Areas of hypoxia were defined using CA-IX expression. Tumor hypoxia was not significantly affected by nicotine administration. Moreover, Hif-1 expression was only minimally increased in areas of hypoxia in CON animals. In STN animals, Hif-1 expression was very similar to CON animals. In contrast, LTN animals demonstrated widespread marked increases in Hif-1 expression at the viable: necrotic tumor interface. Separately, xenografts removed at day 6 demonstrated similar widespread Hif-1 expression confirming that Hif-1 expression is significantly increased after 6 days of nicotine administration. Conclusions: This study demonstrates that widespread Hif-1 expression may be dominated by the presence of nicotine rather than hypoxia. Furthermore, acute removal of nicotine results in the restoration of basal low-level Hif-1 expression within 3 days of nicotine removal. This data may significantly limit the prognostic utility of clinical Hif-1 expression in the absence of simultaneous nicotine assessment. 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 3729.