Analysis Of Monocarboxylate Transporter 4 As A Biomarker Shows Prognostic Significance As An Indicator Of Radiotherapy In Squamous Cell Carcinoma Of The Head And Neck

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC BACKGROUND: Hypoxia is known to contribute significantly to tumor progression and resistance to radiotherapy, decreasing local tumor control and lowering the rates of disease free and overall survival. Research to target hypoxia in the clinic has produced varying results; hence the discovery of hypoxia markers has become more significant. Monocarboxylate Transporter 4 (MCT4) is a hypoxia-regulated transporter of lactate out of the cell, preventing its intra-cellular accumulation, enabling sustained high glycolytic rates and maintenance of intra-cellular pH. AIM: To evaluate MCT4 immunohistochemically as a potential biomarker for prognosis of patients with head and neck squamous cell carcinoma (SCC) of tonsil or tongue undergoing radiotherapy, and to determine the impact of MCT4 expression on radiotherapy resistance. METHODS: 155 histologically confirmed SCC pre-treatment diagnostic biopsies, originating from the tonsil or posterior third of the tongue, were collected retrospectively from a diagnostic archive. The biopsies were analyzed immunohistochemically to evaluate MCT4 membrane expression. MCT4 expression was assessed in a double blind study using a semi-quantitative scoring system. Scores were analyzed for possible correlations with clinicopathological data relating to outcome 5 years post diagnosis, where all patients had received radiotherapy to the primary site. siRNA against MCT4 was used in SCC cell lines to evaluate radiosensitivity of wild-type and MCT4-knockdown cells by colony forming assays. RESULTS: A univariate analysis to assess high MCT4 expression (top 25% of scores) vs low MCT4 expression (lower 75%) showed that MCT4 is a significant adverse prognostic factor in the series of biopsies. High MCT4 expression correlates with poor loco-regional control (p = 0.017), reduced cancer-specific survival (p = 0.02) and reduced overall survival (p = 0.055). In a multivariate analysis high MCT4 expression retained prognostic significance for poor loco-regional control (p = 0.007). This was confirmed by clonogenic assay in FaDu and PE/CA-PJ-34 cell lines, MCT4-knockdown cells showed a marked increase in radiosensitivity compared to wild-type cells. CONCLUSIONS: MCT4 is a significant biomarker for prognosis and treatment outcome following radiotherapy in SCC of tonsil and tongue. The increase in significance from overall survival to loco-regional control is consistent with a hypoxia-regulated marker of radiotherapy resistance. The functional role of MCT4 as a lactate transporter in hypoxia may be of key underlying biological importance to this finding, maintaining intracellular pH in an hypoxic microenvironment. This suggests that drug inhibition of MCT4 may potentially sensitize tumor cells to radiation treatment. 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 5635.