Abstract 4123: Monocarboxylate transporter 4 expression is a prognostic factor for radiotherapy outcome in squamous cell carcinoma of the head and neck
Authors: Chadwick Amy L. , Womack Chris , Watkins Gillian , Bola Becky M. , Slevin Nick , Homer Jarrod , Smith Paul , Critchlow Susan E. , West Catharine M. , Wedge Stephen R. , Stratford Ian J. 
Published: August 2014

Background: Hypoxia contributes significantly to tumor progression and resistance to radiotherapy, decreasing local tumor control and lowering the rates of disease-free and overall survival. Hypoxic tumor cells utilize the glycolytic pathway for survival, producing vast quantities of lactate. Monocarboxylate Transporters (MCTs) 1 and 4 are key transporters of lactate, enabling sustained high glycolytic rates and maintenance of intra-cellular pH.

Aim: To carry out the first study evaluating tumor MCT1 and 4 expression as potential biomarkers of prognosis in patients with head and neck squamous cell carcinoma (HNSCC) undergoing radiotherapy, and to determine the impact of MCT expression on radiation resistance.

Methods: 125 histologically confirmed SCC pre-treatment diagnostic oropharyngeal cancer biopsies (tonsil or posterior third of the tongue) were collected retrospectively from diagnostic archives. The biopsies were analyzed immunohistochemically to evaluate MCT1 and 4 membrane expression. MCT expression was assessed in a double blind manner 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. FaDu HNSCC cells expressing doxycycline inducible shRNA targeting MCT4 were used to evaluate radiosensitivity of wild-type and MCT4-knockdown cells.

Results: A univariate analysis comparing high (top 25% of scores) vs low MCT expression (lower 75%) showed that MCT4, but not MCT1, is a significant adverse prognostic factor for radiotherapy outcome. 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). Confirmation of MCT4 as a novel target for increasing hypoxic radiosensitivity was carried out by clonogenic assay in FaDu wild-type and shMCT4 cell lines, MCT4-knockdown cells showed a marked increase in hypoxic radiosensitivity compared to wild-type cells.

Conclusions: 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 a hypoxic microenvironment. These findings suggest that inhibition of MCT4 may modify hypoxic tumor regions and sensitize tumor cells to radiation treatment.

Therefore, MCT4 should be explored further as a novel target and biomarker for prognosis and prediction of benefit from hypoxia-modifying therapy in patients undergoing radiotherapy.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4123. doi:10.1158/1538-7445.AM2011-4123