Intratumoral lactate metabolism in Barrett’s esophagus and adenocarcinoma

// Heikki Huhta 1, 2, 3, 4, * , Olli Helminen 1, 2, 3, 4, * , Sami Palomaki 3, 4, * , Joonas H. Kauppila 1, 2, 3, 4, 5 , Juha Saarnio 2, 3, 4 , Petri P. Lehenkari 2, 3, 4 , Tuomo J. Karttunen 1, 3, 4 1 Departments of Pathology, University of Oulu, Oulu, Finland 2 Departments of Surgery, University of Oulu, Oulu, Finland 3 Medical Research Center Oulu, Oulu, Finland 4 Oulu University Hospital, Oulu, Finland 5 Upper Gastrointestinal Surgery, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden * These authors contributed equally to these work Correspondence to: Heikki Huhta, email: heikki.huhta@oulu.fi Keywords: MCT1, MCT4, MTCO1, esophageal adenocarcinoma, Barrett’s esophagus Received: October 20, 2016      Accepted: January 27, 2017      Published: February 11, 2017 ABSTRACT Background: Monocarboxylate transporters (MCTs) are cell membrane proteins which transport pyruvate, lactate and ketone bodies across the plasma membrane. MCTs are activated in various cancers, but their expression in esophageal adenocarcinoma is not known. The present study was conducted to elucidate the expression of MCTs in esophageal adenocarcinoma and its precursor lesions. Results: Cytoplasmic MCT1, MCT4 and MTCO1 expression linearly increased from normal epithelium to Barrett's mucosa to dysplasia and cancer. Low cytoplasmic MCT1 expression associated with high T-class ( P < 0.01), positive lymph node metastases ( P < 0.05), positive distant metastases ( P < 0.01) and high tumor stage ( P < 0.01). High cytoplasmic MCT4 expression correlated significantly with positive distant metastases ( P < 0.05). Both low MCT1 and high MCT4 histoscore predicted survival in univariate analysis ( P < 0.01). MCT4 histoscore predicted survival in multivariate analysis ( P = 0.043; HR 1.8 95%CI 1.0–3.1). MTCO1 expression was not correlated to clinicopathological variables or survival. Materials and Methods: MCT1, MCT4 and mitochondrial cytochrome c oxidase (MTCO1) expression were determined with immunohistochemistry in esophageal specimens from 129 patients with columnar dysplasia or adenocarcinoma. Specimens including normal esophagus ( n = 88), gastric ( n = 67) or intestinal metaplasia ( n = 51), low-grade ( n = 42), high-grade dysplasia ( n = 37) and esophageal adenocarcinoma ( n = 99) were evaluated. Conclusions: Major increase in markers of tumor metabolism occurs during carcinogenesis and progression of esophageal adenocarcinoma. MCT1 and MCT4 are prognostic factors in esophageal adenocarcinoma.