Monocarboxylate Transporters 1 and 4 and Prognosis in Small Bowel Neuroendocrine Tumors

SIMPLE SUMMARY: Monocarboxylate transporters (MCT) are cell membrane proteins transporting lactate, pyruvate, and ketone bodies. For most non-neoplastic cells, the aforementioned energy metabolites are waste products and must be exported via MCTs. However, it seems tumor cells have developed means to shuttle these metabolites through MCTs and utilize them for energy production. MCTs contribute to the acidification of the tumor microenvironment and are associated with drug resistance making them potential therapeutic targets. MCT expression has been shown to correlate with prognosis in a range of human solid tumors. In small bowel neuroendocrine tumors, the expression of MCTs 1 and 4 is reported for the first time. High MCT4 expression is associated with improved prognosis. ABSTRACT: Monocarboxylate transporters (MCTs) are cell membrane proteins transporting lactate, pyruvate, and ketone bodies across the plasma membrane. The prognostic role of MCTs in neuroendocrine tumors is unknown. We aimed to analyze MCT1 and MCT4 expression in small bowel neuroendocrine tumors (SB-NETs). The cohort included 109 SB-NETs and 61 SB-NET lymph node metastases from two Finnish hospitals. Tumor samples were immunohistochemically stained with MCT1 and MCT4 monoclonal antibodies. The staining intensity, percentage of positive cells, and stromal staining were assessed. MCT1 and MCT4 scores (0, 1 or 2) were composed based on the staining intensity and the percentage of positive cells. Survival analyses were performed with the Kaplan–Meier method and Cox regression, adjusted for confounders. The primary outcome was disease-specific survival (DSS). A high MCT4 intensity in SB-NETs was associated with better DSS when compared to low intensity (85.7 vs. 56.6%, p = 0.020). A high MCT4 percentage of positive cells resulted in better DSS when compared to a low percentage (77.4 vs. 49.1%, p = 0.059). MCT4 scores 0, 1, and 2 showed DSS of 52.8 vs. 58.8 vs. 100% (p = 0.025), respectively. After adjusting for confounders, the mortality hazard was lowest in the patients with a high MCT4 score. MCT1 showed no association with survival. According to our study, a high MCT4 expression is associated with an improved prognosis in SB-NETs.