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

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.

Prognostic Value of Monocarboxylate Transporter 1 Overexpression in Cancer: A Systematic Review

“…Patient ages ranged between 18 to 98 years, and all samples were collected from adult patients (considering the studies where information on age was available). MCT1 expression was assessed in different cancers: one study in melanoma [ 41 ], oral cavity tumours [ 42 ], endometrial cancer [ 43 ], testicular germ cell tumours [ 44 ], soft tissue sarcoma [ 45 ], head and neck cancer [ 46 ], pancreatic ductal adenocarcinoma (PDAC) [ 47 ], small bowel neuroendocrine tumours [ 48 ], synovial sarcoma [ 49 ], adrenocortical carcinoma [ 50 ], small cell lung cancer (SCLC) [ 35 ], gastrointestinal stromal tumours (GIST) [ 51 ], osteosarcoma [ 30 ], malignant pleural mesothelioma [ 52 ], Hodgkin lymphoma [ 53 ], oropharyngeal squamous cell carcinoma (OSCC) [ 54 ] and cancer of unknown primary origin [ 55 ]; two studies in prostate adenocarcinoma [ 56 , 57 ], colorectal cancer (CRC) [ 58 , 59 ], clear cell renal cell carcinoma (RCC) [ 60 , 61 ], esophageal squamous cell carcinoma (ESCC) [ 62 , 63 ], non-Hodgkin lymphoma (NHL) [ 64 , 65 ] and gastric cancer [ 66 , 67 ]; three studies in non-small cell lung cancer (NSCLC) [ 68 , 69 , 70 ] and breast cancer [ 71 , 72 , 73 ]; and four studies in bladder cancer [ 27 , 74 , 75 , 76 ].…”

“…Most studies did not mention positive or negative controls [ 30 , 35 , 47 , 49 , 51 , 52 , 53 , 55 , 56 , 58 , 60 , 61 , 62 , 64 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 ]. Two and six studies (respectively) reported the use of negative [ 43 , 46 ] or positive [ 42 , 44 , 48 , 54 , 60 , 66 ] controls, and eight studies reported using both negative and positive controls [ 27 , 41 , 45 , 50 , 57 , 59 , 63 , 65 ]. For negative controls, replacement or abolishment of primary antibodies were the most reported methods; for positive controls, the most used samples were colon and colorectal carcinoma.…”

“…Additionally, Martins et al [ 59 ] found that although MCT1 expression was increased in CRC primary tumours, a decrease was noted towards lymph nodes and hepatic metastasis [ 59 ]. Thirteen studies were not able to establish or did not report any association between MCT1 expression and the clinicopathological parameters [ 35 , 42 , 43 , 46 , 48 , 50 , 52 , 54 , 56 , 58 , 61 , 69 , 70 ].…”

“…MCT1 nuclear expression was found to be associated with higher overall survival of soft-tissue sarcoma patients in the study by Pinheiro et al [ 45 ]. On the other hand, ten studies reported that MCT1 expression did not have an impact on prognostic parameters [ 44 , 48 , 52 , 54 , 57 , 58 , 65 , 66 , 68 , 70 ].…”

“…However, in some cohort studies, we found that MCT1 positivity did not correlate with prognosis, being denominated as non-relevant. For instance, in small bowel neuroendocrine tumours, MCT1 expression showed no prognostic value, although Hiltunen et al [ 48 ] indicated the absence of MCT1 positivity in lymph node metastasis tissues, suggesting that only MCT1-negative cells were prone to develop metastasis. Some confounding factors described by the authors could influence the outcome, such as the low sample size, specifically related to the number of cancer-related deaths; the setting of an optimal cut-off, as the authors observed a decrease in mortality risk associated with an increase in MCT4-positive staining; and the inclusion of only G1 and G2 small bowel neuroendocrine tumour tissues, restraining the correlation of the results with G3 tumours [ 48 ].…”