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.

[1]  J. Mrena,et al.  Exercise capacity in the stair-climbing test predicts outcomes of operable esophageal cancer in minimally invasive era. , 2021, European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology.

[2]  J. Väyrynen,et al.  CD3+, CD8+, CD4+ and FOXP3+ T Cells in the Immune Microenvironment of Small Bowel Neuroendocrine Tumors , 2021, Diseases.

[3]  J. Kauppila,et al.  Monocarboxylate Transporters 1 and 4 and MTCO1 in Gastric Cancer , 2021, Cancers.

[4]  Joseph M Pappachan,et al.  Gastroenteropancreatic neuroendocrine neoplasms: A clinical snapshot , 2021, World journal of gastrointestinal surgery.

[5]  J. G. van den Berg,et al.  Survival in Patients with Neuroendocrine Tumours of the Small Intestine: Nomogram Validation and Predictors of Survival , 2020, Journal of clinical medicine.

[6]  K. Juvale,et al.  Monocarboxylate transporter 1 and 4 inhibitors as potential therapeutics for treating solid tumours: A review with structure-activity relationship insights. , 2020, European journal of medicinal chemistry.

[7]  M. Falconi,et al.  Gastroenteropancreatic neuroendocrine neoplasms: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. , 2020, Annals of oncology : official journal of the European Society for Medical Oncology.

[8]  Peter Schirmacher,et al.  The 2019 WHO classification of tumours of the digestive system , 2019, Histopathology.

[9]  Pierre Sonveaux,et al.  Monocarboxylate transporters in cancer , 2019, Molecular metabolism.

[10]  C. Divino,et al.  Predicting Survival of Small Intestine Neuroendocrine Tumors: Experience From a Major Referral Center , 2019, Pancreas.

[11]  P. Swietach.  What is pH regulation, and why do cancer cells need it? , 2019, Cancer and Metastasis Reviews.

[12]  T. Torigoe,et al.  The prognostic significance of the expression of monocarboxylate transporter 4 in patients with right‐ or left‐sided colorectal cancer , 2018, Asia-Pacific journal of clinical oncology.

[13]  Shouhao Zhou,et al.  Trends in the Incidence, Prevalence, and Survival Outcomes in Patients With Neuroendocrine Tumors in the United States , 2017, JAMA oncology.

[14]  Shuyi Zhang,et al.  MACC1 mediates chemotherapy sensitivity of 5-FU and cisplatin via regulating MCT1 expression in gastric cancer. , 2017, Biochemical and biophysical research communications.

[15]  P. Lehenkari,et al.  Intratumoral lactate metabolism in Barrett's esophagus and adenocarcinoma , 2017, Oncotarget.

[16]  O. Faiz,et al.  Predicting the survival of patients with small bowel neuroendocrine tumours: comparison of 3 systems , 2017, Endocrine connections.

[17]  Jin Hyun Cho,et al.  MCT4 as a potential therapeutic target for metastatic gastric cancer with peritoneal carcinomatosis , 2016, Oncotarget.

[18]  D. Hanahan,et al.  Metabolic Symbiosis Enables Adaptive Resistance to Anti-angiogenic Therapy that Is Dependent on mTOR Signaling , 2016, Cell reports.

[19]  J. Locasale,et al.  The Warburg Effect: How Does it Benefit Cancer Cells? , 2016, Trends in biochemical sciences.

[20]  Y. Nordby,et al.  Organized metabolic crime in prostate cancer: The coexpression of MCT1 in tumor and MCT4 in stroma is an independent prognosticator for biochemical failure. , 2015, Urologic oncology.

[21]  John L Cleveland,et al.  Targeting lactate metabolism for cancer therapeutics. , 2013, Journal of Clinical Investigation.

[22]  E. Baudin,et al.  Rare neuroendocrine tumours: results of the surveillance of rare cancers in Europe project. , 2013, European journal of cancer.

[23]  A. Halestrap.  The SLC16 gene family - structure, role and regulation in health and disease. , 2013, Molecular aspects of medicine.

[24]  I. Modlin,et al.  Differential signal pathway activation and 5-HT function: the role of gut enterochromaffin cells as oxygen sensors. , 2012, American journal of physiology. Gastrointestinal and liver physiology.

[25]  M. Dewhirst,et al.  Targeting the Lactate Transporter MCT1 in Endothelial Cells Inhibits Lactate-Induced HIF-1 Activation and Tumor Angiogenesis , 2012, PloS one.

[26]  A. Halestrap.  The monocarboxylate transporter family—Structure and functional characterization , 2012, IUBMB Life - A Journal of the International Union of Biochemistry and Molecular Biology.

[27]  R. Reis,et al.  Monocarboxylate transporter 4 (MCT4) and CD147 overexpression is associated with poor prognosis in prostate cancer , 2011, BMC Cancer.

[28]  Y. Sasaguri,et al.  Monocarboxylate transporters 1 and 4 are involved in the invasion activity of human lung cancer cells , 2011, Cancer science.

[29]  Pierre Sonveaux,et al.  Lactate influx through the endothelial cell monocarboxylate transporter MCT1 supports an NF-κB/IL-8 pathway that drives tumor angiogenesis. , 2011, Cancer research.

[30]  I. Modlin,et al.  A Nomogram to Assess Small-Intestinal Neuroendocrine Tumor (‘Carcinoid’) Survival , 2010, Neuroendocrinology.

[31]  F. Schmitt,et al.  Monocarboxylate transporter 1 is up‐regulated in basal‐like breast carcinoma , 2010, Histopathology.

[32]  P. Fortina,et al.  The reverse Warburg effect: Aerobic glycolysis in cancer associated fibroblasts and the tumor stroma , 2009, Cell cycle.

[33]  Julien Verrax,et al.  Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. , 2008, The Journal of clinical investigation.

[34]  Manal M. Hassan,et al.  One hundred years after "carcinoid": epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[35]  A. Longatto-Filho,et al.  Increased expression of monocarboxylate transporters 1, 2, and 4 in colorectal carcinomas , 2008, Virchows Archiv.

[36]  A. Giatromanolaki,et al.  Lung cancer: An organized cellular and metabolic domain , 2007 .

[37]  A. Harris,et al.  Microvascular density and hypoxia-inducible factor pathway in pancreatic endocrine tumours: negative correlation of microvascular density and VEGF expression with tumour progression , 2004, British Journal of Cancer.

[38]  R. Gillies,et al.  Why do cancers have high aerobic glycolysis? , 2004, Nature Reviews Cancer.

[39]  Belghiti,et al.  Expression of vascular endothelial growth factor in digestive neuroendocrine tumours , 1998, Histopathology.

[40]  O. Warburg.  [Origin of cancer cells]. , 1956, Oncologia.