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

Energy production by cancer is driven by accelerated glycolysis, independently of oxygen levels, which results in increased lactate production. Lactate is shuttled to and from cancer cells via monocarboxylate transporters (MCTs). MCT1 works both as an importer and an extruder of lactate, being widely studied in recent years and generally associated with a cancer aggressiveness phenotype. The aim of this systematic review was to assess the prognostic value of MCT1 immunoexpression in different malignancies. Study collection was performed by searching nine different databases (PubMed, EMBASE, ScienceDirect, Scopus, Cochrane Library, Web of Science, OVID, TRIP and PsycINFO), using the keywords “cancer”, “Monocarboxylate transporter 1”, “SLC16A1” and “prognosis”. Results showed that MCT1 is an indicator of poor prognosis and decreased survival for cancer patients in sixteen types of malignancies; associations between the transporter’s overexpression and larger tumour sizes, higher disease stage/grade and metastasis occurrence were also frequently observed. Yet, MCT1 overexpression correlated with better outcomes in colorectal cancer, pancreatic ductal adenocarcinoma and non-small cell lung cancer patients. These results support the applicability of MCT1 as a biomarker of prognosis, although larger cohorts would be necessary to validate the overall role of MCT1 as an outcome predictor.

[1]  A. Le,et al.  Glucose Metabolism in Cancer: The Warburg Effect and Beyond , 2022, Advances in experimental medicine and biology.

[2]  Ziqin Deng,et al.  Glycolysis in tumor microenvironment as a target to improve cancer immunotherapy , 2022, Frontiers in Cell and Developmental Biology.

[3]  Wei Li,et al.  Lactylation, an emerging hallmark of metabolic reprogramming: Current progress and open challenges , 2022, Frontiers in Cell and Developmental Biology.

[4]  J. Väyrynen,et al.  Monocarboxylate Transporters 1 and 4 and Prognosis in Small Bowel Neuroendocrine Tumors , 2022, Cancers.

[5]  F. Baltazar,et al.  In Vivo Anticancer Activity of AZD3965: A Systematic Review , 2021, Molecules.

[6]  Qiuhong Yang,et al.  Immunohistochemical evaluation and prognostic value of monocarboxylate transporter 1 (MCT1) and 4 (MCT4) in T-cell non-Hodgkin lymphoma , 2021, Clinical and Experimental Medicine.

[7]  Pei Zhang,et al.  Lactate in the tumour microenvironment: From immune modulation to therapy , 2021, EBioMedicine.

[8]  G. Úrrutia,et al.  The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. , 2021, Revista espanola de cardiologia.

[9]  R. Reis,et al.  MCT1 Is a New Prognostic Biomarker and Its Therapeutic Inhibition Boosts Response to Temozolomide in Human Glioblastoma , 2021, Cancers.

[10]  A. Longatto-Filho,et al.  Expression of Glycolysis-Related Proteins in Cancer of Unknown Primary Origin , 2021, Frontiers in Oncology.

[11]  M. Dyer,et al.  Phase I expansion study of the first-in-class monocarboxylate transporter 1 (MCT1) inhibitor AZD3965 in patients with diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL). , 2021 .

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

[13]  B. Firestein,et al.  Mechanisms of Metabolic Reprogramming in Cancer Cells Supporting Enhanced Growth and Proliferation , 2021, Cells.

[14]  J. Ferlay,et al.  Cancer statistics for the year 2020: An overview , 2021, International journal of cancer.

[15]  K. Ueda,et al.  Liquid Biopsy Targeting Monocarboxylate Transporter 1 on the Surface Membrane of Tumor-Derived Extracellular Vesicles from Synovial Sarcoma , 2021, Cancers.

[16]  E. Mayo-Wilson,et al.  The PRISMA 2020 statement: an updated guideline for reporting systematic reviews , 2021, BMJ.

[17]  L. Fang,et al.  High expression of monocarboxylate transporter 4 (MCT 4), but not MCT 1, predicts poor prognosis in patients with non-small cell lung cancer , 2021, Translational cancer research.

[18]  M. Canis,et al.  Monocarboxylate transporter-1 (MCT1) protein expression in head and neck cancer affects clinical outcome , 2021, Scientific Reports.

[19]  Tong Li,et al.  Prognostic implications of combined high expression of CD47 and MCT1 in breast cancer: a retrospective study during a 10-year period , 2021, Translational cancer research.

[20]  D. Rassl,et al.  Tissue expression of lactate transporters (MCT1 and MCT4) and prognosis of malignant pleural mesothelioma (brief report) , 2020, Journal of translational medicine.

[21]  Yang Liu,et al.  Role of Proton-Coupled Monocarboxylate Transporters in Cancer: From Metabolic Crosstalk to Therapeutic Potential , 2020, Frontiers in Cell and Developmental Biology.

[22]  M. Morris,et al.  In Vitro and In Vivo Efficacy of AZD3965 and Alpha-Cyano-4-Hydroxycinnamic Acid in the Murine 4T1 Breast Tumor Model , 2020, The AAPS Journal.

[23]  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.

[24]  F. Baltazar,et al.  Lactate Beyond a Waste Metabolite: Metabolic Affairs and Signaling in Malignancy , 2020, Frontiers in Oncology.

[25]  Ç. Biray Avcı,et al.  Crucial Players in Glycolysis: Cancer Progress. , 2020, Gene.

[26]  Xiaomei Lu,et al.  Clinicopathological and prognostic involvements of MCT1, MCT4 and IL7R in esophageal squamous cell carcinoma , 2019 .

[27]  C. Frezza.  Metabolism and cancer: the future is now , 2019, British Journal of Cancer.

[28]  C. Lebbé,et al.  CD147 Is a Promising Target of Tumor Progression and a Prognostic Biomarker , 2019, Cancers.

[29]  J. Manzo-Merino,et al.  Lactate in the Regulation of Tumor Microenvironment and Therapeutic Approaches , 2019, Front. Oncol..

[30]  M. Kojima,et al.  Expression of Monocarboxylate Transporter 1 Is Associated With Better Prognosis and Reduced Nodal Metastasis in Pancreatic Ductal Adenocarcinoma. , 2019, Pancreas.

[31]  E. Nice,et al.  MCT1 relieves osimertinib-induced CRC suppression by promoting autophagy through the LKB1/AMPK signaling , 2019, Cell Death & Disease.

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

[33]  Arslaan Javaeed,et al.  MCT4 has a potential to be used as a prognostic biomarker - a systematic review and meta-analysis , 2019, Oncology reviews.

[34]  J. Quinn,et al.  The association between markers of tumour cell metabolism, the tumour microenvironment and outcomes in patients with colorectal cancer , 2019, International journal of cancer.

[35]  W. Zhou,et al.  Monocarboxylate transporter 1 is an independent prognostic factor in esophageal squamous cell carcinoma. , 2019, Oncology reports.

[36]  A. Longatto-Filho,et al.  Clinical significance of metabolism-related biomarkers in non-Hodgkin lymphoma – MCT1 as potential target in diffuse large B cell lymphoma , 2019, Cellular Oncology.

[37]  M. Morris,et al.  In Vitro and In Vivo Efficacy of the Monocarboxylate Transporter 1 Inhibitor AR-C155858 in the Murine 4T1 Breast Cancer Tumor Model , 2018, The AAPS Journal.

[38]  Changhua Wang,et al.  Monocarboxylate transporters in breast cancer and adipose tissue are novel biomarkers and potential therapeutic targets. , 2018, Biochemical and biophysical research communications.

[39]  Guiming Zhang,et al.  MCT1 regulates aggressive and metabolic phenotypes in bladder cancer , 2018, Journal of Cancer.

[40]  C. Scapulatempo-Neto,et al.  The clinicopathological significance of monocarboxylate transporters in testicular germ cell tumors , 2018, Oncotarget.

[41]  Wei Zhang,et al.  Monocarboxylate transporters MCT1 and MCT4 are independent prognostic biomarkers for the survival of patients with clear cell renal cell carcinoma and those receiving therapy targeting angiogenesis. , 2018, Urologic oncology.

[42]  I. Stratford,et al.  Monocarboxylate Transporter 1 (MCT1) is an independent prognostic biomarker in endometrial cancer , 2017, BMC Clinical Pathology.

[43]  P. Porporato,et al.  Cancer metabolism in space and time: Beyond the Warburg effect. , 2017, Biochimica et biophysica acta. Bioenergetics.

[44]  B. Leiby,et al.  Hodgkin lymphoma: A complex metabolic ecosystem with glycolytic reprogramming of the tumor microenvironment. , 2017, Seminars in oncology.

[45]  S. Halford,et al.  A first-in-human first-in-class (FIC) trial of the monocarboxylate transporter 1 (MCT1) inhibitor AZD3965 in patients with advanced solid tumours. , 2017 .

[46]  A. Giatromanolaki,et al.  Expression of enzymes related to glucose metabolism in non-small cell lung cancer and prognosis , 2017, Experimental lung research.

[47]  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.

[48]  J. Palazzo,et al.  MCT1 in Invasive Ductal Carcinoma: Monocarboxylate Metabolism and Aggressive Breast Cancer , 2017, Front. Cell Dev. Biol..

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

[50]  J. Rodrigo,et al.  Clinically relevant HIF-1α-dependent metabolic reprogramming in oropharyngeal squamous cell carcinomas includes coordinated activation of CAIX and the miR-210/ISCU signaling axis, but not MCT1 and MCT4 upregulation , 2017, Oncotarget.

[51]  G. Brooks,et al.  Reexamining cancer metabolism: lactate production for carcinogenesis could be the purpose and explanation of the Warburg Effect , 2016, Carcinogenesis.

[52]  I. Novak,et al.  Monocarboxylate Transporters MCT1 and MCT4 Regulate Migration and Invasion of Pancreatic Ductal Adenocarcinoma Cells , 2016, Pancreas.

[53]  P. Liu,et al.  Targeting of MCT1 and PFKFB3 influences cell proliferation and apoptosis in bladder cancer by altering the tumor microenvironment. , 2016, Oncology reports.

[54]  A. Longatto-Filho,et al.  Significance of glycolytic metabolism-related protein expression in colorectal cancer, lymph node and hepatic metastasis , 2016, BMC Cancer.

[55]  A. Longatto-Filho,et al.  Prognostic significance of monocarboxylate transporter expression in oral cavity tumors , 2016, Cell cycle.

[56]  A. Longatto-Filho,et al.  The metabolic microenvironment of melanomas: Prognostic value of MCT1 and MCT4 , 2016, Cell cycle.

[57]  R. Montironi,et al.  Metabolic phenotype of bladder cancer. , 2016, Cancer treatment reviews.

[58]  A. Longatto-Filho,et al.  Metabolic coupling in urothelial bladder cancer compartments and its correlation to tumor aggressiveness , 2016, Cell cycle.

[59]  C. Thompson,et al.  The Emerging Hallmarks of Cancer Metabolism. , 2016, Cell metabolism.

[60]  U. Martinez-outschoorn,et al.  Prognostic Indications of Elevated MCT4 and CD147 across Cancer Types: A Meta-Analysis , 2015, BioMed research international.

[61]  A. Longatto-Filho,et al.  Metabolic reprogramming: a new relevant pathway in adult adrenocortical tumors , 2015, Oncotarget.

[62]  A. Longatto-Filho,et al.  CD147 and MCT1‐potential partners in bladder cancer aggressiveness and cisplatin resistance , 2015, Molecular carcinogenesis.

[63]  Toshio Matsumoto,et al.  Effective impairment of myeloma cells and their progenitors by blockade of monocarboxylate transportation , 2015, Oncotarget.

[64]  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.

[65]  Fan Yang,et al.  MCT1 promotes the cisplatin-resistance by antagonizing Fas in epithelial ovarian cancer. , 2015, International journal of clinical and experimental pathology.

[66]  Stephanie M. Tortorella,et al.  Cancer metabolism and the Warburg effect: the role of HIF-1 and PI3K , 2015, Molecular Biology Reports.

[67]  Hushan Yang,et al.  Genetic variations in monocarboxylate transporter genes as predictors of clinical outcomes in non-small cell lung cancer , 2015, Tumor Biology.

[68]  R. Deberardinis,et al.  MCT4 defines a glycolytic subtype of pancreatic cancer with poor prognosis and unique metabolic dependencies. , 2014, Cell reports.

[69]  E. Richardsen,et al.  Monocarboxylate Transporters 1–4 in NSCLC: MCT1 Is an Independent Prognostic Marker for Survival , 2014, PloS one.

[70]  A. Longatto-Filho,et al.  Characterization of monocarboxylate transporter activity in hepatocellular carcinoma. , 2014, World journal of gastroenterology.

[71]  Ju-Han Lee,et al.  Prognostic significance of lactate/proton symporters MCT1, MCT4, and their chaperone CD147 expressions in urothelial carcinoma of the bladder. , 2014, Urology.

[72]  F. Baltazar,et al.  A lactate shuttle system between tumour and stromal cells is associated with poor prognosis in prostate cancer , 2014, BMC Cancer.

[73]  R. Reis,et al.  Characterization of monocarboxylate transporters (MCTs) expression in soft tissue sarcomas: distinct prognostic impact of MCT1 sub-cellular localization , 2014, Journal of Translational Medicine.

[74]  Paul D. Smith,et al.  Activity of the Monocarboxylate Transporter 1 Inhibitor AZD3965 in Small Cell Lung Cancer , 2013, Clinical Cancer Research.

[75]  F. Baltazar,et al.  Monocarboxylate transporter 2 (MCT2) as putative biomarker in prostate cancer , 2013, The Prostate.

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

[77]  J. Verrax,et al.  Lactate Activates HIF-1 in Oxidative but Not in Warburg-Phenotype Human Tumor Cells , 2012, PloS one.

[78]  M. Weller,et al.  Synthesis of cytochrome c oxidase 2: a p53-dependent metabolic regulator that promotes respiratory function and protects glioma and colon cancer cells from hypoxia-induced cell death , 2012, Oncogene.

[79]  A. Carvalho,et al.  Co-expression of monocarboxylate transporter 1 (MCT1) and its chaperone (CD147) is associated with low survival in patients with gastrointestinal stromal tumors (GISTs) , 2012, Journal of Bioenergetics and Biomembranes.

[80]  Franziska Hirschhaeuser,et al.  Lactate: a metabolic key player in cancer. , 2011, Cancer research.

[81]  Adam Ertel,et al.  Evidence for a stromal-epithelial “lactate shuttle” in human tumors , 2011, Cell cycle.

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

[83]  L. Cantley,et al.  Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation , 2009, Science.

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

[85]  D. Sabatini,et al.  Cancer Cell Metabolism: Warburg and Beyond , 2008, Cell.

[86]  O. Warburg,et al.  THE METABOLISM OF TUMORS IN THE BODY , 1927, The Journal of general physiology.

[87]  F. Baltazar,et al.  Lactate and Lactate Transporters as Key Players in the Maintenance of the Warburg Effect. , 2020, Advances in experimental medicine and biology.

[88]  F. Baltazar,et al.  New horizons on pH regulators as cancer biomarkers and targets for pharmacological intervention , 2020 .

[89]  Ju-Han Lee,et al.  Expression of lactate/H⁺ symporters MCT1 and MCT4 and their chaperone CD147 predicts tumor progression in clear cell renal cell carcinoma: immunohistochemical and The Cancer Genome Atlas data analyses. , 2015, Human pathology.

[90]  Yuanzhong Wu,et al.  Downregulation of MCT1 inhibits tumor growth, metastasis and enhances chemotherapeutic efficacy in osteosarcoma through regulation of the NF-κB pathway. , 2014, Cancer letters.

[91]  H. Izumi,et al.  Prognostic significance of monocarboxylate transporter 4 expression in patients with colorectal cancer. , 2012, Experimental and therapeutic medicine.