Clinical significance of metabolism-related biomarkers in non-Hodgkin lymphoma – MCT1 as potential target in diffuse large B cell lymphoma

Abstract

Purpose Increased glycolytic activity with accumulation of extracellular lactate is regarded as a hallmark of cancer. In lymphomas, FDG-PET has undeniable diagnostic and prognostic value, corroborating that these tumours are avid for glucose. However, the role of glycolytic metabolism-related molecules in lymphoma is not well known. Here, we aimed to evaluate the clinical and prognostic significance of a panel of glycolytic metabolism-related molecules in primary non-Hodgkin lymphomas (NHL) and to test in vitro the putative therapeutic impact of lactate transport inhibition. Methods We assessed, by immunohistochemistry, the expression of the metabolism-related molecules MCT1, MCT2, MCT4, CD147, GLUT1, LDHA and CAIX in both tumour and stroma compartments of tissue sections obtained from 104 NHL patients. In addition, the lymphoma-derived cell lines OZ and DOHH-2 were used to evaluate the effect of AZD3965 on their viability and on apoptosis induction, as well as on extracellular lactate accumulation. Results We found that expression of MCT1 in the NHL tumour compartment was significantly associated with a poor clinicopathological profile. We also found that MCT4 and CAIX were present in the stromal compartment and correlated with an aggressive phenotype, while MCT1 was absent in this compartment. In addition, we found that AZD3965-mediated disruption of MCT1 activity led to inhibited NHL cell viability and extracellular lactate accumulation, while increasing apoptotic cell death.Conclusions Our results indicate that elevated glycolytic activity is associated with NHL aggressiveness, pointing at metabolic cooperation, mediated by MCT1 and MCT4, between tumour cells and their surrounding stroma. MCT1 may serve as a target to treat NHL (diffuse large B cell lymphoma) patients with high MCT1/low MCT4 expressing tumours. Further (pre-)clinical studies are required to allow the design of novel therapeutic strategies aimed at e.g. reprogramming the tumour microenvironment.

Tumor Metabolism as a Regulator of Tumor–Host Interactions in the B-Cell Lymphoma Microenvironment—Fueling Progression and Novel Brakes for Therapy

“…Thereby, they acquire the increased ability to export lactate. Corresponding upregulation of MCT1 on malignant cells subsequently increases import of lactate, which, in turn, is used to fuel the TCA cycle for energy production [82,85]. A similar change of expression profile was found in Hodgkin lymphoma, where transformed cells showed high expression of MCT1, and TAMs of MCT4 [86].…”

“…In non-Hodgkin lymphomas (NHL), higher glycolytic activity is associated with higher aggressiveness, which is implemented through an interaction between the lymphoma cells and their surrounding microenvironment [82]. A higher expression of the lactate transporter monocarboxylate transporter 1 (MCT1) in NHL is associated with poor clinicopathological profile and the expression of MCT1 and MCT4 is associated with high-grade disease [82]. MCT1 expression may be regulated by MYC as MCT1 was significantly upregulated in c-MYC amplified lymphomas, also correlating with poor prognosis and survival [83,84].…”

“…CD147 is associated with tumor aggressiveness and chemoresistance and its silencing leads to less proliferation and increased chemosensitivity in hematological malignancies [88,89,90]. Interruption of MCT1 activity by AZD3965 inhibited NHL cell viability, led to intracellular accumulation of lactate, and increased apoptotic cell death [82]. This effect could be further potentiated by adding metformin, which augments glycolysis in the cells, to the treatment [83].…”

Diffuse large B-cell lymphoma

“…The role of immunophenotype variability for the therapeutic outcome has long been the cornerstone for DLBCL management strategy, largely because the treatment of lymphomas evolves toward new therapies (immunotherapy, targeted therapy), which is made possible by analyzing the biology and the signaling pathways of this disease [34,35]. Furthermore, a growing number of biological agents are available, varying from interferon to rituximab or radiolabeled antibodies, but also the more recent acquisitions in targeted therapy, such as ibrutinib, acalabrutinib, and daratumumab [36][37][38].…”

Role of Proton-Coupled Monocarboxylate Transporters in Cancer: From Metabolic Crosstalk to Therapeutic Potential

“…The metabolic interplay between tumor cells and these stromal cells provides advantages for tumor proliferation and progression. MCT1 and MCT4 play the most dominant role in the transport of monocarboxylates, and they have been found to be significantly upregulated and associated with poor prognosis in multiple malignant tumors including peritoneal carcinomatosis, prostate cancer, lymphoma, and oral cavity cancer ( Pértega-Gomes et al, 2011 ; Simões-Sousa et al, 2016 ; Kim et al, 2018 ; Afonso et al, 2019 ). Compared to MCT1 and MCT4, MCT2 and MCT3 have been less studied in cancer.…”