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

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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.

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Acknowledgements

This work was developed under the scope of project NORTE-01-0145-FEDER- 000013, supported by the Northern Portugal Regional Operational Programme (NORTE 2020) under the Portugal Partnership Agreement, through the European Regional Development Fund (FEDER), and through the Competitiveness Factors Operational Programme (COMPETE) and by National funds, through the Foundation for Science and Technology (FCT), under the scope of project POCI-01-0145-FEDER-007038. JA received a fellowship from FCT, ref. SFRH/BPD/116784/2016.

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  1. Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057, Braga, Portugal

    Julieta Afonso, Tatiana Pinto, Susana Simões-Sousa, Adhemar Longatto-Filho, Céline Pinheiro, Herlander Marques & Fátima Baltazar

  2. ICVS/3B’s - PT Government Associate Laboratory, Braga/Guimarães, Portugal

    Julieta Afonso, Tatiana Pinto, Susana Simões-Sousa, Adhemar Longatto-Filho, Céline Pinheiro, Herlander Marques & Fátima Baltazar

  3. Division of Cancer Biology, The Institute of Cancer Research, London, UK

    Susana Simões-Sousa

  4. Institute of Molecular Pathology and Immunology (IPATIMUP) and Medical Faculty, University of Porto, Porto, Portugal

    Fernando Schmitt

  5. Laboratory of Medical Investigation (LIM 14), Faculty of Medicine, São Paulo State University, São Paulo, Brazil

    Adhemar Longatto-Filho

  6. Molecular Oncology Research Center, Barretos Cancer Hospital, São Paulo, Brazil

    Adhemar Longatto-Filho & Céline Pinheiro

  7. Barretos School of Health Sciences Dr. Paulo Prata – FACISB, São Paulo, Brazil

    Céline Pinheiro

  8. Department of Oncology, Hospital de Braga, Braga, Portugal

    Herlander Marques

  9. CINTESIS, Center for Health Technology and Services Research, Faculty of Medicine, University of Porto, Porto, Portugal

    Herlander Marques

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Afonso, J., Pinto, T., Simões-Sousa, S. et al. Clinical significance of metabolism-related biomarkers in non-Hodgkin lymphoma – MCT1 as potential target in diffuse large B cell lymphoma. Cell Oncol. 42, 303–318 (2019). https://doi.org/10.1007/s13402-019-00426-2

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