Advertisement

Non-Hodgkin Lymphoma Metabolism

  • Brian James Kirsch
  • Shu-Jyuan Chang
  • Anne Le
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1063)

Abstract

Non-Hodgkin lymphomas (NHLs) are a heterogeneous group of lymphoid neoplasms with differing biological characteristics. About 90% of all lymphomas in the United States originate from B lymphocytes, while the remaining originate from T cells [1]. The treatment of NHLs depends on neoplastic histology and the stage of the tumor, which will indicate whether radiotherapy, chemotherapy, or a combination is the best suitable treatment [2]. The American Cancer Society describes the staging of lymphoma as follows: Stage I is lymphoma in a single node or area. Stage II is when that lymphoma has spread to another node or organ tissue. Stage III is when it has spread to lymph nodes in two sides of the diaphragm. Stage IV is when the cancer has significantly spread to organs outside the lymph system. Radiation therapy is the traditional therapeutic route for localized follicular and mucosa-associated lymphomas. Chemotherapy is utilized for the treatment of large cell lymphomas and high-grade lymphomas [2]. However, treatment of indolent lymphomas remains problematic as the patients often have metastasis for which no standard approach exists [2].

Keywords

Heterogeneous malignant lymphomas Lactic acidosis Aerobic glycolysis Glutamine metabolism Fatty acid metabolism Gene expression mTOR signaling 

Abbreviations

13C MRS

13C magnetic resonance spectroscopy

2-DG

2-Deoxyglucose

acetyl-CoA

Acetyl coenzyme A

AMPK

5′AMP-activated protein kinase

ATP

Adenosine triphosphate

BCR

B-cell receptor

B-NHL

B-cell non-Hodgkin lymphomas

DLBCL

Diffuse large B-cell lymphoma

FAO

Fatty acid oxidation

FAS

Fatty acid synthesis

FASN

Fatty acid synthesizing enzyme

FDG-PET

18F-deoxyglucose positron emission tomography

FL

Follicular lymphoma

HIF-1

Hypoxia-inducible factor-1

LDH

Lactate dehydrogenase

mTOR

Mammalian target of rapamycin

mTORC

Mammalian target of rapamycin complex

NF-κB

Nuclear factor kappa-light-chain-enhancer of activated B cells

NHLs

Non-Hodgkin lymphomas

OAA

Oxaloacetate

OXPHOS

Oxidative phosphorylation

PDK1

Pyruvate dehydrogenase kinase, isozyme 1

PEL

Primary effusion lymphoma

PI3K

Phosphatidylinositol-3-kinase

POX/PRODH

Proline dehydrogenase

PRPS2

Phosphoribosyl-pyrophosphate synthetase 2

TCA

Tricarboxylic acid

tFL

Transformed follicular lymphoma

VEGF

Vascular endothelial growth factor

References

  1. 1.
    Shankland, K. R., Armitage, J. O., & Hancock, B. W. (2012). Non-Hodgkin lymphoma. Lancet, 380(9844), 848–857.CrossRefGoogle Scholar
  2. 2.
    Winkfield, K. M., Tsang, R. W., & Gospodarowicz, M. K. (2016). Non-Hodgkin’s lymphoma. In Clinical radiation oncology (4th ed., pp. 1524–1546.e7). Philadelphia: Elsevier.CrossRefGoogle Scholar
  3. 3.
    Advani, R. H., et al. (2013). Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. Journal of Clinical Oncology, 31(1), 88–94.CrossRefGoogle Scholar
  4. 4.
    Kridel, R., Sehn, L. H., & Gascoyne, R. D. (2012). Pathogenesis of follicular lymphoma. The Journal of Clinical Investigation, 122(10), 3424–3431.CrossRefGoogle Scholar
  5. 5.
    Wong, E., & Dickinson, M. (2012). Transformation in follicular lymphoma: Biology, prognosis, and therapeutic options. Current Oncology Reports, 14(5), 424–432.CrossRefGoogle Scholar
  6. 6.
    Bouska, A., et al. (2014). Genome-wide copy number analyses reveal genomic abnormalities involved in transformation of follicular lymphoma. Blood, 123, 1681.CrossRefGoogle Scholar
  7. 7.
    Okosun, J., et al. (2014). Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma. Nature Genetics, 46(2), 176–181.CrossRefGoogle Scholar
  8. 8.
    Oricchio, E., & Wendel, H. G. (2014). Frequent disruption of the RB pathway in indolent follicular lymphoma suggests a new combination therapy. Journal of Experimental Medicine, 211, 1379.CrossRefGoogle Scholar
  9. 9.
    Biswas, S. K. (2015). Metabolic reprogramming of immune cells in cancer progression. Immunity, 43(3), 435–449.CrossRefGoogle Scholar
  10. 10.
    Newman, J. S., et al. (1994). Imaging of lymphoma with PET with 2-[F-18]-fluoro-2-deoxy-D-glucose: Correlation with CT. Radiology, 190(1), 111–116.CrossRefGoogle Scholar
  11. 11.
    Okada, J., et al. (1992). Positron emission tomography using fluorine-18-fluorodeoxyglucose in malignant lymphoma: A comparison with proliferative activity. Journal of Nuclear Medicine, 33(3), 325–329.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Mediani, L., et al. (2016). Reversal of the glycolytic phenotype of primary effusion lymphoma cells by combined targeting of cellular metabolism and PI3K/Akt/mTOR signaling. Oncotarget, 7(5), 5521–5537.CrossRefGoogle Scholar
  13. 13.
    Yadav, C., et al. (2016). Serum lactate dehydrogenase in non-Hodgkin’s lymphoma: A prognostic indicator. Indian Journal of Clinical Biochemistry, 31(2), 240–242.CrossRefGoogle Scholar
  14. 14.
    Fasola, G., et al. (1984). Serum LDH concentration in non-Hodgkin’s lymphomas. Relationship to histologic type, tumor mass, and presentation features. Acta Haematologica, 72(4), 231–238.CrossRefGoogle Scholar
  15. 15.
    Cowan, R. A., et al. (1989). Prognostic factors in high and intermediate grade non-Hodgkin’s lymphoma. British Journal of Cancer, 59(2), 276–282.CrossRefGoogle Scholar
  16. 16.
    Claudino, W. M., et al. (2015). Type B lactic acidosis: A rare but life threatening hematologic emergency. A case illustration and brief review. American Journal of Blood Research, 5(1), 25–29.PubMedPubMedCentralGoogle Scholar
  17. 17.
    de Groot, R., et al. (2011). Type B lactic acidosis in solid malignancies. The Netherlands Journal of Medicine, 69(3), 120–123.PubMedPubMedCentralGoogle Scholar
  18. 18.
    Mizock, B. A. (1989). Lactic acidosis. Disease-a-Month, 35(4), 233–300.CrossRefGoogle Scholar
  19. 19.
    Ruiz, J. P., Singh, A. K., & Hart, P. (2011). Type B lactic acidosis secondary to malignancy: Case report, review of published cases, insights into pathogenesis, and prospects for therapy. Scientific World Journal, 11, 1316–1324.CrossRefGoogle Scholar
  20. 20.
    Dogan, E., et al. (2005). Fatal lactic acidosis due to leukemic transformation in a patient with non-Hodgkin’s lymphoma: Case report. Advances in Therapy, 22(5), 443–446.CrossRefGoogle Scholar
  21. 21.
    Chan, F. H., Carl, D., & Lyckholm, L. J. (2009). Severe lactic acidosis in a patient with B-cell lymphoma: A case report and review of the literature. Case Reports in Medicine, 2009, 534561.CrossRefGoogle Scholar
  22. 22.
    Andersen, L. W., et al. (2013). Etiology and therapeutic approach to elevated lactate levels. Mayo Clinic Proceedings, 88(10), 1127–1140.CrossRefGoogle Scholar
  23. 23.
    Sia, P., Plumb, T. J., & Fillaus, J. A. (2013). Type B lactic acidosis associated with multiple myeloma. American Journal of Kidney Diseases, 62(3), 633–637.CrossRefGoogle Scholar
  24. 24.
    DeBerardinis, R. J., & Chandel, N. S. (2016). Fundamentals of cancer metabolism. Science Advances, 2(5), e1600200.CrossRefGoogle Scholar
  25. 25.
    Stine, Z. E., et al. (2015). MYC, metabolism, and cancer. Cancer Discovery, 5(10), 1024–1039.CrossRefGoogle Scholar
  26. 26.
    Laplante, M., & Sabatini, D. M. (2012). mTOR signaling in growth control and disease. Cell, 149(2), 274–293.CrossRefGoogle Scholar
  27. 27.
    Korac, P., et al. (2017). Role of MYC in B cell lymphomagenesis. Genes (Basel), 8(4), 115.CrossRefGoogle Scholar
  28. 28.
    Le, A., et al. (2010). Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression. Proceedings of the National Academy of Sciences of the United States of America, 107(5), 2037–2042.CrossRefGoogle Scholar
  29. 29.
    Doherty, J. R., et al. (2014). Blocking lactate export by inhibiting the Myc target MCT1 disables glycolysis and glutathione synthesis. Cancer Research, 74(3), 908–920.CrossRefGoogle Scholar
  30. 30.
    Cairns, R. A., Harris, I. S., & Mak, T. W. (2011). Regulation of cancer cell metabolism. Nature Reviews Cancer, 11(2), 85–95.CrossRefGoogle Scholar
  31. 31.
    Tran, T. Q., et al. (2017). Tumor-associated mutant p53 promotes cancer cell survival upon glutamine deprivation through p21 induction. Oncogene, 36(14), 1991–2001.CrossRefGoogle Scholar
  32. 32.
    Bhatt, A. P., et al. (2012). Dysregulation of fatty acid synthesis and glycolysis in non-Hodgkin lymphoma. Proceedings of the National Academy of Sciences of the United States of America, 109(29), 11818–11823.CrossRefGoogle Scholar
  33. 33.
    Bhatt, A. P., et al. (2010). Dual inhibition of PI3K and mTOR inhibits autocrine and paracrine proliferative loops in PI3K/Akt/mTOR-addicted lymphomas. Blood, 115(22), 4455–4463.CrossRefGoogle Scholar
  34. 34.
    Faber, A. C., et al. (2006). Inhibition of phosphatidylinositol 3-kinase-mediated glucose metabolism coincides with resveratrol-induced cell cycle arrest in human diffuse large B-cell lymphomas. Biochemical Pharmacology, 72(10), 1246–1256.CrossRefGoogle Scholar
  35. 35.
    Sin, S. H., et al. (2007). Rapamycin is efficacious against primary effusion lymphoma (PEL) cell lines in vivo by inhibiting autocrine signaling. Blood, 109(5), 2165–2173.CrossRefGoogle Scholar
  36. 36.
    Jeon, S. M., Chandel, N. S., & Hay, N. (2012). AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress. Nature, 485(7400), 661–665.CrossRefGoogle Scholar
  37. 37.
    Caro, P., et al. (2012). Metabolic signatures uncover distinct targets in molecular subsets of diffuse large B cell lymphoma. Cancer Cell, 22(4), 547–560.CrossRefGoogle Scholar
  38. 38.
    Young, R. M., et al. (2015). B-cell receptor signaling in diffuse large B-cell lymphoma. Seminars in Hematology, 52(2), 77–85.CrossRefGoogle Scholar
  39. 39.
    Havranek, O., et al. (2017). Tonic B-cell receptor signaling in diffuse large B-cell lymphoma. Blood, 130(8), 995–1006.CrossRefGoogle Scholar
  40. 40.
    Martinez-Outschoorn, U. E., et al. (2017). Cancer metabolism: A therapeutic perspective. Nature Reviews Clinical Oncology, 14(1), 11–31.CrossRefGoogle Scholar
  41. 41.
    Wilson, P. M., et al. (2014). Standing the test of time: Targeting thymidylate biosynthesis in cancer therapy. Nature Reviews Clinical Oncology, 11(5), 282–298.CrossRefGoogle Scholar
  42. 42.
    Visentin, M., Zhao, R., & Goldman, I. D. (2012). The antifolates. Hematology/Oncology Clinics of North America, 26(3), 629–648. ix.CrossRefGoogle Scholar
  43. 43.
    Cunningham, J. T., et al. (2014). Protein and nucleotide biosynthesis are coupled by a single rate-limiting enzyme, PRPS2, to drive cancer. Cell, 157(5), 1088–1103.CrossRefGoogle Scholar
  44. 44.
    Duvel, K., et al. (2010). Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Molecular Cell, 39(2), 171–183.CrossRefGoogle Scholar
  45. 45.
    Kuhajda, F. P. (2000). Fatty-acid synthase and human cancer: New perspectives on its role in tumor biology. Nutrition, 16(3), 202–208.CrossRefGoogle Scholar
  46. 46.
    Vazquez-Martin, A., et al. (2008). Overexpression of fatty acid synthase gene activates HER1/HER2 tyrosine kinase receptors in human breast epithelial cells. Cell Proliferation, 41(1), 59–85.CrossRefGoogle Scholar
  47. 47.
    Flavin, R., et al. (2010). Fatty acid synthase as a potential therapeutic target in cancer. Future Oncology, 6(4), 551–562.CrossRefGoogle Scholar
  48. 48.
    Gasperini, P., & Tosato, G. (2009). Targeting the mammalian target of Rapamycin to inhibit VEGF and cytokines for the treatment of primary effusion lymphoma. Leukemia, 23(10), 1867–1874.CrossRefGoogle Scholar
  49. 49.
    Shestov, A. A., et al. (2016). (13)C MRS and LC-MS flux analysis of tumor intermediary metabolism. Frontiers in Oncology, 6, 135.CrossRefGoogle Scholar
  50. 50.
    Dang, C. V. (2010). Rethinking the Warburg effect with Myc micromanaging glutamine metabolism. Cancer Research, 70(3), 859–862.CrossRefGoogle Scholar
  51. 51.
    Kim, J., Lee, J. H., & Iyer, V. R. (2008). Global identification of Myc target genes reveals its direct role in mitochondrial biogenesis and its E-box usage in vivo. PLoS One, 3(3), e1798.CrossRefGoogle Scholar
  52. 52.
    Kim, J. W., et al. (2007). Hypoxia-inducible factor 1 and dysregulated c-Myc cooperatively induce vascular endothelial growth factor and metabolic switches hexokinase 2 and pyruvate dehydrogenase kinase 1. Molecular and Cellular Biology, 27(21), 7381–7393.CrossRefGoogle Scholar
  53. 53.
    Li, F., et al. (2005). Myc stimulates nuclearly encoded mitochondrial genes and mitochondrial biogenesis. Molecular and Cellular Biology, 25(14), 6225–6234.CrossRefGoogle Scholar
  54. 54.
    Folmes, C. D., et al. (2011). Somatic oxidative bioenergetics transitions into pluripotency-dependent glycolysis to facilitate nuclear reprogramming. Cell Metabolism, 14(2), 264–271.CrossRefGoogle Scholar
  55. 55.
    Le, A., et al. (2012). Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells. Cell Metabolism, 15(1), 110–121.CrossRefGoogle Scholar
  56. 56.
    Miller, D. M., et al. (2012). c-Myc and cancer metabolism. Clinical Cancer Research, 18(20), 5546–5553.CrossRefGoogle Scholar
  57. 57.
    Liu, W., et al. (2012). Reprogramming of proline and glutamine metabolism contributes to the proliferative and metabolic responses regulated by oncogenic transcription factor c-MYC. Proceedings of the National Academy of Sciences of the United States of America, 109(23), 8983–8988.CrossRefGoogle Scholar
  58. 58.
    Bertout, J. A., Patel, S. A., & Simon, M. C. (2008). The impact of O2 availability on human cancer. Nature Reviews Cancer, 8(12), 967–975.CrossRefGoogle Scholar
  59. 59.
    Qiao, Q., et al. (2010). NF-kappaB mediates aberrant activation of HIF-1 in malignant lymphoma. Experimental Hematology, 38(12), 1199–1208.CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Brian James Kirsch
    • 1
    • 2
  • Shu-Jyuan Chang
    • 3
  • Anne Le
    • 4
  1. 1.Department of PathologyJohns Hopkins University School of MedicineBaltimoreUSA
  2. 2.Johns Hopkins University, Whiting School of Engineering, Chemical and Biomolecular EngineeringBaltimoreUSA
  3. 3.Graduate Institute of MedicineCollege of Medicine, Kaohsiung Medical UniversityKaohsiungTaiwan
  4. 4.Department of Pathology and OncologyJohns Hopkins University School of MedicineBaltimoreUSA

Personalised recommendations