Advertisement

The Intratumoral Heterogeneity of Cancer Metabolism

  • Karim Nabi
  • Anne Le
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1063)

Abstract

Cancer is one of the deadliest diseases in the world, especially within the past few decades, causing over half a million deaths a year in the USA only [1]. Despite recent advances made in the field of cancer biology and the therapies that have been developed, it is clear that more advances are necessary for us to classify cancer as curable. The logical question that arises is simple: Why, despite all the technologies and medical innovations of our time, has a cure eluded us? This chapter will shed light on one of cancer’s most impactful attributes: its heterogeneity and, more specifically, the intratumoral heterogeneity of cancer metabolism. Simply put, what makes cancer one of the deadliest known diseases is its ability to change and adapt. Cancer cells’ rapid evolution, coupled with their irrepressible ability to divide, gives them the advantage over our immune systems. In this chapter, we will delve into the complexities of this adaptability and the vital role that metabolism plays in the rise and progression of this heterogeneity.

Keywords

Intratumoral heterogeneity Metabolism Genetic and metabolic adaptation Angiogenesis Hypoxia 

Abbreviations

aKG

Alpha-ketoglutarate

CAF

Cancer-associated fibroblasts

BPTES

Bis-2-(5-phenylacetomido-1,3,4-thiadiazol-2-yl)ethyl sulfide

CSC

Cancer stem cell

DTC

Disseminated tumor cells

EC

Endothelial cells

FBP1

Fructose-1,6-bisphosphatase 1

FBP2

Fructose-1,6-bisphosphatase 1

FH

Fumarate hydratase

GLUT-1

Glucose transporter type 1

HIF-1α

Hypoxia-inducible factor-1α

LDHA

Lactate dehydrogenase A

OXPHOS

Oxidative phosphorylation

PET

Positron emission tomography

PKM2

Pyruvate kinase muscle isoform 2

SDH

Succinate dehydrogenase

TCA

Tricarboxylic acid

VEGF

Vascular Endothelial Growth Factor

References

  1. 1.
    Siegel, R. L., Miller, K. D., & Jemal, A. (2018). Cancer statistics, 2018. A Cancer Journal for Clinicians, 68(1), 7–30.Google Scholar
  2. 2.
    Gonzalez-Angulo, A. M., Morales-Vasquez, F., & Hortobagyi, G. N. (2007). Overview of resistance to systemic therapy in patients with breast cancer. Advances in Experimental Medicine and Biology, 608, 1–22.CrossRefPubMedGoogle Scholar
  3. 3.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Prasetyanti, P. R., & Medema, J. P. (2017). Intra-tumor heterogeneity from a cancer stem cell perspective. Molecular Cancer, 16(1), 41.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Jogi, A., et al. (2012). Cancer cell differentiation heterogeneity and aggressive behavior in solid tumors. Upsala Journal of Medical Sciences, 117(2), 217–224.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Bu, Y., & Cao, D. (2012). The origin of cancer stem cells. Frontiers in Bioscience (Scholar Edition), 4, 819–830.Google Scholar
  7. 7.
    Yang, T., et al. (2014). Cancer stem cells: Constantly evolving and functionally heterogeneous therapeutic targets. Cancer Research, 74(11), 2922–2927.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Gonzalez-Garcia, I., Sole, R. V., & Costa, J. (2002). Metapopulation dynamics and spatial heterogeneity in cancer. Proceedings of the National Academy of Sciences of the United States of America, 99(20), 13085–13089.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Gerlinger, M., et al. (2012). Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. The New England Journal of Medicine, 366(10), 883–892.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Park, S. Y., et al. (2010). Cellular and genetic diversity in the progression of in situ human breast carcinomas to an invasive phenotype. The Journal of Clinical Investigation, 120(2), 636–644.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Greger, V., et al. (1994). Frequency and parental origin of hypermethylated RB1 alleles in retinoblastoma. Human Genetics, 94(5), 491–496.CrossRefPubMedGoogle Scholar
  12. 12.
    Parker, N. R., et al. (2016). Intratumoral heterogeneity identified at the epigenetic, genetic and transcriptional level in glioblastoma. Scientific Reports, 6, 22477.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Okegawa, T., et al. (2017). Intratumor heterogeneity in primary kidney cancer revealed by metabolic profiling of multiple spatially separated samples within tumors. eBioMedicine, 19, 31–38.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Masson, N., & Ratcliffe, P. J. (2014). Hypoxia signaling pathways in cancer metabolism: The importance of co-selecting interconnected physiological pathways. Cancer & Metabolism, 2(1), 3.CrossRefGoogle Scholar
  15. 15.
    Semenza, G. L. (2013). HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. The Journal of Clinical Investigation, 123(9), 3664–3671.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Lee, S. L., & Fanburg, B. L. (1987). Glycolytic activity and enhancement of serotonin uptake by endothelial cells exposed to hypoxia/anoxia. Circulation Research, 60(5), 653–658.CrossRefPubMedGoogle Scholar
  17. 17.
    Cox, T. R., & Erler, J. T. (2011). Remodeling and homeostasis of the extracellular matrix: Implications for fibrotic diseases and cancer. Disease Models & Mechanisms, 4(2), 165–178.CrossRefGoogle Scholar
  18. 18.
    Forsythe, J. A., et al. (1996). Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Molecular and Cellular Biology, 16(9), 4604–4613.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Mazure, N. M., et al. (1996). Oncogenic transformation and hypoxia synergistically act to modulate vascular endothelial growth factor expression. Cancer Research, 56(15), 3436–3440.PubMedGoogle Scholar
  20. 20.
    Brychtova, S., et al. (2008). The role of vascular endothelial growth factors and their receptors in malignant melanomas. Neoplasma, 55(4), 273–279.PubMedGoogle Scholar
  21. 21.
    De Bock, K., et al. (2013). Role of PFKFB3-driven glycolysis in vessel sprouting. Cell, 154(3), 651–663.CrossRefGoogle Scholar
  22. 22.
    Parra-Bonilla, G., et al. (2010). Critical role for lactate dehydrogenase A in aerobic glycolysis that sustains pulmonary microvascular endothelial cell proliferation. American Journal of Physiology. Lung Cellular and Molecular Physiology, 299(4), L513–L522.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Peters, K., et al. (2009). Changes in human endothelial cell energy metabolic capacities during in vitro cultivation. The role of “aerobic glycolysis” and proliferation. Cellular Physiology and Biochemistry, 24(5-6), 483–492.CrossRefPubMedGoogle Scholar
  24. 24.
    Polet, F., & Feron, O. (2013). Endothelial cell metabolism and tumour angiogenesis: Glucose and glutamine as essential fuels and lactate as the driving force. Journal of Internal Medicine, 273(2), 156–165.CrossRefPubMedGoogle Scholar
  25. 25.
    Merchan, J. R., et al. (2010). Antiangiogenic activity of 2-deoxy-D-glucose. PLoS One, 5(10), e13699.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Wang, Q., et al. (2011). 2-Deoxy-D-glucose treatment of endothelial cells induces autophagy by reactive oxygen species-mediated activation of the AMP-activated protein kinase. PLoS One, 6(2), e17234.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Yeh, W. L., Lin, C. J., & Fu, W. M. (2008). Enhancement of glucose transporter expression of brain endothelial cells by vascular endothelial growth factor derived from glioma exposed to hypoxia. Molecular Pharmacology, 73(1), 170–177.CrossRefPubMedGoogle Scholar
  28. 28.
    Kimura, H., et al. (1996). Fluctuations in red cell flux in tumor microvessels can lead to transient hypoxia and reoxygenation in tumor parenchyma. Cancer Research, 56(23), 5522–5528.PubMedGoogle Scholar
  29. 29.
    Lanzen, J., et al. (2006). Direct demonstration of instabilities in oxygen concentrations within the extravascular compartment of an experimental tumor. Cancer Research, 66(4), 2219–2223.CrossRefPubMedGoogle Scholar
  30. 30.
    Bennewith, K. L., & Durand, R. E. (2004). Quantifying transient hypoxia in human tumor xenografts by flow cytometry. Cancer Research, 64(17), 6183–6189.CrossRefPubMedGoogle Scholar
  31. 31.
    Secomb, T. W., et al. (1993). Analysis of oxygen transport to tumor tissue by microvascular networks. International Journal of Radiation Oncology, Biology, Physics, 25(3), 481–489.CrossRefPubMedGoogle Scholar
  32. 32.
    Barger, J. F., & Plas, D. R. (2010). Balancing biosynthesis and bioenergetics: Metabolic programs in oncogenesis. Endocrine-Related Cancer, 17(4), R287–R304.CrossRefPubMedGoogle Scholar
  33. 33.
    Schafer, Z. T., et al. (2009). Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment. Nature, 461(7260), 109–113.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Samudio, I., et al. (2010). Pharmacologic inhibition of fatty acid oxidation sensitizes human leukemia cells to apoptosis induction. The Journal of Clinical Investigation, 120(1), 142–156.CrossRefPubMedGoogle Scholar
  35. 35.
    Buzzai, M., et al. (2005). The glucose dependence of Akt-transformed cells can be reversed by pharmacologic activation of fatty acid beta-oxidation. Oncogene, 24(26), 4165–4173.CrossRefPubMedGoogle Scholar
  36. 36.
    Le, A., Stine, Z. E., Nguyen, C., Afzal, J., Sun, P., Hamaker, M., et al. (2014). Tumorigenicity of hypoxic respiring cancer cells revealed by a hypoxia-cell cycle dual reporter. Proceedings of the National Academy of Sciences, 111(34), 12486–12491.CrossRefGoogle Scholar
  37. 37.
    Zheng, J. (2012). Energy metabolism of cancer: Glycolysis versus oxidative phosphorylation (Review). Oncology Letters, 4(6), 1151–1157.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Martinez-Outschoorn, U. E., Lisanti, M. P., & Sotgia, F. (2014). Catabolic cancer-associated fibroblasts transfer energy and biomass to anabolic cancer cells, fueling tumor growth. Seminars in Cancer Biology, 25, 47–60.CrossRefPubMedGoogle Scholar
  39. 39.
    Elgogary, A., et al. (2016). Combination therapy with BPTES nanoparticles and metformin targets the metabolic heterogeneity of pancreatic cancer. Proceedings of the National Academy of Sciences of the United States of America, 113(36), E5328–E5336.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Fluegen, G., et al. (2017). Phenotypic heterogeneity of disseminated tumour cells is preset by primary tumour hypoxic microenvironments. Nature Cell Biology, 19(2), 120–132.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Eales, K. L., Hollinshead, K. E., & Tennant, D. A. (2016). Hypoxia and metabolic adaptation of cancer cells. Oncogene, 5, e190.CrossRefGoogle Scholar
  42. 42.
    Wong, N., De Melo, J., & Tang, D. (2013). PKM2, a central point of regulation in cancer metabolism. International Journal of Cell Biology, 2013, 242513.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Kidd, E. A., & Grigsby, P. W. (2008). Intratumoral metabolic heterogeneity of cervical cancer. Clinical Cancer Research, 14(16), 5236–5241.CrossRefPubMedGoogle Scholar
  44. 44.
    Zhao, S., et al. (2005). Biologic correlates of intratumoral heterogeneity in 18F-FDG distribution with regional expression of glucose transporters and hexokinase-II in experimental tumor. Journal of Nuclear Medicine, 46(4), 675–682.PubMedGoogle Scholar
  45. 45.
    Farwell, M. D., Pryma, D. A., & Mankoff, D. A. (2014). PET/CT imaging in cancer: Current applications and future directions. Cancer, 120(22), 3433–3445.CrossRefPubMedGoogle Scholar
  46. 46.
    Plathow, C., & Weber, W. A. (2008). Tumor cell metabolism imaging. Journal of Nuclear Medicine, 49(Suppl 2), 43S–63S.CrossRefPubMedGoogle Scholar
  47. 47.
    Mena, E., et al. (2017). Value of intratumoral metabolic heterogeneity and quantitative 18F-FDG PET/CT parameters to predict prognosis in patients with HPV-positive primary oropharyngeal squamous cell carcinoma. Clinical Nuclear Medicine, 42(5), e227–e234.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Ojelabi, O. A., et al. (2016). WZB117 (2-Fluoro-6-(m-hydroxybenzoyloxy) Phenyl m-Hydroxybenzoate) inhibits GLUT1-mediated sugar transport by binding reversibly at the exofacial sugar binding site. The Journal of Biological Chemistry, 291(52), 26762–26772.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Rapisarda, A., et al. (2004). Topoisomerase I-mediated inhibition of hypoxia-inducible factor 1: Mechanism and therapeutic implications. Cancer Research, 64(4), 1475–1482.CrossRefPubMedGoogle Scholar
  50. 50.
    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.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of PathologyJohns Hopkins University School of MedicineBaltimoreUSA
  2. 2.Department of Pathology and OncologyJohns Hopkins University School of MedicineBaltimoreUSA

Personalised recommendations