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The Intricate Metabolism of Pancreatic Cancers

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

Abstract

Currently, approximately 95% of pancreatic cancers are pancreatic ductal adenocarcinoma (PDAC), which is the most aggressive form and the fourth leading cause of cancer death with extremely poor prognosis [1]. Poor prognosis is primarily attributed to the late diagnosis of the disease when patients are no longer candidates for surgical resection [2]. Cancer cells are dependent on the oncogenes that allow them to proliferate limitlessly. Thus, targeting the expression of known oncogenes in pancreatic cancer has been shown to lead to more effective treatment [3]. This chapter will discuss the complexity of metabolic features in pancreatic cancers. To be able to fully comprehend the heterogeneous nature of cancer metabolism, we need to take into account the close relationship between cancer metabolism and genetics. Gene expression varies tremendously, not only among different types of cancers, but also within the same type of cancer among different patients. Cancer metabolism heterogeneity is often prompted and perpetuated not only by genetic mutations in oncogenes and tumor suppressor genes but also by the innate diversity of the tumor microenvironment. Much effort has been focused on elucidating the genetic alterations that correlate with disease progression and treatment response [4]. However, the precise mechanism by which tumor metabolism contributes to cancer growth, survival, mobility, and aggressiveness represents a functional readout of tumor progression.

Keywords

Pancreatic ductal adenocarcinoma KRAS mutation Glucose metabolism Glutamine metabolism Combined therapy 

Abbreviations

ASP

Aspartate

EGFR

Epidermal growth factor receptor

GLS

Glutaminase

GLUD1

Glutamate dehydrogenase 1

GLUT

Glucose transporter

GOT1

Glutamic-oxaloacetic transaminase 1

HIF-1α

Hypoxia-inducible factor 1-alpha

HK2

Hexokinase 2

KRAS

Kirsten rat sarcoma viral oncogene homolog

LDH

Lactate dehydrogenase

MCT

Monocarboxylate transporter

OAA

Oxaloacetate

PDAC

Pancreatic ductal adenocarcinoma

PFK1

Phosphofructokinase 1

TCA

Tricarboxylic acid cycle

References

  1. 1.
    Hariharan, D., Saied, A., & Kocher, H. M. (2008). Analysis of mortality rates for pancreatic cancer across the world. HPB: The Official Journal of the International Hepato Pancreato Biliary Association, 10(1), 58–62.CrossRefGoogle Scholar
  2. 2.
    Hidalgo, M. (2010). Pancreatic cancer. The New England Journal of Medicine, 362(17), 1605–1617.CrossRefGoogle Scholar
  3. 3.
    Weinstein, I. B., & Joe, A. (2008). Oncogene addiction. Cancer Research, 68(9), 3077–3080. discussion 3080.CrossRefGoogle Scholar
  4. 4.
    Verhaak, R. G., et al. (2010). Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell, 17(1), 98–110.CrossRefGoogle Scholar
  5. 5.
    Birnbaum, D. J., et al. (2011). Genome profiling of pancreatic adenocarcinoma. Genes, Chromosomes & Cancer, 50(6), 456–465.CrossRefGoogle Scholar
  6. 6.
    Son, J., et al. (2013). Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature, 496(7443), 101–105.CrossRefGoogle Scholar
  7. 7.
    Lyssiotis, C. A., et al. (2013). Pancreatic cancers rely on a novel glutamine metabolism pathway to maintain redox balance. Cell Cycle, 12(13), 1987–1988.CrossRefGoogle Scholar
  8. 8.
    di Magliano, M. P., & Logsdon, C. D. (2013). Roles for KRAS in pancreatic tumor development and progression. Gastroenterology, 144(6), 1220–1229.CrossRefGoogle Scholar
  9. 9.
    Sousa, C. M., & Kimmelman, A. C. (2014). The complex landscape of pancreatic cancer metabolism. Carcinogenesis, 35(7), 1441–1450.CrossRefGoogle Scholar
  10. 10.
    Ying, H., et al. (2012). Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell, 149(3), 656–670.CrossRefGoogle Scholar
  11. 11.
    Chaika, N. V., et al. (2012). Differential expression of metabolic genes in tumor and stromal components of primary and metastatic loci in pancreatic adenocarcinoma. PLoS One, 7(3), e32996.CrossRefGoogle Scholar
  12. 12.
    Maher, J. C., et al. (2005). Differential sensitivity to 2-deoxy-D-glucose between two pancreatic cell lines correlates with GLUT-1 expression. Pancreas, 30(2), e34–e39.CrossRefGoogle Scholar
  13. 13.
    Yun, J., et al. (2009). Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells. Science, 325(5947), 1555–1559.CrossRefGoogle Scholar
  14. 14.
    Chaika, N. V., et al. (2012). MUC1 mucin stabilizes and activates hypoxia-inducible factor 1 alpha to regulate metabolism in pancreatic cancer. Proceedings of the National Academy of Sciences of the United States of America, 109(34), 13787–13792.CrossRefGoogle Scholar
  15. 15.
    Rajeshkumar, N. V., et al. (2015). Therapeutic targeting of the Warburg effect in pancreatic cancer relies on an absence of p53 function. Cancer Research, 75(16), 3355–3364.CrossRefGoogle Scholar
  16. 16.
    Surget, S., Khoury, M. P., & Bourdon, J. C. (2013). Uncovering the role of p53 splice variants in human malignancy: A clinical perspective. Onco Targets and Therapy, 7, 57–68.Google Scholar
  17. 17.
    Bensaad, K., et al. (2006). TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell, 126(1), 107–120.CrossRefGoogle Scholar
  18. 18.
    Weinberg, S. E., & Chandel, N. S. (2015). Targeting mitochondria metabolism for cancer therapy. Nature Chemical Biology, 11(1), 9–15.CrossRefGoogle Scholar
  19. 19.
    Alistar, A., et al. (2017). Safety and tolerability of the first-in-class agent CPI-613 in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer: A single-Centre, open-label, dose-escalation, phase 1 trial. The Lancet Oncology, 18(6), 770–778.CrossRefGoogle Scholar
  20. 20.
    Stuart, S. D., et al. (2014). A strategically designed small molecule attacks alpha-ketoglutarate dehydrogenase in tumor cells through a redox process. Cancer & Metabolism, 2(1), 4.CrossRefGoogle Scholar
  21. 21.
    Pardee, T. S., et al. (2014). A phase I study of the first-in-class antimitochondrial metabolism agent, CPI-613, in patients with advanced hematologic malignancies. Clinical Cancer Research, 20(20), 5255–5264.CrossRefGoogle Scholar
  22. 22.
    Sancho, P., et al. (2015). MYC/PGC-1alpha balance determines the metabolic phenotype and plasticity of pancreatic cancer stem cells. Cell Metabolism, 22(4), 590–605.CrossRefGoogle Scholar
  23. 23.
    Lonardo, E., et al. (2013). Metformin targets the metabolic achilles heel of human pancreatic cancer stem cells. PLoS One, 8(10), e76518.CrossRefGoogle Scholar
  24. 24.
    Evans, J. M., et al. (2005). Metformin and reduced risk of cancer in diabetic patients. BMJ, 330(7503), 1304–1305.CrossRefGoogle Scholar
  25. 25.
    Sadeghi, N., et al. (2012). Metformin use is associated with better survival of diabetic patients with pancreatic cancer. Clinical Cancer Research, 18(10), 2905–2912.CrossRefGoogle Scholar
  26. 26.
    Viale, A., et al. (2014). Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function. Nature, 514(7524), 628–632.CrossRefGoogle Scholar
  27. 27.
    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.CrossRefGoogle Scholar
  28. 28.
    Rahib, L., et al. (2014). Projecting cancer incidence and deaths to 2030: The unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Research, 74(11), 2913–2921.CrossRefGoogle Scholar
  29. 29.
    Rossi, M. L., Rehman, A. A., & Gondi, C. S. (2014). Therapeutic options for the management of pancreatic cancer. World Journal of Gastroenterology, 20(32), 11142–11159.CrossRefGoogle 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

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