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The Intricate Metabolism of Pancreatic Cancers

  • Chapter
The Heterogeneity of Cancer Metabolism

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1063))

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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.

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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. 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.

    Article  CAS  Google Scholar 

  2. Hidalgo, M. (2010). Pancreatic cancer. The New England Journal of Medicine, 362(17), 1605–1617.

    Article  CAS  PubMed  Google Scholar 

  3. Weinstein, I. B., & Joe, A. (2008). Oncogene addiction. Cancer Research, 68(9), 3077–3080. discussion 3080.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Birnbaum, D. J., et al. (2011). Genome profiling of pancreatic adenocarcinoma. Genes, Chromosomes & Cancer, 50(6), 456–465.

    Article  CAS  Google Scholar 

  6. Son, J., et al. (2013). Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature, 496(7443), 101–105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. di Magliano, M. P., & Logsdon, C. D. (2013). Roles for KRAS in pancreatic tumor development and progression. Gastroenterology, 144(6), 1220–1229.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Sousa, C. M., & Kimmelman, A. C. (2014). The complex landscape of pancreatic cancer metabolism. Carcinogenesis, 35(7), 1441–1450.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ying, H., et al. (2012). Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell, 149(3), 656–670.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  13. Yun, J., et al. (2009). Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells. Science, 325(5947), 1555–1559.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. Bensaad, K., et al. (2006). TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell, 126(1), 107–120.

    Article  CAS  PubMed  Google Scholar 

  18. Weinberg, S. E., & Chandel, N. S. (2015). Targeting mitochondria metabolism for cancer therapy. Nature Chemical Biology, 11(1), 9–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  23. Lonardo, E., et al. (2013). Metformin targets the metabolic achilles heel of human pancreatic cancer stem cells. PLoS One, 8(10), e76518.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Evans, J. M., et al. (2005). Metformin and reduced risk of cancer in diabetic patients. BMJ, 330(7503), 1304–1305.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Viale, A., et al. (2014). Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function. Nature, 514(7524), 628–632.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Felipe Camelo

  2. Department of Pathology and Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Anne Le

Authors
  1. Felipe Camelo
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  2. Anne Le
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Correspondence to Anne Le .

Editor information

Editors and Affiliations

  1. Johns Hopkins Medicine, Baltimore, MD, USA

    Anne Le MD, HDR

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Camelo, F., Le, A. (2018). The Intricate Metabolism of Pancreatic Cancers. In: Le, A. (eds) The Heterogeneity of Cancer Metabolism. Advances in Experimental Medicine and Biology, vol 1063. Springer, Cham. https://doi.org/10.1007/978-3-319-77736-8_5

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