1. Employing Metabolism to Improve the Diagnosis and Treatment of Pancreatic Cancer 
Christopher J. Halbrook, Costas A. Lyssiotis 
Cancer Cell 
Volume 31, Issue 1, Pages 5-19 (January 2017)
DOI: /j.ccell
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2. Figure 1 Cancer-Stromal Interactions Shape the Pathophysiology of PDAC
(A) Physical changes. Physical changes in the tumor microenvironment are driven by cancer cell-mediated activation of fibroblasts, which produce a stiff hyaluronic acid (HA)-rich matrix that leads to increased interstitial pressure and vasculature collapse, limiting nutrient and chemotherapy availability. The stiff matrix itself also promotes tumor aggression through physical stress exerted on the cancer cells, yet acts to restrain progression (Jacobetz et al., 2013; Laklai et al., 2016; Olive et al., 2009; Ozdemir et al., 2014; Provenzano et al., 2012; Rhim et al., 2014).
(B) Immune suppression. The epithelial and stromal compartments cooperate to produce a tumor microenvironment that is strongly immunosuppressive and inhibits T cell clearance of cancer cells (Bayne et al., 2012; Feig et al., 2013; Mathew et al., 2016; Pylayeva-Gupta et al., 2012; Zhang et al., 2017).
(C) Crosstalk mechanisms. Limitation of nutrient availability is overcome in part by exchange of growth factors, cytokines, and metabolites between the stromal and epithelial compartments (Mathew et al., 2014; McAllister et al., 2014; Pylayeva-Gupta et al., 2016; Sousa et al., 2016; Waghray et al., 2016).
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3. Figure 2 Metabolic Pathways in PDAC
Pancreatic cancer cells scavenge the limited extracellular glucose available in the pancreatic tumor microenvironment through oncogenic Kras-mediated elevation of the glucose transporter GLUT1. In addition, Kras modulates the expression of other glycolytic enzymes, resulting in elevated glycolytic flux. The NAD+ necessary to maintain glycolysis is regenerated by the conversion of pyruvate to lactate via LDHA. Glucose also serves as an important source of carbon for anabolic metabolism in the pentose phosphate pathway and the hexosamine biosynthetic pathway. PDAC cells rely on a Kras-rewired glutamine (Gln) metabolic pathway for redox balance. Gln is converted to glutamate (Glu) then aspartate (Asp) in the mitochondria, after which it is shuttled to the cytosol and utilized through a series of reactions to generate NADPH. This maintains the reduced glutathione (GSH) levels required for redox homeostasis. Metabolites and metabolic pathways utilizing Gln carbon are presented in blue. Only those enzymes specifically discussed in the text are presented. Ala, alanine; αKG, alpha-ketoglutarate; Cit, citrate; Cys, cysteine; Fum, fumarate; Gly, glycine; GSSH, oxidized glutathione; Iso, isocitrate; Lac, lactate; Mal, malate; OAA, oxaloacetic acid; Pyr, pyruvate; R5P, ribose 5-phosphate; Suc, succinate; UDP-GlcNAC, uridine diphosphate N-acetylglucosamine.
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4. Figure 3 Methods of Nutrient Acquisition Utilized by PDAC
Pancreatic cancer cells engage in metabolic crosstalk with stromal cells by multiple avenues. Growth factors (GF) released from the PDAC cells can metabolically reprogram fibroblasts, which respond by the release of different GFs capable of reciprocal reprogramming of the epithelial cells. PDAC cells also induce autophagy in pancreatic stellate cells, stimulating the release of growth-promoting alanine (Ala). Metabolite exchange also occurs among cancer cells, as PDAC cells in hypoxic environments release lactate (Lac) which fuels proliferation in normoxic cancer cells. Pancreatic cancer cells are capable of utilizing recycling pathways and engage in multiple mechanisms of scavenging extracellular nutrient sources, including non-specific macropinocytosis and lipid uptake, to obtain nutrients in the austere pancreatic tumor microenvironment.
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5. Figure 4 Metabolic Imaging Agents Available for Detection of PDAC
(A) Positron emission tomography (PET)-based imaging agents accumulate in tissues and emit positrons proportional to the tissue accumulation of the probe.
(B) Hyperpolarized magnetic resonance spectroscopy (HP-MRS)-based imaging agents allows both the measurement of uptake as well as a readout of conversion into other metabolites. This information can be used to monitor the flux through various metabolic pathways in the tumor. 6PG, 6-phosphogluconate; DHA, dehydroascorbate; 18F-DG, 18F-labeled fluorodeoxyglucose; Glc, glucose; Glc-6P, glucose 6-phosphate; Pyr, pyruvate.
Cancer Cell  , 5-19DOI: ( /j.ccell )
Copyright © 2016 Elsevier Inc. Terms and Conditions