Abstract
Cancer cell metabolism is heavily influenced by microenvironmental factors, including nutrient availability. Therefore, knowledge of microenvironmental nutrient levels is essential to understand tumor metabolism. To measure the extracellular nutrient levels available to tumors, we utilized quantitative metabolomics methods to measure the absolute concentrations of >118 metabolites in plasma and tumor interstitial fluid, the extracellular fluid that perfuses tumors. Comparison of nutrient levels in tumor interstitial fluid and plasma revealed that the nutrients available to tumors differ from those present in circulation. Further, by comparing interstitial fluid nutrient levels between autochthonous and transplant models of murine pancreatic and lung adenocarcinoma, we found that tumor type, anatomical location and animal diet affect local nutrient availability. These data provide a comprehensive characterization of the nutrients present in the tumor microenvironment of widely used models of lung and pancreatic cancer and identify factors that influence metabolite levels in tumors.
Highlights
Tumors exhibit altered metabolism compared to non-transformed tissues (DeBerardinis and Chandel, 2016)
We first focused on isolating and analyzing tumor interstitial fluid (TIF) nutrient levels in pancreatic ductal adenocarcinoma (PDAC), as this tumor type is known to have inadequate vasculature leading to tumor hypoxia (Koong et al, 2000) and nutrient deprivation (Commisso et al, 2013; Kamphorst et al, 2015; Lyssiotis and Kimmelman, 2017; Sherman et al, 2017; Sousa et al, 2016)
By measuring LDH activity in KP-/-C tumor, plasma, and TIF samples, we determined that the LDH activity in the entire TIF volume is
Summary
Tumors exhibit altered metabolism compared to non-transformed tissues (DeBerardinis and Chandel, 2016). Animal limbs transformed with oncogenic viruses exhibit increased glucose uptake and lactate secretion relative to unaffected limbs (Cori and Cori, 1925). Some aspects of tumor metabolism, including higher rates of glucose fermentation to lactate, are cell-intrinsic features that are retained when cancer cells are isolated from tumors (Koppenol et al, 2011). Numerous studies have delineated how cell-intrinsic factors such as oncogenic lesions or epigenetic state alter cellular metabolism, causing phenotypes such as increased glycolysis (Nagarajan et al, 2016). The metabolic utilization of both glucose and the amino acid glutamine differs between cells growing in culture and murine tumor models
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