23
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Quantification of microenvironmental metabolites in murine cancers reveals determinants of tumor nutrient availability

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          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.

          eLife digest

          In the body, cancer cells can rely on different nutrients than normal cells, and they can use these nutrients in a different way. What cancer cells consume also depends on what is available in their immediate environment. In a tumor, cells grab nutrients from the ‘interstitial’ fluid that surrounds them, but what is present in this liquid may vary within tumors arising in different locations. Understanding what nutrients are ‘on the menu’ in specific tumors would help to target diseased cells while sparing healthy ones, but this knowledge has been difficult to obtain.

          To investigate this, Sullivan et al. used a technique called mass spectrometry to measure the amounts of 120 nutrients present in the interstitial fluid of mouse pancreas and lung tumors. Different levels of nutrients were found in the two types of tumors, and analyses showed that what was present in the interstitial fluid depended on the type of cancer cells, where the tumor was located, and what the animals ate. This suggests that cancer cells may have different needs because they are limited in what they have access to.

          It remains to be seen whether the nutrients levels found in mouse tumors are the same as those in humans. Armed with this knowledge, it may then be possible to feed cancer cells grown in the laboratory with the nutrient menu that they would have access to in the body. This could help identify new cancer treatments.

          Related collections

          Most cited references60

          • Record: found
          • Abstract: found
          • Article: found

          Oncogenic Kras Maintains Pancreatic Tumors through Regulation of Anabolic Glucose Metabolism

          Tumor maintenance relies on continued activity of driver oncogenes, although their rate-limiting role is highly context dependent. Oncogenic Kras mutation is the signature event in pancreatic ductal adenocarcinoma (PDAC), serving a critical role in tumor initiation. Here, an inducible Kras(G12D)-driven PDAC mouse model establishes that advanced PDAC remains strictly dependent on Kras(G12D) expression. Transcriptome and metabolomic analyses indicate that Kras(G12D) serves a vital role in controlling tumor metabolism through stimulation of glucose uptake and channeling of glucose intermediates into the hexosamine biosynthesis and pentose phosphate pathways (PPP). These studies also reveal that oncogenic Kras promotes ribose biogenesis. Unlike canonical models, we demonstrate that Kras(G12D) drives glycolysis intermediates into the nonoxidative PPP, thereby decoupling ribose biogenesis from NADP/NADPH-mediated redox control. Together, this work provides in vivo mechanistic insights into how oncogenic Kras promotes metabolic reprogramming in native tumors and illuminates potential metabolic targets that can be exploited for therapeutic benefit in PDAC. Copyright © 2012 Elsevier Inc. All rights reserved.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Tumour acidosis: from the passenger to the driver's seat

            This Review by Corbet and Feron summarizes recent data showing that tumour acidosis influences cancer metabolism and contributes to cancer progression; it also highlights advances in therapeutic modalities aimed at either inhibiting or exploiting tumour acidification.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Tumor-derived granulocyte-macrophage colony-stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer.

              Cancer-associated inflammation is thought to be a barrier to immune surveillance, particularly in pancreatic ductal adenocarcinoma (PDA). Gr-1(+) CD11b(+) cells are a key feature of cancer inflammation in PDA, but remain poorly understood. Using a genetically engineered mouse model of PDA, we show that tumor-derived granulocyte-macrophage colony-stimulating factor (GM-CSF) is necessary and sufficient to drive the development of Gr-1(+) CD11b(+) cells that suppressed antigen-specific T cells. In vivo, abrogation of tumor-derived GM-CSF inhibited the recruitment of Gr-1(+) CD11b(+) cells to the tumor microenvironment and blocked tumor development-a finding that was dependent on CD8(+) T cells. In humans, PDA tumor cells prominently expressed GM-CSF in vivo. Thus, tumor-derived GM-CSF is an important regulator of inflammation and immune suppression within the tumor microenvironment. Copyright © 2012 Elsevier Inc. All rights reserved.
                Bookmark

                Author and article information

                Contributors
                Role: Reviewing Editor
                Role: Senior Editor
                Journal
                eLife
                Elife
                eLife
                eLife
                eLife Sciences Publications, Ltd
                2050-084X
                16 April 2019
                2019
                : 8
                : e44235
                Affiliations
                [1 ]deptKoch Institute for Integrative Cancer Research, Department of Biology Massachusetts Institute of Technology CambridgeUnited States
                [2 ]deptDepartment of Biochemistry and Molecular Biology University of Massachusetts AmherstUnited States
                [3 ]deptWhitehead Institute for Biomedical Research Massachusetts Institute of Technology CambridgeUnited States
                [4 ]Dana-Farber Cancer Institute BostonUnited States
                [5 ]deptBen May Department for Cancer Research University of Chicago ChicagoUnited States
                UT Southwestern Medical Center United States
                The Netherlands Cancer Institute Netherlands
                UT Southwestern Medical Center United States
                UT Southwestern Medical Center United States
                University of Cambridge United Kingdom
                Author information
                http://orcid.org/0000-0001-5765-0459
                http://orcid.org/0000-0003-1787-5084
                https://orcid.org/0000-0002-6702-4192
                https://orcid.org/0000-0003-3811-3054
                Article
                44235
                10.7554/eLife.44235
                6510537
                30990168
                dc437ef4-2c6a-4685-b671-4602946a896a
                © 2019, Sullivan et al

                This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

                History
                : 10 December 2018
                : 04 April 2019
                Funding
                Funded by: Koch Institute for Integrative Cancer Research;
                Award ID: Koch Institute Graduate Fellowship
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000054, National Cancer Institute;
                Award ID: F32CA210421
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100009729, Ludwig Institute for Cancer Research;
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100005979, Lustgarten Foundation;
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000011, Howard Hughes Medical Institute;
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100009730, Stand Up To Cancer;
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000054, National Cancer Institute;
                Award ID: R01CA168653
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000054, National Cancer Institute;
                Award ID: R01CA201276
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000054, National Cancer Institute;
                Award ID: P30CA1405141
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000054, National Cancer Institute;
                Award ID: F32CA213810
                Award Recipient :
                The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
                Categories
                Research Article
                Biochemistry and Chemical Biology
                Cancer Biology
                Custom metadata
                The nutrients available in some tumors and the factors that influence tumor nutrient availability are characterized, which provides insight into the metabolic constraints of the tumor microenvironment.

                Life sciences
                cancer,metabolism,microenvironment,mass spectrometry,metabolomics,pancreatic adenocarcinoma,mouse

                Comments

                Comment on this article