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Mitochondrial and glycolytic metabolic compartmentalization in diffuse large B-cell lymphoma.

Abstract Metabolic heterogeneity between neoplastic cells and surrounding stroma has been described in several epithelial malignancies; however, the metabolic phenotypes of neoplastic lymphocytes and neighboring stroma in diffuse large B-cell lymphoma (DLBCL) is unknown. We investigated the metabolic phenotypes of human DLBCL tumors by using immunohistochemical markers of glycolytic and mitochondrial oxidative phosphorylation (OXPHOS) metabolism. The lactate importer MCT4 is a marker of glycolysis, whereas the lactate importer MCT1 and TOMM20 are markers of OXPHOS metabolism. Staining patterns were assessed in 33 DLBCL samples as well as 18 control samples (non-neoplastic lymph nodes). TOMM20 and MCT1 were highly expressed in neoplastic lymphocytes, indicating an OXPHOS phenotype, whereas non-neoplastic lymphocytes in the control samples did not express these markers. Stromal cells in DLBCL samples strongly expressed MCT4, displaying a glycolytic phenotype, a feature not seen in stromal elements of non-neoplastic lymphatic tissue. Furthermore, the differential expression of lactate exporters (MCT4) on tumor-associated stroma and lactate importers (MCT1) on neoplastic lymphocytes support the hypothesis that neoplastic cells are metabolically linked to the stroma likely via mutually beneficial reprogramming. MCT4 is a marker of tumor-associated stroma in neoplastic tissue. Our findings suggest that disruption of neoplastic-stromal cell metabolic heterogeneity including MCT1 and MCT4 blockade should be studied to determine if it could represent a novel treatment target in DLBCL.
PMID
Related Publications
Authors

Mayor MeshTerms

Glycolysis

Oxidative Phosphorylation

Keywords

Glycolysis

Monocarboxylate Transporter

Oxidative Phosphorylation

Tumor-Microenvironment

Journal Title seminars in oncology
Publication Year Start




PMID- 29248132
OWN - NLM
STAT- MEDLINE
DCOM- 20171226
LR  - 20171226
IS  - 1532-8708 (Electronic)
IS  - 0093-7754 (Linking)
VI  - 44
IP  - 3
DP  - 2017 Jun
TI  - Mitochondrial and glycolytic metabolic compartmentalization in diffuse large
      B-cell lymphoma.
PG  - 204-217
LID - S0093-7754(17)30135-5 [pii]
LID - 10.1053/j.seminoncol.2017.10.002 [doi]
AB  - Metabolic heterogeneity between neoplastic cells and surrounding stroma has been 
      described in several epithelial malignancies; however, the metabolic phenotypes
      of neoplastic lymphocytes and neighboring stroma in diffuse large B-cell lymphoma
      (DLBCL) is unknown. We investigated the metabolic phenotypes of human DLBCL
      tumors by using immunohistochemical markers of glycolytic and mitochondrial
      oxidative phosphorylation (OXPHOS) metabolism. The lactate importer MCT4 is a
      marker of glycolysis, whereas the lactate importer MCT1 and TOMM20 are markers of
      OXPHOS metabolism. Staining patterns were assessed in 33 DLBCL samples as well as
      18 control samples (non-neoplastic lymph nodes). TOMM20 and MCT1 were highly
      expressed in neoplastic lymphocytes, indicating an OXPHOS phenotype, whereas
      non-neoplastic lymphocytes in the control samples did not express these markers. 
      Stromal cells in DLBCL samples strongly expressed MCT4, displaying a glycolytic
      phenotype, a feature not seen in stromal elements of non-neoplastic lymphatic
      tissue. Furthermore, the differential expression of lactate exporters (MCT4) on
      tumor-associated stroma and lactate importers (MCT1) on neoplastic lymphocytes
      support the hypothesis that neoplastic cells are metabolically linked to the
      stroma likely via mutually beneficial reprogramming. MCT4 is a marker of
      tumor-associated stroma in neoplastic tissue. Our findings suggest that
      disruption of neoplastic-stromal cell metabolic heterogeneity including MCT1 and 
      MCT4 blockade should be studied to determine if it could represent a novel
      treatment target in DLBCL.
CI  - Copyright (c) 2017 Elsevier Inc. All rights reserved.
FAU - Gooptu, Mahasweta
AU  - Gooptu M
AD  - Department of Medical Oncology, Dana Farber Cancer Institute, Harvard University 
      Medical School, Boston, MA.
FAU - Whitaker-Menezes, Diana
AU  - Whitaker-Menezes D
AD  - Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson
      University, Philadelphia, PA.
FAU - Sprandio, John
AU  - Sprandio J
AD  - Consultants in Medical Oncology and Hematology, Broomall, PA.
FAU - Domingo-Vidal, Marina
AU  - Domingo-Vidal M
AD  - Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson
      University, Philadelphia, PA.
FAU - Lin, Zhao
AU  - Lin Z
AD  - Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson
      University, Philadelphia, PA.
FAU - Uppal, Guldeep
AU  - Uppal G
AD  - Department of Pathology, Anatomy and Cell Biology, Sidney Kimmel Cancer Center,
      Thomas Jefferson University, Philadelphia, PA.
FAU - Gong, Jerald
AU  - Gong J
AD  - Department of Pathology, Anatomy and Cell Biology, Sidney Kimmel Cancer Center,
      Thomas Jefferson University, Philadelphia, PA.
FAU - Fratamico, Roberto
AU  - Fratamico R
AD  - Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson
      University, Philadelphia, PA.
FAU - Leiby, Benjamin
AU  - Leiby B
AD  - Department of Clinical Pharmacology, Division of Biostatistics, Thomas Jefferson 
      University, Philadelphia, PA, USA.
FAU - Dulau-Florea, Alina
AU  - Dulau-Florea A
AD  - Department of Laboratory Medicine, Hematology, National Institutes of Health,
      Bethesda, MD.
FAU - Caro, Jaime
AU  - Caro J
AD  - Department of Medicine, Cardeza Foundation for Hematological Research, Thomas
      Jefferson University, Philadelphia, PA USA.
FAU - Martinez-Outschoorn, Ubaldo
AU  - Martinez-Outschoorn U
AD  - Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson
      University, Philadelphia, PA. Electronic address:
      [email protected]
LA  - eng
GR  - K08 CA175193/CA/NCI NIH HHS/United States
GR  - P30 CA056036/CA/NCI NIH HHS/United States
PT  - Journal Article
DEP - 20171010
PL  - United States
TA  - Semin Oncol
JT  - Seminars in oncology
JID - 0420432
RN  - 0 (Membrane Transport Proteins)
RN  - 0 (Monocarboxylic Acid Transporters)
RN  - 0 (Muscle Proteins)
RN  - 0 (Receptors, Cell Surface)
RN  - 0 (SLC16A4 protein, human)
RN  - 0 (Symporters)
RN  - 0 (TOMM20 protein, human)
RN  - 0 (monocarboxylate transport protein 1)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Case-Control Studies
MH  - Female
MH  - *Glycolysis
MH  - Humans
MH  - Immunohistochemistry
MH  - Lymphocytes/metabolism
MH  - Lymphoma, Large B-Cell, Diffuse/*metabolism
MH  - Male
MH  - Membrane Transport Proteins/metabolism
MH  - Middle Aged
MH  - Mitochondria/*metabolism
MH  - Monocarboxylic Acid Transporters/metabolism
MH  - Muscle Proteins/metabolism
MH  - *Oxidative Phosphorylation
MH  - Receptors, Cell Surface/metabolism
MH  - Stromal Cells/metabolism
MH  - Symporters/metabolism
PMC - PMC5737785
MID - NIHMS912399
OTO - NOTNLM
OT  - Glycolysis
OT  - Monocarboxylate Transporter
OT  - Oxidative Phosphorylation
OT  - Tumor-Microenvironment
EDAT- 2017/12/19 06:00
MHDA- 2017/12/27 06:00
CRDT- 2017/12/18 06:00
PMCR- 2018/10/10 00:00
PHST- 2017/10/05 00:00 [received]
PHST- 2017/10/05 00:00 [accepted]
PHST- 2018/10/10 00:00 [pmc-release]
PHST- 2017/12/18 06:00 [entrez]
PHST- 2017/12/19 06:00 [pubmed]
PHST- 2017/12/27 06:00 [medline]
AID - S0093-7754(17)30135-5 [pii]
AID - 10.1053/j.seminoncol.2017.10.002 [doi]
PST - ppublish
SO  - Semin Oncol. 2017 Jun;44(3):204-217. doi: 10.1053/j.seminoncol.2017.10.002. Epub 
      2017 Oct 10.