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Hodgkin lymphoma: A complex metabolic ecosystem with glycolytic reprogramming of the tumor microenvironment.

Abstract Twenty percent of patients with classical Hodgkin Lymphoma (cHL) have aggressive disease defined as relapsed or refractory disease to initial therapy. At present we cannot identify these patients pre-treatment. The microenvironment is very important in cHL because non-cancer cells constitute the majority of the cells in these tumors. Non-cancer intra-tumoral cells, such as tumor-associated macrophages (TAMs) have been shown to promote tumor growth in cHL via crosstalk with the cancer cells. Metabolic heterogeneity is defined as high mitochondrial metabolism in some tumor cells and glycolysis in others. We hypothesized that there are metabolic differences between cancer cells and non-cancer tumor cells, such as TAMs and tumor-infiltrating lymphocytes in cHL and that greater metabolic differences between cancer cells and TAMs are associated with poor outcomes.
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Authors

Mayor MeshTerms

Glycolysis

Oxidative Phosphorylation

Tumor Microenvironment

Keywords

Hodgkin lymphoma

glycolysis

ketone bodies

lactate

mitochondria

oxidative phosphorylation

Journal Title seminars in oncology
Publication Year Start




PMID- 29248133
OWN - NLM
STAT- MEDLINE
DCOM- 20171226
LR  - 20171226
IS  - 1532-8708 (Electronic)
IS  - 0093-7754 (Linking)
VI  - 44
IP  - 3
DP  - 2017 Jun
TI  - Hodgkin lymphoma: A complex metabolic ecosystem with glycolytic reprogramming of 
      the tumor microenvironment.
PG  - 218-225
LID - S0093-7754(17)30134-3 [pii]
LID - 10.1053/j.seminoncol.2017.10.003 [doi]
AB  - BACKGROUND: Twenty percent of patients with classical Hodgkin Lymphoma (cHL) have
      aggressive disease defined as relapsed or refractory disease to initial therapy. 
      At present we cannot identify these patients pre-treatment. The microenvironment 
      is very important in cHL because non-cancer cells constitute the majority of the 
      cells in these tumors. Non-cancer intra-tumoral cells, such as tumor-associated
      macrophages (TAMs) have been shown to promote tumor growth in cHL via crosstalk
      with the cancer cells. Metabolic heterogeneity is defined as high mitochondrial
      metabolism in some tumor cells and glycolysis in others. We hypothesized that
      there are metabolic differences between cancer cells and non-cancer tumor cells, 
      such as TAMs and tumor-infiltrating lymphocytes in cHL and that greater metabolic
      differences between cancer cells and TAMs are associated with poor outcomes.
      METHODS: A case-control study was conducted with 22 tissue samples of cHL at
      diagnosis from a single institution. The case samples were from 11 patients with 
      aggressive cHL who had relapsed after standard treatment with adriamycin,
      bleomycin, vinblastine, and dacarbazine (ABVD) or were refractory to this
      treatment. The control samples were from 11 patients with cHL who achieved a
      remission and never relapsed after ABVD. Reactive non-cancerous lymph nodes from 
      four subjects served as additional controls. Samples were stained by
      immunohistochemistry for three metabolic markers: translocase of the outer
      mitochondrial membrane 20 (TOMM20), monocarboxylate transporter 1 (MCT1), and
      monocarboxylate transporter 4 (MCT4). TOMM20 is a marker of mitochondrial
      oxidative phosphorylation (OXPHOS) metabolism. Monocarboxylate transporter 1
      (MCT1) is the main importer of lactate into cells and is a marker of OXPHOS.
      Monocarboxylate transporter 4 (MCT4) is the main lactate exporter out of cells
      and is a marker of glycolysis. The immunoreactivity for TOMM20, MCT1, and MCT4
      was scored based on staining intensity and percentage of positive cells, as
      follows: 0 for no detectable staining in > 50% of cells; 1+ for faint to moderate
      staining in > 50% of cells, and 2+ for high or strong staining in > 50% of cells.
      RESULTS: TOMM20, MCT1, and MCT4 expression was significantly different in Hodgkin
      and Reed Sternberg (HRS) cells, which are the cancerous cells in cHL compared
      with TAMs and tumor-associated lymphocytes. HRS have high expression of TOMM20
      and MCT1, while TAMs have absent expression of TOMM20 and MCT1 in all but two
      cases. Tumor-infiltrating lymphocytes have low TOMM20 expression and absent MCT1 
      expression. Conversely, high MCT4 expression was found in TAMs, but absent in HRS
      cells in all but one case. Tumor-infiltrating lymphocytes had absent MCT4
      expression. Reactive lymph nodes in contrast to cHL tumors had low TOMM20, MCT1, 
      and MCT4 expression in lymphocytes and macrophages. High TOMM20 and MCT1
      expression in cancer cells with high MCT4 expression in TAMs is a signature of
      high metabolic heterogeneity between cancer cells and the tumor microenvironment.
      A high metabolic heterogeneity signature was associated with relapsed or
      refractory cHL with a hazard ratio of 5.87 (1.16-29.71; two-sided P < .05)
      compared with the low metabolic heterogeneity signature. CONCLUSION: Aggressive
      cHL exhibits features of metabolic heterogeneity with high mitochondrial
      metabolism in cancer cells and high glycolysis in TAMs, which is not seen in
      reactive lymph nodes. Future studies will need to confirm the value of these
      markers as prognostic and predictive biomarkers in clinical practice. Treatment
      intensity may be tailored in the future to the metabolic profile of the tumor
      microenvironment and drugs that target metabolic heterogeneity may be valuable in
      this disease.
CI  - Copyright (c) 2017 Elsevier Inc. All rights reserved.
FAU - Mikkilineni, Lekha
AU  - Mikkilineni L
AD  - Department of Medical Oncology, National Cancer Institute, Bethesda, MD.
FAU - Whitaker-Menezes, Diana
AU  - Whitaker-Menezes D
AD  - Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA.
FAU - Domingo-Vidal, Marina
AU  - Domingo-Vidal M
AD  - Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA.
FAU - Sprandio, John
AU  - Sprandio J
AD  - Department of Medical Oncology, Chester County Memorial Hospital, West Chester,
      PA.
FAU - Avena, Paola
AU  - Avena P
AD  - Department of Pharmacy and Health and Nutritional Sciences, University of
      Calabria, Calabria, Italy.
FAU - Cotzia, Paolo
AU  - Cotzia P
AD  - Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY.
FAU - Dulau-Florea, Alina
AU  - Dulau-Florea A
AD  - Department of Pathology, National Institutes of Health, Bethesda, MD.
FAU - Gong, Jerald
AU  - Gong J
AD  - Department of Pathology, Thomas Jefferson University, Philadelphia, PA.
FAU - Uppal, Guldeep
AU  - Uppal G
AD  - Department of Pathology, Thomas Jefferson University, Philadelphia, PA.
FAU - Zhan, Tingting
AU  - Zhan T
AD  - Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson
      University, Philadelphia, PA.
FAU - Leiby, Benjamin
AU  - Leiby B
AD  - Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson
      University, Philadelphia, PA.
FAU - Lin, Zhao
AU  - Lin Z
AD  - Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA.
FAU - Pro, Barbara
AU  - Pro B
AD  - Division of Medical Oncology, Northwestern University, Evanston, IL.
FAU - Sotgia, Federica
AU  - Sotgia F
AD  - School of Environment and Life Sciences, University of Salford, Salford, UK.
FAU - Lisanti, Michael P
AU  - Lisanti MP
AD  - School of Environment and Life Sciences, University of Salford, Salford, UK.
FAU - Martinez-Outschoorn, Ubaldo
AU  - Martinez-Outschoorn U
AD  - Department of Medical Oncology, 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)
RN  - 11056-06-7 (Bleomycin)
RN  - 5V9KLZ54CY (Vinblastine)
RN  - 7GR28W0FJI (Dacarbazine)
RN  - 80168379AG (Doxorubicin)
SB  - IM
MH  - Adult
MH  - Antineoplastic Combined Chemotherapy Protocols/therapeutic use
MH  - Bleomycin/administration & dosage
MH  - Case-Control Studies
MH  - Dacarbazine/administration & dosage
MH  - Doxorubicin/administration & dosage
MH  - Female
MH  - *Glycolysis
MH  - Hodgkin Disease/drug therapy/*metabolism
MH  - Humans
MH  - Immunohistochemistry
MH  - Lymphocytes, Tumor-Infiltrating/metabolism
MH  - Macrophages/metabolism
MH  - Male
MH  - Membrane Transport Proteins/*metabolism
MH  - Middle Aged
MH  - Mitochondria/*metabolism
MH  - Monocarboxylic Acid Transporters/*metabolism
MH  - Muscle Proteins/metabolism
MH  - Neoplasm Recurrence, Local/*metabolism
MH  - *Oxidative Phosphorylation
MH  - Receptors, Cell Surface/*metabolism
MH  - Reed-Sternberg Cells/*metabolism
MH  - Remission Induction
MH  - Symporters/*metabolism
MH  - *Tumor Microenvironment
MH  - Vinblastine/administration & dosage
PMC - PMC5737784
MID - NIHMS912400
OTO - NOTNLM
OT  - Hodgkin lymphoma
OT  - glycolysis
OT  - ketone bodies
OT  - lactate
OT  - mitochondria
OT  - oxidative phosphorylation
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)30134-3 [pii]
AID - 10.1053/j.seminoncol.2017.10.003 [doi]
PST - ppublish
SO  - Semin Oncol. 2017 Jun;44(3):218-225. doi: 10.1053/j.seminoncol.2017.10.003. Epub 
      2017 Oct 10.