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1Division of Endocrinology and Metabolism, Department of Internal Medicine, Chungnam National University Hospital, Daejeon, Korea
2Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon, Korea
3Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea
Copyright © 2024 Korean Endocrine Society
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
CONFLICTS OF INTEREST
No potential conflict of interest relevant to this article was reported.
Components of TME | Metabolic changes | Reference |
---|---|---|
Cancer-associated fibroblasts (CAFs) | Protein expression of TOMM20 was high in PTC, but low in CAFs | |
Protein expression of MCT4 was high in CAFs in advanced PTC | [84] | |
Quiescent fibroblasts treated with ATC cell-secreted factors | ||
→ Src/Akt pathway activation, as well as increased CAF markers (PDGFR-β and α-SMA) and GLUT1 expression | ||
FTC cell line treated with CAF-secreted factors | ||
→ Increased proliferation, invasiveness, and induction of epithelial-to-mesenchymal transition | [87] | |
Natural killer (NK) cells | Kynurenine enters into NK cells via AhR | |
→ STAT1 and STAT3 pathway activation | ||
→ NKG2D and NKp46 receptor expression ↓ | [99] | |
PGE2 binds to EP2 and EP4 receptors on NK cells | ||
→ MAPK/ERK and NF-κB pathway inhibition | ||
→ NK activating receptors↓ and NK inhibitory receptors↑ | ||
→ Decreased cytotoxicity and IFN-γ production | [100] | |
Tumor-associated macrophages (TAMs) | Lactate activates the lactate receptor GPR81 on TAMs | |
→ AKT1/mTOR pathway activation | ||
→ Aerobic glycolysis ↑ (PFKFB3, PKM2 ↑) | ||
→ Long-term epigenetic histone modification (H3K4me3) and upregulation of cytokine production | [102] | |
Upregulation of fatty acid synthesis and enrichment of phospholipids and sphingomyelins in TAM | ||
Upregulation of glycolysis | ||
Release of M1-like cytokines (TNF-α, IL-6) ↑ and M2-like cytokine (IL-10) ↑ with increased ROS production | [103] | |
TAMs were positive for GLUT1 and NOX2, part of the NADPH oxidase complex for ROS production | [104] |
TME, tumor microenvironment; TOMM20, translocase of outer mitochondrial membrane 20; PTC, papillary thyroid cancer; MCT4, monocarboxylate transporter 4; ATC, anaplastic thyroid cancer; PDGFR-β, platelet-derived growth factor receptor-β; α-SMA, α-smooth muscle actin; GLUT1, glucose transporter 1; FTC, follicular thyroid cancer; AhR, aryl hydrocarbon receptor; STAT, signal transducer and activator of transcription; NKG2D, natural killer group 2, member D; NKp46, natural killer cell p46-related protein; PGE2, prostaglandin E2; EP, prostaglandin E2 receptor; MAPK, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinase; NF-κB, nuclear factor κB; IFN-γ, interferon-γ; GPR81, G-protein-coupled receptor 81; mTOR, mammalian target of rapamycin; PFKFB3, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3; PKM2, pyruvate kinase M2; TNF-α, tumor necrosis factor-α; IL, interleukin; ROS, reactive oxygen species; NOX2, nicotinamide adenine dinucleotide phosphate oxidase 2; NADPH, nicotinamide adenine dinucleotide phosphate.
Target metabolic pathway | Metabolic inhibitors | Drugs | Preclinical data | Clinical data |
---|---|---|---|---|
Glycolysis | HK2 inhibitor | 2-DG | PTC, with doxorubicin or sorafenib [128] | |
PTC and FTC, with metformin [129] | ||||
ATC [75] | ||||
3-BP | ATC [130] | |||
PDTC [131] | ||||
Oxidative phosphorylation | OXPHOS inhibitor | Metformin | PTC [116-123] | DTC, with RAI (NCT03109847) |
- Biguanides | PTC, with etoposide and epirubicin [132] | |||
FTC [124] | ||||
ATC [125] | ||||
ATC, with pioglitazone [133] | ||||
ATC, with doxorubicin and cisplatin [134] | ||||
ATC, with vemurafenib [135,136] | ||||
ATC, with sorafenib [137] | ||||
ATC, MTC, and FTC [138] | ||||
Phenformin | PTC and PDTC [126] | |||
Glutaminolysis | Glutaminase inhibitor | BPTES | PTC [127,139] | |
CB-839 | PTC [127,140] |
HK2, hexokinase 2; 2-DG, 2-deoxyglucose; 3-BP, 3-bromopyruvate; PTC, papillary thyroid cancer; FTC, follicular thyroid cancer; ATC, anaplastic thyroid cancer; PDTC, poorly differentiated thyroid cancer; OXPHOS, oxidative phosphorylation; MTC, medullary thyroid cancer; DTC, differentiated thyroid cancer; RAI, radioactive iodine.
Components of TME | Metabolic changes | Reference |
---|---|---|
Cancer-associated fibroblasts (CAFs) | Protein expression of TOMM20 was high in PTC, but low in CAFs | |
Protein expression of MCT4 was high in CAFs in advanced PTC | [84] | |
Quiescent fibroblasts treated with ATC cell-secreted factors | ||
→ Src/Akt pathway activation, as well as increased CAF markers (PDGFR-β and α-SMA) and GLUT1 expression | ||
FTC cell line treated with CAF-secreted factors | ||
→ Increased proliferation, invasiveness, and induction of epithelial-to-mesenchymal transition | [87] | |
Natural killer (NK) cells | Kynurenine enters into NK cells via AhR | |
→ STAT1 and STAT3 pathway activation | ||
→ NKG2D and NKp46 receptor expression ↓ | [99] | |
PGE2 binds to EP2 and EP4 receptors on NK cells | ||
→ MAPK/ERK and NF-κB pathway inhibition | ||
→ NK activating receptors↓ and NK inhibitory receptors↑ | ||
→ Decreased cytotoxicity and IFN-γ production | [100] | |
Tumor-associated macrophages (TAMs) | Lactate activates the lactate receptor GPR81 on TAMs | |
→ AKT1/mTOR pathway activation | ||
→ Aerobic glycolysis ↑ (PFKFB3, PKM2 ↑) | ||
→ Long-term epigenetic histone modification (H3K4me3) and upregulation of cytokine production | [102] | |
Upregulation of fatty acid synthesis and enrichment of phospholipids and sphingomyelins in TAM | ||
Upregulation of glycolysis | ||
Release of M1-like cytokines (TNF-α, IL-6) ↑ and M2-like cytokine (IL-10) ↑ with increased ROS production | [103] | |
TAMs were positive for GLUT1 and NOX2, part of the NADPH oxidase complex for ROS production | [104] |
Target metabolic pathway | Metabolic inhibitors | Drugs | Preclinical data | Clinical data |
---|---|---|---|---|
Glycolysis | HK2 inhibitor | 2-DG | PTC, with doxorubicin or sorafenib [128] | |
PTC and FTC, with metformin [129] | ||||
ATC [75] | ||||
3-BP | ATC [130] | |||
PDTC [131] | ||||
Oxidative phosphorylation | OXPHOS inhibitor | Metformin | PTC [116-123] | DTC, with RAI (NCT03109847) |
- Biguanides | PTC, with etoposide and epirubicin [132] | |||
FTC [124] | ||||
ATC [125] | ||||
ATC, with pioglitazone [133] | ||||
ATC, with doxorubicin and cisplatin [134] | ||||
ATC, with vemurafenib [135,136] | ||||
ATC, with sorafenib [137] | ||||
ATC, MTC, and FTC [138] | ||||
Phenformin | PTC and PDTC [126] | |||
Glutaminolysis | Glutaminase inhibitor | BPTES | PTC [127,139] | |
CB-839 | PTC [127,140] |
TME, tumor microenvironment; TOMM20, translocase of outer mitochondrial membrane 20; PTC, papillary thyroid cancer; MCT4, monocarboxylate transporter 4; ATC, anaplastic thyroid cancer; PDGFR-β, platelet-derived growth factor receptor-β; α-SMA, α-smooth muscle actin; GLUT1, glucose transporter 1; FTC, follicular thyroid cancer; AhR, aryl hydrocarbon receptor; STAT, signal transducer and activator of transcription; NKG2D, natural killer group 2, member D; NKp46, natural killer cell p46-related protein; PGE2, prostaglandin E2; EP, prostaglandin E2 receptor; MAPK, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinase; NF-κB, nuclear factor κB; IFN-γ, interferon-γ; GPR81, G-protein-coupled receptor 81; mTOR, mammalian target of rapamycin; PFKFB3, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3; PKM2, pyruvate kinase M2; TNF-α, tumor necrosis factor-α; IL, interleukin; ROS, reactive oxygen species; NOX2, nicotinamide adenine dinucleotide phosphate oxidase 2; NADPH, nicotinamide adenine dinucleotide phosphate.
HK2, hexokinase 2; 2-DG, 2-deoxyglucose; 3-BP, 3-bromopyruvate; PTC, papillary thyroid cancer; FTC, follicular thyroid cancer; ATC, anaplastic thyroid cancer; PDTC, poorly differentiated thyroid cancer; OXPHOS, oxidative phosphorylation; MTC, medullary thyroid cancer; DTC, differentiated thyroid cancer; RAI, radioactive iodine.