TGF-β in Cancer: Metabolic Driver of the Tolerogenic Crosstalk in the Tumor Microenvironment
Abstract
Simple Summary
Abstract
1. Introduction
1.1. The Tumor Metabolic Reprogramming
1.2. Transforming Growth Factor Beta Signaling in Tumors
2. TGF-β Induced Cancer-Associated Fibroblast (CAF) Metabolic Reprogramming
2.1. CAF General Function
2.2. How Does TGF-β Directly Alter CAF Functions?
2.3. Does the TGF-β Dependent CAF Activity Shape the Tumor Metabolism?
3. TGF-β Induced Endothelial Metabolic Reprogramming
3.1. Endothelial Cell (EC) General Function
3.2. How Does TGF-β Directly Alter EC Metabolic Reprogramming?
3.3. Does the EC Activity Shape the Tumor Metabolism?
4. Immune Cells Tgfb-Induced Metabolism
4.1. How Does TGF-β Make-Up the Immune Landscape of the Tumor Microenvironment?
4.2. How Does Immune-Metabolism Shape the Tumor Microenvironment?
4.3. How Does TGF-β Influence Immune-Metabolism in the Tumor Microenvironment?
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Lau, A.N.; Vander Heiden, M.G. Metabolism in the Tumor Microenvironment. Annu. Rev. Cancer Biol. 2020, 4, 17–40. [Google Scholar] [CrossRef]
- DeBerardinis, R.J.; Chandel, N.S. We Need to Talk about the Warburg Effect. Nat. Metab. 2020, 2, 127–129. [Google Scholar] [CrossRef] [PubMed]
- Warburg, O.; Wind, F.; Negelein, E. The Metabolism of Tumors in the body. J. Gen. Physiol. 1927, 8, 519–530. [Google Scholar] [CrossRef] [PubMed]
- DeBerardinis, R.J.; Chandel, N.S. Fundamentals of Cancer Metabolism. Sci. Adv. 2016, 2, e1600200. [Google Scholar] [CrossRef]
- Tong, X.; Zhao, F.; Thompson, C.B. The Molecular Determinants of de Novo Nucleotide Biosynthesis in Cancer Cells. Curr. Opin. Genet. Dev. 2009, 19, 32–37. [Google Scholar] [CrossRef]
- Zhong, H.; De Marzo, A.M.; Laughner, E.; Lim, M.; Hilton, D.A.; Zagzag, D.; Buechler, P.; Isaacs, W.B.; Semenza, G.L.; Simons, J.W. Overexpression of Hypoxia-Inducible Factor 1alpha in Common Human Cancers and Their Metastases. Cancer Res. 1999, 59, 5830–5835. [Google Scholar]
- Dang, C.V. C-Myc Target Genes Involved in Cell Growth, Apoptosis, and Metabolism. Mol. Cell. Biol. 1999, 19, 1–11. [Google Scholar] [CrossRef]
- Li, L.; Liang, Y.; Kang, L.; Liu, Y.; Gao, S.; Chen, S.; Li, Y.; You, W.; Dong, Q.; Hong, T.; et al. Transcriptional Regulation of the Warburg Effect in Cancer by SIX1. Cancer Cell 2018, 33, 368–385.e7. [Google Scholar] [CrossRef]
- Massagué, J. TGFβ in Cancer. Cell 2008, 134, 215–230. [Google Scholar] [CrossRef]
- David, C.J.; Massagué, J. Contextual Determinants of TGFβ Action in Development, Immunity and Cancer. Nat. Rev. Mol. Cell Biol. 2018, 19, 419–435. [Google Scholar] [CrossRef]
- Travis, M.A.; Sheppard, D. TGF-β Activation and Function in Immunity. Annu. Rev. Immunol. 2014, 32, 51–82. [Google Scholar] [CrossRef] [PubMed]
- Shi, M.; Zhu, J.; Wang, R.; Chen, X.; Mi, L.; Walz, T.; Springer, T.A. Latent TGF-β Structure and Activation. Nature 2011, 474, 343–349. [Google Scholar] [CrossRef] [PubMed]
- Crawford, S.E.; Stellmach, V.; Murphy-Ullrich, J.E.; Ribeiro, S.M.F.; Lawler, J.; Hynes, R.O.; Boivin, G.P.; Bouck, N. Thrombospondin-1 Is a Major Activator of TGF-Β1 In Vivo. Cell 1998, 93, 1159–1170. [Google Scholar] [CrossRef]
- Tran, D.Q.; Andersson, J.; Wang, R.; Ramsey, H.; Unutmaz, D.; Shevach, E.M. GARP (LRRC32) Is Essential for the Surface Expression of Latent TGF-Beta on Platelets and Activated FOXP3+ Regulatory T Cells. Proc. Natl. Acad. Sci. USA 2009, 106, 13445–13450. [Google Scholar] [CrossRef]
- Qin, Y.; Garrison, B.S.; Ma, W.; Wang, R.; Jiang, A.; Li, J.; Mistry, M.; Bronson, R.T.; Santoro, D.; Franco, C.; et al. A Milieu Molecule for TGF-β Required for Microglia Function in the Nervous System. Cell 2018, 174, 156–171.e16. [Google Scholar] [CrossRef] [PubMed]
- Kobayashi, T.; Kim, H.; Liu, X.; Sugiura, H.; Kohyama, T.; Fang, Q.; Wen, F.-Q.; Abe, S.; Wang, X.; Atkinson, J.J.; et al. Matrix Metalloproteinase-9 Activates TGF-β and Stimulates Fibroblast Contraction of Collagen Gels. Am. J. Physiol. Lung Cell. Mol. Physiol. 2014, 306, L1006–L1015. [Google Scholar] [CrossRef]
- Zhu, H.J.; Sizeland, A.M. A Pivotal Role for the Transmembrane Domain in Transforming Growth Factor-Beta Receptor Activation. J. Biol. Chem. 1999, 274, 11773–11781. [Google Scholar] [CrossRef]
- López-Casillas, F.; Wrana, J.L.; Massagué, J. Betaglycan Presents Ligand to the TGFβ Signaling Receptor. Cell 1993, 73, 1435–1444. [Google Scholar] [CrossRef]
- Hata, A.; Chen, Y.-G. TGF-β Signaling from Receptors to Smads. Cold Spring Harb. Perspect. Biol. 2016, 8, a022061. [Google Scholar] [CrossRef]
- Macias, M.J.; Martin-Malpartida, P.; Massagué, J. Structural Determinants of Smad Function in TGF-β Signaling. Trends Biochem. Sci. 2015, 40, 296–308. [Google Scholar] [CrossRef]
- Zhang, Y.E. Non-Smad Pathways in TGF-β Signaling. Cell Res. 2009, 19, 128–139. [Google Scholar] [CrossRef]
- Edlund, S.; Landström, M.; Heldin, C.-H.; Aspenström, P. Transforming Growth Factor-Beta-Induced Mobilization of Actin Cytoskeleton Requires Signaling by Small GTPases Cdc42 and RhoA. Mol. Biol. Cell 2002, 13, 902–914. [Google Scholar] [CrossRef] [PubMed]
- Colak, S.; Ten Dijke, P. Targeting TGF-β Signaling in Cancer. Trends Cancer 2017, 3, 56–71. [Google Scholar] [CrossRef] [PubMed]
- Vincent, T.; Neve, E.P.A.; Johnson, J.R.; Kukalev, A.; Rojo, F.; Albanell, J.; Pietras, K.; Virtanen, I.; Philipson, L.; Leopold, P.L.; et al. A SNAIL1-SMAD3/4 Transcriptional Repressor Complex Promotes TGF-Beta Mediated Epithelial-Mesenchymal Transition. Nat. Cell Biol. 2009, 11, 943–950. [Google Scholar] [CrossRef] [PubMed]
- Lamouille, S.; Derynck, R. Cell Size and Invasion in TGF-β–Induced Epithelial to Mesenchymal Transition Is Regulated by Activation of the MTOR Pathway. J. Cell Biol. 2007, 178, 437–451. [Google Scholar] [CrossRef] [PubMed]
- Harvey, R.F.; Pöyry, T.A.A.; Stoneley, M.; Willis, A.E. Signaling from MTOR to EIF2α Mediates Cell Migration in Response to the Chemotherapeutic Doxorubicin. Sci. Signal. 2019, 12, eaaw6763. [Google Scholar] [CrossRef]
- Chiarugi, P.; Cirri, P. Metabolic Exchanges within Tumor Microenvironment. Cancer Lett. 2016, 380, 272–280. [Google Scholar] [CrossRef]
- Cirri, P.; Chiarugi, P. Cancer Associated Fibroblasts: The Dark Side of the Coin. Am. J. Cancer Res. 2011, 1, 482–497. [Google Scholar]
- Shiga, K.; Hara, M.; Nagasaki, T.; Sato, T.; Takahashi, H.; Takeyama, H. Cancer-Associated Fibroblasts: Their Characteristics and Their Roles in Tumor Growth. Cancers 2015, 7, 2443–2458. [Google Scholar] [CrossRef]
- Sahai, E.; Astsaturov, I.; Cukierman, E.; DeNardo, D.G.; Egeblad, M.; Evans, R.M.; Fearon, D.; Greten, F.R.; Hingorani, S.R.; Hunter, T.; et al. A Framework for Advancing Our Understanding of Cancer-Associated Fibroblasts. Nat. Rev. Cancer 2020, 20, 174–186. [Google Scholar] [CrossRef]
- Sugimoto, H.; Mundel, T.M.; Kieran, M.W.; Kalluri, R. Identification of Fibroblast Heterogeneity in the Tumor Microenvironment. Cancer Biol. Ther. 2006, 5, 1640–1646. [Google Scholar] [CrossRef] [PubMed]
- Sanford-Crane, H.; Abrego, J.; Sherman, M.H. Fibroblasts as Modulators of Local and Systemic Cancer Metabolism. Cancers 2019, 11, 619. [Google Scholar] [CrossRef] [PubMed]
- Kalluri, R. The Biology and Function of Fibroblasts in Cancer. Nat. Rev. Cancer 2016, 16, 582–598. [Google Scholar] [CrossRef] [PubMed]
- Nathan, S.S.; Huvos, A.G.; Casas-Ganem, J.E.; Yang, R.; Linkov, I.; Sowers, R.; DiResta, G.R.; Gorlick, R.; Healey, J.H. Tumor Interstitial Fluid Pressure May Regulate Angiogenic Factors in Osteosarcoma. J. Orthop. Res. 2008, 26, 1520–1525. [Google Scholar] [CrossRef]
- Malik, R.; Lelkes, P.I.; Cukierman, E. Biomechanical and Biochemical Remodeling of Stromal Extracellular Matrix in Cancer. Trends Biotechnol. 2015, 33, 230–236. [Google Scholar] [CrossRef]
- Ulrich, T.A.; de Juan Pardo, E.M.; Kumar, S. The Mechanical Rigidity of the Extracellular Matrix Regulates the Structure, Motility, and Proliferation of Glioma Cells. Cancer Res. 2009, 69, 4167–4174. [Google Scholar] [CrossRef]
- Monteran, L.; Erez, N. The Dark Side of Fibroblasts: Cancer-Associated Fibroblasts as Mediators of Immunosuppression in the Tumor Microenvironment. Front. Immunol. 2019, 10, 1835. [Google Scholar] [CrossRef]
- Catalano, V.; Turdo, A.; Di Franco, S.; Dieli, F.; Todaro, M.; Stassi, G. Tumor and Its Microenvironment: A Synergistic Interplay. Semin. Cancer Biol. 2013, 23, 522–532. [Google Scholar] [CrossRef]
- Yoon, Y.-S.; Lee, J.-H.; Hwang, S.-C.; Choi, K.S.; Yoon, G. TGF Beta1 Induces Prolonged Mitochondrial ROS Generation through Decreased Complex IV Activity with Senescent Arrest in Mv1Lu Cells. Oncogene 2005, 24, 1895–1903. [Google Scholar] [CrossRef]
- Byun, H.-O.; Jung, H.-J.; Seo, Y.-H.; Lee, Y.-K.; Hwang, S.-C.; Hwang, E.S.; Yoon, G. GSK3 Inactivation Is Involved in Mitochondrial Complex IV Defect in Transforming Growth Factor (TGF) Β1-Induced Senescence. Exp. Cell Res. 2012, 318, 1808–1819. [Google Scholar] [CrossRef]
- Michaeloudes, C.; Sukkar, M.B.; Khorasani, N.M.; Bhavsar, P.K.; Chung, K.F. TGF-β Regulates Nox4, MnSOD and Catalase Expression, and IL-6 Release in Airway Smooth Muscle Cells. Am. J. Physiol. Lung Cell. Mol. Physiol. 2010, 300, L295–L304. [Google Scholar] [CrossRef] [PubMed]
- Liu, R.-M.; Vayalil, P.K.; Ballinger, C.; Dickinson, D.A.; Huang, W.-T.; Wang, S.; Kavanagh, T.J.; Matthews, Q.L.; Postlethwait, E.M. Transforming Growth Factor β Suppresses Glutamate-Cysteine Ligase Gene Expression and Induces Oxidative Stress in A Lung Fibrosis Model. Free Radic. Biol. Med. 2012, 53, 554–563. [Google Scholar] [CrossRef] [PubMed]
- Hecker, L.; Logsdon, N.J.; Kurundkar, D.; Kurundkar, A.; Bernard, K.; Hock, T.; Meldrum, E.; Sanders, Y.Y.; Thannickal, V.J. Reversal of Persistent Fibrosis in Aging by Targeting Nox4-Nrf2 Redox Imbalance. Sci. Transl. Med. 2014, 6, 231ra47. [Google Scholar] [CrossRef] [PubMed]
- Avagliano, A.; Granato, G.; Ruocco, M.R.; Romano, V.; Belviso, I.; Carfora, A.; Montagnani, S.; Arcucci, A. Metabolic Reprogramming of Cancer Associated Fibroblasts: The Slavery of Stromal Fibroblasts. BioMed Res. Int. 2018, 2018, 6075403. [Google Scholar] [CrossRef]
- Martinez-Outschoorn, U.E.; Pavlides, S.; Whitaker-Menezes, D.; Daumer, K.M.; Milliman, J.N.; Chiavarina, B.; Migneco, G.; Witkiewicz, A.K.; Martinez-Cantarin, M.P.; Flomenberg, N.; et al. Tumor Cells Induce the Cancer Associated Fibroblast Phenotype via Caveolin-1 Degradation: Implications for Breast Cancer and DCIS Therapy with Autophagy Inhibitors. Cell Cycle 2010, 9, 2423–2433. [Google Scholar] [CrossRef]
- Hou, X.; Zhang, J.; Wang, Y.; Xiong, W.; Mi, J. TGFBR-IDH1-Cav1 Axis Promotes TGF-β Signalling in Cancer-Associated Fibroblast. Oncotarget 2017, 8, 83962–83974. [Google Scholar] [CrossRef]
- Sotgia, F.; Martinez-Outschoorn, U.E.; Howell, A.; Pestell, R.G.; Pavlides, S.; Lisanti, M.P. Caveolin-1 and Cancer Metabolism in the Tumor Microenvironment: Markers, Models, and Mechanisms. Annu. Rev. Pathol. 2012, 7, 423–467. [Google Scholar] [CrossRef]
- Shiroto, T.; Romero, N.; Sugiyama, T.; Sartoretto, J.L.; Kalwa, H.; Yan, Z.; Shimokawa, H.; Michel, T. Caveolin-1 Is A Critical Determinant of Autophagy, Metabolic Switching, and Oxidative Stress in Vascular Endothelium. PLoS ONE 2014, 9, e87871. [Google Scholar] [CrossRef]
- Martinez-Outschoorn, U.E.; Balliet, R.M.; Rivadeneira, D.; Chiavarina, B.; Pavlides, S.; Wang, C.; Whitaker-Menezes, D.; Daumer, K.; Lin, Z.; Witkiewicz, A.; et al. Oxidative Stress in Cancer Associated Fibroblasts Drives Tumor-Stroma Co-Evolution. Cell Cycle 2010, 9, 3276–3296. [Google Scholar] [CrossRef]
- Trimmer, C.; Sotgia, F.; Whitaker-Menezes, D.; Balliet, R.M.; Eaton, G.; Martinez-Outschoorn, U.E.; Pavlides, S.; Howell, A.; Iozzo, R.V.; Pestell, R.G.; et al. Caveolin-1 and Mitochondrial SOD2 (MnSOD) Function as Tumor Suppressors in the Stromal Microenvironment: A New Genetically Tractable Model for Human Cancer Associated Fibroblasts. Cancer Biol. Ther. 2011, 11, 383–394. [Google Scholar] [CrossRef]
- Jezierska-Drutel, A.; Rosenzweig, S.A.; Neumann, C.A. Role of Oxidative Stress and the Microenvironment in Breast Cancer Development and Progression. Adv. Cancer Res. 2013, 119, 107–125. [Google Scholar] [PubMed]
- Calon, A.; Tauriello, D.V.F.; Batlle, E. TGF-Beta in CAF-Mediated Tumor Growth and Metastasis. Semin. Cancer Biol. 2014, 25, 15–22. [Google Scholar] [CrossRef] [PubMed]
- Capparelli, C.; Guido, C.; Whitaker-Menezes, D.; Bonuccelli, G.; Balliet, R.; Pestell, T.G.; Goldberg, A.F.; Pestell, R.G.; Howell, A.; Sneddon, S.; et al. Autophagy and Senescence in Cancer-Associated Fibroblasts Metabolically Supports Tumor Growth and Metastasis via Glycolysis and Ketone Production. Cell Cycle 2012, 11, 2285–2302. [Google Scholar] [CrossRef] [PubMed]
- Taddei, M.L.; Cavallini, L.; Comito, G.; Giannoni, E.; Folini, M.; Marini, A.; Gandellini, P.; Morandi, A.; Pintus, G.; Raspollini, M.R.; et al. Senescent Stroma Promotes Prostate Cancer Progression: The Role of MiR-210. Mol. Oncol. 2014, 8, 1729–1746. [Google Scholar] [CrossRef] [PubMed]
- Coppé, J.-P.; Desprez, P.-Y.; Krtolica, A.; Campisi, J. The Senescence-Associated Secretory Phenotype: The Dark Side of Tumor Suppression. Annu. Rev. Pathol. 2010, 5, 99–118. [Google Scholar] [CrossRef] [PubMed]
- Lee, S.; Schmitt, C.A. The Dynamic Nature of Senescence in Cancer. Nat. Cell Biol. 2019, 21, 94–101. [Google Scholar] [CrossRef] [PubMed]
- Martinez-Outschoorn, U.E.; Pavlides, S.; Howell, A.; Pestell, R.G.; Tanowitz, H.B.; Sotgia, F.; Lisanti, M.P. Stromal–Epithelial Metabolic Coupling in Cancer: Integrating Autophagy and Metabolism in the Tumor Microenvironment. Int. J. Biochem. Cell Biol. 2011, 43, 1045–1051. [Google Scholar] [CrossRef]
- Fu, Y.; Liu, S.; Yin, S.; Niu, W.; Xiong, W.; Tan, M.; Li, G.; Zhou, M. The Reverse Warburg Effect Is Likely to Be an Achilles’ Heel of Cancer That Can Be Exploited for Cancer Therapy. Oncotarget 2017, 8, 57813–57825. [Google Scholar] [CrossRef]
- Contreras-Baeza, Y.; Sandoval, P.Y.; Alarcón, R.; Galaz, A.; Cortés-Molina, F.; Alegría, K.; Baeza-Lehnert, F.; Arce-Molina, R.; Guequén, A.; Flores, C.A.; et al. Monocarboxylate Transporter 4 (MCT4) Is a High Affinity Transporter Capable of Exporting Lactate in High-Lactate Microenvironments. J. Biol. Chem. 2019, 294, 20135–20147. [Google Scholar] [CrossRef]
- Apicella, M.; Giannoni, E.; Fiore, S.; Ferrari, K.J.; Fernández-Pérez, D.; Isella, C.; Granchi, C.; Minutolo, F.; Sottile, A.; Comoglio, P.M.; et al. Increased Lactate Secretion by Cancer Cells Sustains Non-Cell-Autonomous Adaptive Resistance to MET and EGFR Targeted Therapies. Cell Metab. 2018, 28, 848–865.e6. [Google Scholar] [CrossRef]
- Becker, L.M.; O’Connell, J.T.; Vo, A.P.; Cain, M.P.; Tampe, D.; Bizarro, L.; Sugimoto, H.; McGow, A.K.; Asara, J.M.; Lovisa, S.; et al. Epigenetic Reprogramming of Cancer-Associated Fibroblasts Deregulates Glucose Metabolism and Facilitates Progression of Breast Cancer. Cell Rep. 2020, 31, 107701. [Google Scholar] [CrossRef] [PubMed]
- Martinez-Outschoorn, U.E.; Lin, Z.; Whitaker-Menezes, D.; Howell, A.; Lisanti, M.P.; Sotgia, F. Ketone Bodies and Two-Compartment Tumor Metabolism: Stromal Ketone Production Fuels Mitochondrial Biogenesis in Epithelial Cancer Cells. Cell Cycle 2012, 11, 3956–3963. [Google Scholar] [CrossRef] [PubMed]
- Yang, L.; Achreja, A.; Yeung, T.-L.; Mangala, L.S.; Jiang, D.; Han, C.; Baddour, J.; Marini, J.C.; Ni, J.; Nakahara, R.; et al. Targeting Stromal Glutamine Synthetase in Tumors Disrupts Tumor Microenvironment-Regulated Cancer Cell Growth. Cell Metab. 2016, 24, 685–700. [Google Scholar] [CrossRef] [PubMed]
- LaGory, E.L.; Giaccia, A.J. The Ever Expanding Role of HIF in Tumour and Stromal Biology. Nat. Cell Biol. 2016, 18, 356–365. [Google Scholar] [CrossRef] [PubMed]
- Carmeliet, P.; Jain, R.K. Molecular Mechanisms and Clinical Applications of Angiogenesis. Nature 2011, 473, 298–307. [Google Scholar] [CrossRef] [PubMed]
- Dumas, S.J.; García-Caballero, M.; Carmeliet, P. Metabolic Signatures of Distinct Endothelial Phenotypes. Trends Endocrinol. Metab. 2020, 31, 580–595. [Google Scholar] [CrossRef]
- Betz, C.; Lenard, A.; Belting, H.-G.; Affolter, M. Cell Behaviors and Dynamics during Angiogenesis. Development 2016, 143, 2249–2260. [Google Scholar] [CrossRef]
- Mazzone, M.; Dettori, D.; de Oliveira, R.L.; Loges, S.; Schmidt, T.; Jonckx, B.; Tian, Y.-M.; Lanahan, A.A.; Pollard, P.; de Almodovar, C.R.; et al. Heterozygous Deficiency of PHD2 Restores Tumor Oxygenation and Inhibits Metastasis via Endothelial Normalization. Cell 2009, 136, 839–851. [Google Scholar] [CrossRef]
- Lugano, R.; Ramachandran, M.; Dimberg, A. Tumor Angiogenesis: Causes, Consequences, Challenges and Opportunities. Cell. Mol. Life Sci. 2020, 77, 1745–1770. [Google Scholar] [CrossRef]
- Hanahan, D.; Weinberg, R.A. Hallmarks of Cancer: The Next Generation. Cell 2011, 144, 646–674. [Google Scholar] [CrossRef]
- Bennewith, K.L.; Durand, R.E. Quantifying Transient Hypoxia in Human Tumor Xenografts by Flow Cytometry. Cancer Res. 2004, 64, 6183–6189. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Petrova, V.; Annicchiarico-Petruzzelli, M.; Melino, G.; Amelio, I. The Hypoxic Tumour Microenvironment. Oncogenesis 2018, 7, 1–13. [Google Scholar] [CrossRef] [PubMed]
- Zheng, J. Energy Metabolism of Cancer: Glycolysis versus Oxidative Phosphorylation (Review). Oncol. Lett. 2012, 4, 1151–1157. [Google Scholar] [CrossRef] [PubMed]
- Zecchin, A.; Kalucka, J.; Dubois, C.; Carmeliet, P. How Endothelial Cells Adapt Their Metabolism to Form Vessels in Tumors. Front. Immunol. 2017, 8, 1750. [Google Scholar] [CrossRef]
- Glatz, J.F.C.; Luiken, J.J.F.P.; Bonen, A. Membrane Fatty Acid Transporters as Regulators of Lipid Metabolism: Implications for Metabolic Disease. Physiol. Rev. 2010, 90, 367–417. [Google Scholar] [CrossRef]
- Draoui, N.; de Zeeuw, P.; Carmeliet, P. Angiogenesis Revisited from a Metabolic Perspective: Role and Therapeutic Implications of Endothelial Cell Metabolism. Open Biol. 2017, 7, 170219. [Google Scholar] [CrossRef]
- Coomans de Brachène, A.; Demoulin, J.-B. FOXO Transcription Factors in Cancer Development and Therapy. Cell. Mol. Life Sci. 2016, 73, 1159–1172. [Google Scholar] [CrossRef]
- Wilhelm, K.; Happel, K.; Eelen, G.; Schoors, S.; Oellerich, M.F.; Lim, R.; Zimmermann, B.; Aspalter, I.M.; Franco, C.A.; Boettger, T.; et al. FOXO1 Couples Metabolic Activity and Growth State in the Vascular Endothelium. Nature 2016, 529, 216–220. [Google Scholar] [CrossRef]
- Ning, J.; Zhao, Y.; Ye, Y.; Yu, J. Opposing Roles and Potential Antagonistic Mechanism between TGF-β and BMP Pathways: Implications for Cancer Progression. EBioMedicine 2019, 41, 702–710. [Google Scholar] [CrossRef]
- Ghajar, C.M.; Peinado, H.; Mori, H.; Matei, I.R.; Evason, K.J.; Brazier, H.; Almeida, D.; Koller, A.; Hajjar, K.A.; Stainier, D.Y.R.; et al. The Perivascular Niche Regulates Breast Tumor Dormancy. Nat. Cell Biol. 2013, 15, 807–817. [Google Scholar] [CrossRef]
- Prunier, C.; Baker, D.; ten Dijke, P.; Ritsma, L. TGF-β Family Signaling Pathways in Cellular Dormancy. Trends Cancer 2019, 5, 66–78. [Google Scholar] [CrossRef] [PubMed]
- Clere, N.; Renault, S.; Corre, I. Endothelial-to-Mesenchymal Transition in Cancer. Front. Cell Dev. Biol. 2020, 8. [Google Scholar] [CrossRef] [PubMed]
- Ma, J.; Sanchez-Duffhues, G.; Goumans, M.-J.; ten Dijke, P. TGF-β-Induced Endothelial to Mesenchymal Transition in Disease and Tissue Engineering. Front. Cell Dev. Biol. 2020, 8, 260. [Google Scholar] [CrossRef] [PubMed]
- Piera-Velazquez, S.; Jimenez, S.A. Endothelial to Mesenchymal Transition: Role in Physiology and in the Pathogenesis of Human Diseases. Physiol. Rev. 2019, 99, 1281–1324. [Google Scholar] [CrossRef] [PubMed]
- Medici, D.; Potenta, S.; Kalluri, R. Transforming Growth Factor-Β2 Promotes Snail-Mediated Endothelial–Mesenchymal Transition through Convergence of Smad-Dependent and Smad-Independent Signalling. Biochem. J. 2011, 437, 515–520. [Google Scholar] [CrossRef] [PubMed]
- Kokudo, T.; Suzuki, Y.; Yoshimatsu, Y.; Yamazaki, T.; Watabe, T.; Miyazono, K. Snail Is Required for TGFβ-Induced Endothelial-Mesenchymal Transition of Embryonic Stem Cell-Derived Endothelial Cells. J. Cell Sci. 2008, 121, 3317–3324. [Google Scholar] [CrossRef]
- Mammoto, T.; Muyleart, M.; Konduri, G.G.; Mammoto, A. Twist1 in Hypoxia-Induced Pulmonary Hypertension through Transforming Growth Factor-β–Smad Signaling. Am. J. Respir. Cell Mol. Biol. 2017, 58, 194–207. [Google Scholar] [CrossRef]
- Xiong, J.; Kawagishi, H.; Yan, Y.; Liu, J.; Wells, Q.S.; Edmunds, L.R.; Fergusson, M.M.; Yu, Z.-X.; Rovira, I.I.; Brittain, E.L.; et al. A Metabolic Basis for Endothelial-to-Mesenchymal Transition. Mol. Cell 2018, 69, 689–698.e7. [Google Scholar] [CrossRef]
- Cho, J.G.; Lee, A.; Chang, W.; Lee, M.-S.; Kim, J. Endothelial to Mesenchymal Transition Represents a Key Link in the Interaction between Inflammation and Endothelial Dysfunction. Front. Immunol. 2018, 9, 294. [Google Scholar] [CrossRef]
- Verdegem, D.; Moens, S.; Stapor, P.; Carmeliet, P. Endothelial Cell Metabolism: Parallels and Divergences with Cancer Cell Metabolism. Cancer Metab. 2014, 2, 19. [Google Scholar] [CrossRef]
- Cantelmo, A.R.; Conradi, L.-C.; Brajic, A.; Goveia, J.; Kalucka, J.; Pircher, A.; Chaturvedi, P.; Hol, J.; Thienpont, B.; Teuwen, L.-A.; et al. Inhibition of the Glycolytic Activator PFKFB3 in Endothelium Induces Tumor Vessel Normalization, Impairs Metastasis, and Improves Chemotherapy. Cancer Cell 2016, 30, 968–985. [Google Scholar] [CrossRef] [PubMed]
- Wong, B.W.; Marsch, E.; Treps, L.; Baes, M.; Carmeliet, P. Endothelial Cell Metabolism in Health and Disease: Impact of Hypoxia. EMBO J. 2017, 36, 2187–2203. [Google Scholar] [CrossRef] [PubMed]
- Végran, F.; Boidot, R.; Michiels, C.; Sonveaux, P.; Feron, O. Lactate Influx through the Endothelial Cell Monocarboxylate Transporter MCT1 Supports an NF-ΚB/IL-8 Pathway That Drives Tumor Angiogenesis. Cancer Res. 2011, 71, 2550–2560. [Google Scholar] [CrossRef] [PubMed]
- Ruan, G.-X.; Kazlauskas, A. Lactate Engages Receptor Tyrosine Kinases Axl, Tie2, and Vascular Endothelial Growth Factor Receptor 2 to Activate Phosphoinositide 3-Kinase/Akt and Promote Angiogenesis. J. Biol. Chem. 2013, 288, 21161–21172. [Google Scholar] [CrossRef] [PubMed]
- Lee, D.C.; Sohn, H.A.; Park, Z.-Y.; Oh, S.; Kang, Y.K.; Lee, K.-M.; Kang, M.; Jang, Y.J.; Yang, S.-J.; Hong, Y.K.; et al. A Lactate-Induced Response to Hypoxia. Cell 2015, 161, 595–609. [Google Scholar] [CrossRef]
- Wenes, M.; Shang, M.; Di Matteo, M.; Goveia, J.; Martín-Pérez, R.; Serneels, J.; Prenen, H.; Ghesquière, B.; Carmeliet, P.; Mazzone, M. Macrophage Metabolism Controls Tumor Blood Vessel Morphogenesis and Metastasis. Cell Metab. 2016, 24, 701–715. [Google Scholar] [CrossRef]
- Marcuzzi, E.; Angioni, R.; Molon, B.; Calì, B. Chemokines and Chemokine Receptors: Orchestrating Tumor Metastasization. Int. J. Mol. Sci. 2018, 20, 96. [Google Scholar] [CrossRef]
- Chow, M.T.; Luster, A.D. Chemokines in Cancer. Cancer Immunol. Res. 2014, 2, 1125–1131. [Google Scholar] [CrossRef]
- Dranoff, G. Cytokines in Cancer Pathogenesis and Cancer Therapy. Nat. Rev. Cancer 2004, 4, 11–22. [Google Scholar] [CrossRef]
- Nagarsheth, N.; Wicha, M.S.; Zou, W. Chemokines in the Cancer Microenvironment and Their Relevance in Cancer Immunotherapy. Nat. Rev. Immunol. 2017, 17, 559–572. [Google Scholar] [CrossRef]
- Mollica Poeta, V.; Massara, M.; Capucetti, A.; Bonecchi, R. Chemokines and Chemokine Receptors: New Targets for Cancer Immunotherapy. Front. Immunol. 2019, 10, 379. [Google Scholar] [CrossRef] [PubMed]
- Flavell, R.A.; Sanjabi, S.; Wrzesinski, S.H.; Licona-Limón, P. The Polarization of Immune Cells in the Tumour Environment by TGFbeta. Nat. Rev. Immunol. 2010, 10, 554–567. [Google Scholar] [CrossRef] [PubMed]
- Sanjabi, S.; Oh, S.A.; Li, M.O. Regulation of the Immune Response by TGF-β: From Conception to Autoimmunity and Infection. Cold Spring Harb. Perspect. Biol. 2017, 9, a022236. [Google Scholar] [CrossRef] [PubMed]
- Calon, A.; Lonardo, E.; Berenguer-Llergo, A.; Espinet, E.; Hernando-Momblona, X.; Iglesias, M.; Sevillano, M.; Palomo-Ponce, S.; Tauriello, D.V.F.; Byrom, D.; et al. Stromal Gene Expression Defines Poor-Prognosis Subtypes in Colorectal Cancer. Nat. Genet. 2015, 47, 320–329. [Google Scholar] [CrossRef]
- Li, J.; Shen, C.; Wang, X.; Lai, Y.; Zhou, K.; Li, P.; Liu, L.; Che, G. Prognostic Value of TGF-β in Lung Cancer: Systematic Review and Meta-Analysis. BMC Cancer 2019, 19, 691. [Google Scholar] [CrossRef]
- De Kruijf, E.M.; Dekker, T.J.A.; Hawinkels, L.J.A.C.; Putter, H.; Smit, V.T.H.B.M.; Kroep, J.R.; Kuppen, P.J.K.; van de Velde, C.J.H.; ten Dijke, P.; Tollenaar, R.A.E.M.; et al. The Prognostic Role of TGF-β Signaling Pathway in Breast Cancer Patients. Ann. Oncol. 2013, 24, 384–390. [Google Scholar] [CrossRef]
- Gorelik, L.; Flavell, R.A. Immune-Mediated Eradication of Tumors through the Blockade of Transforming Growth Factor-Beta Signaling in T Cells. Nat. Med. 2001, 7, 1118–1122. [Google Scholar] [CrossRef]
- Ganesh, K.; Massagué, J. TGF-β Inhibition and Immunotherapy: Checkmate. Immunity 2018, 48, 626–628. [Google Scholar] [CrossRef]
- Thomas, D.A.; Massagué, J. TGF-β Directly Targets Cytotoxic T Cell Functions during Tumor Evasion of Immune Surveillance. Cancer Cell 2005, 8, 369–380. [Google Scholar] [CrossRef]
- Hugo, W.; Zaretsky, J.M.; Sun, L.; Song, C.; Moreno, B.H.; Hu-Lieskovan, S.; Berent-Maoz, B.; Pang, J.; Chmielowski, B.; Cherry, G.; et al. Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic Melanoma. Cell 2016, 165, 35–44. [Google Scholar] [CrossRef]
- Mariathasan, S.; Turley, S.J.; Nickles, D.; Castiglioni, A.; Yuen, K.; Wang, Y.; Kadel Iii, E.E.; Koeppen, H.; Astarita, J.L.; Cubas, R.; et al. TGFβ Attenuates Tumour Response to PD-L1 Blockade by Contributing to Exclusion of T Cells. Nature 2018, 554, 544–548. [Google Scholar] [CrossRef] [PubMed]
- Tauriello, D.V.F.; Palomo-Ponce, S.; Stork, D.; Berenguer-Llergo, A.; Badia-Ramentol, J.; Iglesias, M.; Sevillano, M.; Ibiza, S.; Cañellas, A.; Hernando-Momblona, X.; et al. TGFβ Drives Immune Evasion in Genetically Reconstituted Colon Cancer Metastasis. Nature 2018, 554, 538–543. [Google Scholar] [CrossRef] [PubMed]
- Chen, M.-L.; Pittet, M.J.; Gorelik, L.; Flavell, R.A.; Weissleder, R.; von Boehmer, H.; Khazaie, K. Regulatory T Cells Suppress Tumor-Specific CD8 T Cell Cytotoxicity through TGF-Beta Signals in Vivo. Proc. Natl. Acad. Sci. USA 2005, 102, 419–424. [Google Scholar] [CrossRef] [PubMed]
- Fantini, M.C.; Becker, C.; Monteleone, G.; Pallone, F.; Galle, P.R.; Neurath, M.F. Cutting Edge: TGF-Beta Induces A Regulatory Phenotype in CD4+CD25- T Cells through Foxp3 Induction and down-Regulation of Smad7. J. Immunol. 2004, 172, 5149–5153. [Google Scholar] [CrossRef]
- Connolly, E.C.; Freimuth, J.; Akhurst, R.J. Complexities of TGF-β Targeted Cancer Therapy. Int. J. Biol. Sci. 2012, 8, 964–978. [Google Scholar] [CrossRef] [PubMed]
- Moo-Young, T.A.; Larson, J.W.; Belt, B.A.; Tan, M.C.; Hawkins, W.G.; Eberlein, T.J.; Goedegebuure, P.S.; Linehan, D.C. Tumor-Derived TGF-Beta Mediates Conversion of CD4+Foxp3+ Regulatory T Cells in A Murine Model of Pancreas Cancer. J. Immunother. 2009, 32, 12–21. [Google Scholar] [CrossRef]
- Downs-Canner, S.; Berkey, S.; Delgoffe, G.M.; Edwards, R.P.; Curiel, T.; Odunsi, K.; Bartlett, D.L.; Obermajer, N. Suppressive IL-17A+Foxp3+ and Ex-Th17 IL-17AnegFoxp3+ Treg Cells Are A Source of Tumour-Associated Treg Cells. Nat. Commun. 2017, 8, 14649. [Google Scholar] [CrossRef]
- Oh, E.; Hong, J.; Yun, C.-O. Regulatory T Cells Induce Metastasis by Increasing Tgf-β and Enhancing the Epithelial–Mesenchymal Transition. Cells 2019, 8, 1387. [Google Scholar] [CrossRef]
- Wan, Y.Y.; Flavell, R.A. “Yin-Yang” Functions of Transforming Growth Factor-Beta and T Regulatory Cells in Immune Regulation. Immunol. Rev. 2007, 220, 199–213. [Google Scholar] [CrossRef]
- Lin, Y.; Xu, J.; Lan, H. Tumor-Associated Macrophages in Tumor Metastasis: Biological Roles and Clinical Therapeutic Applications. J. Hematol. Oncol. 2019, 12, 76. [Google Scholar] [CrossRef]
- Tsunawaki, S.; Sporn, M.; Ding, A.; Nathan, C. Deactivation of Macrophages by Transforming Growth Factor-β. Nature 1988, 334, 260–262. [Google Scholar] [CrossRef] [PubMed]
- Zhang, Q.; Yu, N.; Lee, C. Mysteries of TGF-β Paradox in Benign and Malignant Cells. Front. Oncol. 2014, 4, 94. [Google Scholar] [CrossRef] [PubMed]
- Sica, A.; Schioppa, T.; Mantovani, A.; Allavena, P. Tumour-Associated Macrophages Are A Distinct M2 Polarised Population Promoting Tumour Progression: Potential Targets of Anti-Cancer Therapy. Eur. J. Cancer 2006, 42, 717–727. [Google Scholar] [CrossRef] [PubMed]
- Bierie, B.; Moses, H.L. TGF-Beta and Cancer. Cytokine Growth Factor Rev. 2006, 17, 29–40. [Google Scholar] [CrossRef] [PubMed]
- Standiford, T.J.; Kuick, R.; Bhan, U.; Chen, J.; Newstead, M.; Keshamouni, V.G. TGF-β-Induced IRAK-M Expression in Tumor-Associated Macrophages Regulates Lung Tumor Growth. Oncogene 2011, 30, 2475–2484. [Google Scholar] [CrossRef] [PubMed]
- Wang, Z.; Yang, Y.; Cui, Y.; Wang, C.; Lai, Z.; Li, Y.; Zhang, W.; Mustonen, H.; Puolakkainen, P.; Ye, Y.; et al. Tumor-Associated Macrophages Regulate Gastric Cancer Cell Invasion and Metastasis through TGFβ2/NF-ΚB/Kindlin-2 Axis. Chin. J. Cancer Res. 2020, 32, 72–88. [Google Scholar] [CrossRef]
- Shen, J.; Li, J.; Wang, B.; Jin, H.; Wang, M.; Zhang, Y.; Yang, Y.; Im, H.-J.; O’Keefe, R.; Chen, D. Deletion of the Transforming Growth Factor β Receptor Type II Gene in Articular Chondrocytes Leads to a Progressive Osteoarthritis-like Phenotype in Mice. Arthritis Rheum. 2013, 65, 3107–3119. [Google Scholar] [CrossRef]
- Bonde, A.-K.; Tischler, V.; Kumar, S.; Soltermann, A.; Schwendener, R.A. Intratumoral Macrophages Contribute to Epithelial-Mesenchymal Transition in Solid Tumors. BMC Cancer 2012, 12, 35. [Google Scholar] [CrossRef]
- Jaillon, S.; Ponzetta, A.; Di Mitri, D.; Santoni, A.; Bonecchi, R.; Mantovani, A. Neutrophil Diversity and Plasticity in Tumour Progression and Therapy. Nat. Rev. Cancer 2020, 20, 485–503. [Google Scholar] [CrossRef]
- Allen, S.S.; Mackie, J.T.; Russell, K.; Jeevan, A.; Skwor, T.A.; McMurray, D.N. Altered Inflammatory Responses Following Transforming Growth Factor-Beta Neutralization in Experimental Guinea Pig Tuberculous Pleurisy. Tuberclosis 2008, 88, 430–436. [Google Scholar] [CrossRef]
- Fridlender, Z.G.; Sun, J.; Kim, S.; Kapoor, V.; Cheng, G.; Ling, L.; Worthen, G.S.; Albelda, S.M. Polarization of Tumor-Associated Neutrophil Phenotype by TGF-β: “N1” versus “N2” TAN. Cancer Cell 2009, 16, 183–194. [Google Scholar] [CrossRef] [PubMed]
- Qin, F.; Liu, X.; Chen, J.; Huang, S.; Wei, W.; Zou, Y.; Liu, X.; Deng, K.; Mo, S.; Chen, J.; et al. Anti-TGF-β Attenuates Tumor Growth via Polarization of Tumor Associated Neutrophils towards an Anti-Tumor Phenotype in Colorectal Cancer. J. Cancer 2020, 11, 2580–2592. [Google Scholar] [CrossRef] [PubMed]
- Germann, M.; Zangger, N.; Sauvain, M.-O.; Sempoux, C.; Bowler, A.D.; Wirapati, P.; Kandalaft, L.E.; Delorenzi, M.; Tejpar, S.; Coukos, G.; et al. Neutrophils Suppress Tumor-Infiltrating T Cells in Colon Cancer via Matrix Metalloproteinase-Mediated Activation of TGFβ. EMBO Mol. Med. 2020, 12, e10681. [Google Scholar] [CrossRef] [PubMed]
- De Sanctis, F.; Solito, S.; Ugel, S.; Molon, B.; Bronte, V.; Marigo, I. MDSCs in Cancer: Conceiving New Prognostic and Therapeutic Targets. Biochim. Biophys. Acta 2016, 1865, 35–48. [Google Scholar] [CrossRef]
- Trikha, P.; Carson, W.E. Signaling Pathways Involved in MDSC Regulation. Biochim. Biophys. Acta 2014, 1846, 55–65. [Google Scholar] [CrossRef]
- Liu, Y.; Lai, L.; Chen, Q.; Song, Y.; Xu, S.; Ma, F.; Wang, X.; Wang, J.; Yu, H.; Cao, X.; et al. MicroRNA-494 Is Required for the Accumulation and Functions of Tumor-Expanded Myeloid-Derived Suppressor Cells via Targeting of PTEN. J. Immunol. 2012, 188, 5500–5510. [Google Scholar] [CrossRef]
- Lee, C.-R.; Lee, W.; Cho, S.K.; Park, S.-G. Characterization of Multiple Cytokine Combinations and TGF-β on Differentiation and Functions of Myeloid-Derived Suppressor Cells. Int. J. Mol. Sci. 2018, 19, 869. [Google Scholar] [CrossRef]
- Li, H.; Han, Y.; Guo, Q.; Zhang, M.; Cao, X. Cancer-Expanded Myeloid-Derived Suppressor Cells Induce Anergy of NK Cells through Membrane-Bound TGF-Β1. J. Immunol. 2009, 182, 240–249. [Google Scholar] [CrossRef]
- Lechner, M.G.; Liebertz, D.J.; Epstein, A.L. Characterization of Cytokine-Induced Myeloid-Derived Suppressor Cells from Normal Human Peripheral Blood Mononuclear Cells. J. Immunol. 2010, 185, 2273–2284. [Google Scholar] [CrossRef]
- Jayaraman, P.; Parikh, F.; Newton, J.M.; Hanoteau, A.; Rivas, C.; Krupar, R.; Rajapakshe, K.; Pathak, R.; Kanthaswamy, K.; MacLaren, C.; et al. TGF-Β1 Programmed Myeloid-Derived Suppressor Cells (MDSC) Acquire Immune-Stimulating and Tumor Killing Activity Capable of Rejecting Established Tumors in Combination with Radiotherapy. OncoImmunology 2018, 7, e1490853. [Google Scholar] [CrossRef]
- Biswas, S.K.; Mantovani, A. Orchestration of Metabolism by Macrophages. Cell Metab. 2012, 15, 432–437. [Google Scholar] [CrossRef] [PubMed]
- Ghesquière, B.; Wong, B.W.; Kuchnio, A.; Carmeliet, P. Metabolism of Stromal and Immune Cells in Health and Disease. Nature 2014, 511, 167–176. [Google Scholar] [CrossRef] [PubMed]
- Pearce, E.L.; Pearce, E.J. Metabolic Pathways in Immune Cell Activation and Quiescence. Immunity 2013, 38, 633–643. [Google Scholar] [CrossRef] [PubMed]
- Siska, P.J.; Rathmell, J.C. T Cell Metabolic Fitness in Antitumor Immunity. Trends Immunol. 2015, 36, 257–264. [Google Scholar] [CrossRef]
- Molon, B.; Calì, B.; Viola, A. T Cells and Cancer: How Metabolism Shapes Immunity. Front. Immunol. 2016, 7, 20. [Google Scholar] [CrossRef]
- Brand, A.; Singer, K.; Koehl, G.E.; Kolitzus, M.; Schoenhammer, G.; Thiel, A.; Matos, C.; Bruss, C.; Klobuch, S.; Peter, K.; et al. LDHA-Associated Lactic Acid Production Blunts Tumor Immunosurveillance by T and NK Cells. Cell Metab. 2016, 24, 657–671. [Google Scholar] [CrossRef]
- Ho, P.-C.; Bihuniak, J.D.; Macintyre, A.N.; Staron, M.; Liu, X.; Amezquita, R.; Tsui, Y.-C.; Cui, G.; Micevic, G.; Perales, J.C.; et al. Phosphoenolpyruvate Is A Metabolic Checkpoint of Anti-Tumor T Cell Responses. Cell 2015, 162, 1217–1228. [Google Scholar] [CrossRef]
- Sugiura, A.; Rathmell, J.C. Metabolic Barriers to T Cell Function in Tumors. J. Immunol. 2018, 200, 400–407. [Google Scholar] [CrossRef]
- Munn, D.H.; Mellor, A.L. Indoleamine 2,3 Dioxygenase and Metabolic Control of Immune Responses. Trends Immunol. 2013, 34, 137–143. [Google Scholar] [CrossRef]
- Andrejeva, G.; Rathmell, J.C. Similarities and Distinctions of Cancer and Immune Metabolism in Inflammation and Tumors. Cell Metab. 2017, 26, 49–70. [Google Scholar] [CrossRef]
- Leone, R.D.; Zhao, L.; Englert, J.M.; Sun, I.-M.; Oh, M.-H.; Sun, I.-H.; Arwood, M.L.; Bettencourt, I.A.; Patel, C.H.; Wen, J.; et al. Glutamine Blockade Induces Divergent Metabolic Programs to Overcome Tumor Immune Evasion. Science 2019, 366, 1013–1021. [Google Scholar] [CrossRef] [PubMed]
- Dimeloe, S.; Gubser, P.; Loeliger, J.; Frick, C.; Develioglu, L.; Fischer, M.; Marquardsen, F.; Bantug, G.R.; Thommen, D.; Lecoultre, Y.; et al. Tumor-Derived TGF-β Inhibits Mitochondrial Respiration to Suppress IFN-γ Production by Human CD4+ T Cells. Sci. Signal. 2019, 12, eaav3334. [Google Scholar] [CrossRef] [PubMed]
- Priyadharshini, B.; Loschi, M.; Newton, R.H.; Zhang, J.-W.; Finn, K.K.; Gerriets, V.A.; Huynh, A.; Rathmell, J.C.; Blazar, B.R.; Turka, L.A. Cutting Edge: TGF-β and Phosphatidylinositol 3-Kinase Signals Modulate Distinct Metabolism of Regulatory T Cell Subsets. J. Immunol. 2018, 201, 2215–2219. [Google Scholar] [CrossRef] [PubMed]
- Zaiatz-Bittencourt, V.; Finlay, D.K.; Gardiner, C.M. Canonical TGF-β Signaling Pathway Represses Human NK Cell Metabolism. J. Immunol. 2018, 200, 3934–3941. [Google Scholar] [CrossRef]
- Viel, S.; Marçais, A.; Guimaraes, F.S.-F.; Loftus, R.; Rabilloud, J.; Grau, M.; Degouve, S.; Djebali, S.; Sanlaville, A.; Charrier, E.; et al. TGF-β Inhibits the Activation and Functions of NK Cells by Repressing the MTOR Pathway. Sci. Signal. 2016, 9, ra19. [Google Scholar] [CrossRef]
- Castriconi, R.; Cantoni, C.; Della Chiesa, M.; Vitale, M.; Marcenaro, E.; Conte, R.; Biassoni, R.; Bottino, C.; Moretta, L.; Moretta, A. Transforming Growth Factor Beta 1 Inhibits Expression of NKp30 and NKG2D Receptors: Consequences for the NK-Mediated Killing of Dendritic Cells. Proc. Natl. Acad. Sci. USA 2003, 100, 4120–4125. [Google Scholar] [CrossRef]
- Lee, J.-C.; Lee, K.-M.; Kim, D.-W.; Heo, D.S. Elevated TGF-Beta1 Secretion and down-Modulation of NKG2D Underlies Impaired NK Cytotoxicity in Cancer Patients. J. Immunol. 2004, 172, 7335–7340. [Google Scholar] [CrossRef]
- Van Belle, T.L.; von Herrath, M.G. The Role of the Activating Receptor NKG2D in Autoimmunity. Mol. Immunol. 2009, 47, 8–11. [Google Scholar] [CrossRef]
- Espinoza, J.L.; Takami, A.; Yoshioka, K.; Nakata, K.; Sato, T.; Kasahara, Y.; Nakao, S. Human MicroRNA-1245 down-Regulates the NKG2D Receptor in Natural Killer Cells and Impairs NKG2D-Mediated Functions. Haematologica 2012, 97, 1295–1303. [Google Scholar] [CrossRef]
- Lin, S.; Sun, L.; Lyu, X.; Ai, X.; Du, D.; Su, N.; Li, H.; Zhang, L.; Yu, J.; Yuan, S. Lactate-Activated Macrophages Induced Aerobic Glycolysis and Epithelial-Mesenchymal Transition in Breast Cancer by Regulation of CCL5-CCR5 Axis: A Positive Metabolic Feedback Loop. Oncotarget 2017, 8, 110426–110443. [Google Scholar] [CrossRef]
- Gómez, V.; Eykyn, T.R.; Mustapha, R.; Flores-Borja, F.; Male, V.; Barber, P.R.; Patsialou, A.; Green, R.; Panagaki, F.; Li, C.W.; et al. Breast Cancer–Associated Macrophages Promote Tumorigenesis by Suppressing Succinate Dehydrogenase in Tumor Cells. Sci. Signal. 2020, 13, eaax4585. [Google Scholar] [CrossRef] [PubMed]
- Viola, A.; Munari, F.; Sánchez-Rodríguez, R.; Scolaro, T.; Castegna, A. The Metabolic Signature of Macrophage Responses. Front. Immunol. 2019, 10, 1462. [Google Scholar] [CrossRef] [PubMed]
- Punzo, F.; Bellini, G.; Tortora, C.; Pinto, D.D.; Argenziano, M.; Pota, E.; Paola, A.D.; Martino, M.D.; Rossi, F. Mifamurtide and TAM-like Macrophages: Effect on Proliferation, Migration and Differentiation of Osteosarcoma Cells. Oncotarget 2020, 11, 687–698. [Google Scholar] [CrossRef] [PubMed]
- Guo, X.; Xue, H.; Shao, Q.; Wang, J.; Guo, X.; Zhang, J.; Xu, S.; Li, T.; Zhang, P.; Gao, X.; et al. Hypoxia Promotes Glioma-Associated Macrophage Infiltration via Periostin and Subsequent M2 Polarization by Upregulating TGF-Beta and M-CSFR. Oncotarget 2016, 7, 80521–80542. [Google Scholar] [CrossRef] [PubMed]
- Hossain, F.; Al-Khami, A.A.; Wyczechowska, D.; Hernandez, C.; Zheng, L.; Reiss, K.; Valle, L.D.; Trillo-Tinoco, J.; Maj, T.; Zou, W.; et al. Inhibition of Fatty Acid Oxidation Modulates Immunosuppressive Functions of Myeloid-Derived Suppressor Cells and Enhances Cancer Therapies. Cancer Immunol. Res. 2015, 3, 1236–1247. [Google Scholar] [CrossRef]
- Al-Khami, A.A.; Rodriguez, P.C.; Ochoa, A.C. Energy Metabolic Pathways Control the Fate and Function of Myeloid Immune Cells. J. Leukoc. Biol. 2017, 102, 369–380. [Google Scholar] [CrossRef]
- Klein Geltink, R.I.; Kyle, R.L.; Pearce, E.L. Unraveling the Complex Interplay between T Cell Metabolism and Function. Annu. Rev. Immunol. 2018, 36, 461–488. [Google Scholar] [CrossRef]
- Munn, D.H.; Sharma, M.D.; Baban, B.; Harding, H.P.; Zhang, Y.; Ron, D.; Mellor, A.L. GCN2 Kinase in T Cells Mediates Proliferative Arrest and Anergy Induction in Response to Indoleamine 2,3-Dioxygenase. Immunity 2005, 22, 633–642. [Google Scholar] [CrossRef]
- Molon, B.; Ugel, S.; Del Pozzo, F.; Soldani, C.; Zilio, S.; Avella, D.; De Palma, A.; Mauri, P.; Monegal, A.; Rescigno, M.; et al. Chemokine Nitration Prevents Intratumoral Infiltration of Antigen-Specific T Cells. J. Exp. Med. 2011, 208, 1949–1962. [Google Scholar] [CrossRef] [PubMed]
- Veglia, F.; Perego, M.; Gabrilovich, D. Myeloid-Derived Suppressor Cells Coming of Age. Nat. Immunol. 2018, 19, 108–119. [Google Scholar] [CrossRef] [PubMed]
- Groth, C.; Hu, X.; Weber, R.; Fleming, V.; Altevogt, P.; Utikal, J.; Umansky, V. Immunosuppression Mediated by Myeloid-Derived Suppressor Cells (MDSCs) during Tumour Progression. Br. J. Cancer 2019, 120, 16–25. [Google Scholar] [CrossRef] [PubMed]
- Angioni, R.; Liboni, C.; Herkenne, S.; Sánchez-Rodríguez, R.; Borile, G.; Marcuzzi, E.; Calì, B.; Muraca, M.; Viola, A. CD73+ Extracellular Vesicles Inhibit Angiogenesis through Adenosine A2B Receptor Signalling. J. Extracell. Vesicles 2020, 9, 1757900. [Google Scholar] [CrossRef]
- Li, J.; Wang, L.; Chen, X.; Li, L.; Li, Y.; Ping, Y.; Huang, L.; Yue, D.; Zhang, Z.; Wang, F.; et al. CD39/CD73 Upregulation on Myeloid-Derived Suppressor Cells via TGF-β-MTOR-HIF-1 Signaling in Patients with Non-Small Cell Lung Cancer. OncoImmunology 2017, 6, e1320011. [Google Scholar] [CrossRef]
- Li, W.; Tanikawa, T.; Kryczek, I.; Xia, H.; Li, G.; Wu, K.; Wei, S.; Zhao, L.; Vatan, L.; Wen, B.; et al. Aerobic Glycolysis Controls Myeloid-Derived Suppressor Cells and Tumor Immunity via a Specific CEBPB Isoform in Triple-Negative Breast Cancer. Cell Metab. 2018, 28, 87–103.e6. [Google Scholar] [CrossRef]
- De Sanctis, F.; Sandri, S.; Ferrarini, G.; Pagliarello, I.; Sartoris, S.; Ugel, S.; Marigo, I.; Molon, B.; Bronte, V. The Emerging Immunological Role of Post-Translational Modifications by Reactive Nitrogen Species in Cancer Microenvironment. Front. Immunol. 2014, 5, 69. [Google Scholar] [CrossRef]
- Dzik, J.M. Evolutionary Roots of Arginase Expression and Regulation. Front. Immunol. 2014, 5, 544. [Google Scholar] [CrossRef]
- Bronte, V.; Brandau, S.; Chen, S.-H.; Colombo, M.P.; Frey, A.B.; Greten, T.F.; Mandruzzato, S.; Murray, P.J.; Ochoa, A.; Ostrand-Rosenberg, S.; et al. Recommendations for Myeloid-Derived Suppressor Cell Nomenclature and Characterization Standards. Nat. Commun. 2016, 7, 12150. [Google Scholar] [CrossRef]
- Nagaraj, S.; Gupta, K.; Pisarev, V.; Kinarsky, L.; Sherman, S.; Kang, L.; Herber, D.L.; Schneck, J.; Gabrilovich, D.I. Altered Recognition of Antigen Is a Mechanism of CD8 + T Cell Tolerance in Cancer. Nat. Med. 2007, 13, 828–835. [Google Scholar] [CrossRef]
- Jun, H.S.; Weinstein, D.A.; Lee, Y.M.; Mansfield, B.C.; Chou, J.Y. Molecular Mechanisms of Neutrophil Dysfunction in Glycogen Storage Disease Type Ib. Blood 2014, 123, 2843–2853. [Google Scholar] [CrossRef]
- Newsholme, P.; Curi, R.; Pithon Curi, T.C.; Murphy, C.J.; Garcia, C.; de Melo, M.P. Glutamine Metabolism by Lymphocytes, Macrophages, and Neutrophils: Its Importance in Health and Disease. J. Nutr. Biochem. 1999, 10, 316–324. [Google Scholar] [CrossRef]
- Stanton, R.C. Glucose-6-Phosphate Dehydrogenase, NADPH, and Cell Survival. IUBMB Life 2012, 64, 362–369. [Google Scholar] [CrossRef] [PubMed]
- Rotondo, R.; Barisione, G.; Mastracci, L.; Grossi, F.; Orengo, A.M.; Costa, R.; Truini, M.; Fabbi, M.; Ferrini, S.; Barbieri, O. IL-8 Induces Exocytosis of Arginase 1 by Neutrophil Polymorphonuclears in Nonsmall Cell Lung Cancer. Int. J. Cancer 2009, 125, 887–893. [Google Scholar] [CrossRef]
- Veglia, F.; Tyurin, V.A.; Blasi, M.; De Leo, A.; Kossenkov, A.V.; Donthireddy, L.; To, T.K.J.; Schug, Z.; Basu, S.; Wang, F.; et al. Fatty Acid Transport Protein 2 Reprograms Neutrophils in Cancer. Nature 2019, 569, 73–78. [Google Scholar] [CrossRef] [PubMed]
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Angioni, R.; Sánchez-Rodríguez, R.; Viola, A.; Molon, B. TGF-β in Cancer: Metabolic Driver of the Tolerogenic Crosstalk in the Tumor Microenvironment. Cancers 2021, 13, 401. https://doi.org/10.3390/cancers13030401
Angioni R, Sánchez-Rodríguez R, Viola A, Molon B. TGF-β in Cancer: Metabolic Driver of the Tolerogenic Crosstalk in the Tumor Microenvironment. Cancers. 2021; 13(3):401. https://doi.org/10.3390/cancers13030401
Chicago/Turabian StyleAngioni, Roberta, Ricardo Sánchez-Rodríguez, Antonella Viola, and Barbara Molon. 2021. "TGF-β in Cancer: Metabolic Driver of the Tolerogenic Crosstalk in the Tumor Microenvironment" Cancers 13, no. 3: 401. https://doi.org/10.3390/cancers13030401
APA StyleAngioni, R., Sánchez-Rodríguez, R., Viola, A., & Molon, B. (2021). TGF-β in Cancer: Metabolic Driver of the Tolerogenic Crosstalk in the Tumor Microenvironment. Cancers, 13(3), 401. https://doi.org/10.3390/cancers13030401