Metabolism shapes the tumor microenvironment

Current Opinion in Cell Biology

Volumn 48, Issue , 2017, Pages 47-53

  Reina Campos, Miguel ^a   Moscat, Jorge ^a   Diaz Meco, Maria ^a  

^a BURNHAM INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CANCER ASSOCIATED FIBROBLAST; CANCER CELL; CANCER RESEARCH; CELL FUNCTION; FIBROBLAST; HUMAN; IMMUNOCOMPETENT CELL; METABOLIC REGULATION; METABOLISM; PRIORITY JOURNAL; REVIEW; STELLATE CELL; TUMOR GROWTH; TUMOR IMMUNOLOGY; TUMOR MICROENVIRONMENT; ANIMAL; IMMUNOLOGY; NEOPLASM; PATHOLOGY;

GLUCOSE;

ANIMALS; FIBROBLASTS; GLUCOSE; HUMANS; METABOLIC NETWORKS AND PATHWAYS; NEOPLASMS; TUMOR MICROENVIRONMENT;

EID: 85020446378     PISSN: 09550674     EISSN: 18790410     Source Type: Journal    
DOI: 10.1016/j.ceb.2017.05.006     Document Type: Review

References (67)

1. 1 Pavlova, N.N., Thompson, C.B., The emerging hallmarks of cancer metabolism. Cell Metab. 23 (2016), 27–47.
2. 2 Lu, P., Weaver, V.M., Werb, Z., The extracellular matrix: a dynamic niche in cancer progression. J. Cell Biol. 196 (2012), 395–406.
3. 3 Pattabiraman, D.R., Weinberg, R.A., Tackling the cancer stem cells—what challenges do they pose. Nat. Rev. Drug Discov. 13 (2014), 497–512.
4. 4 Hanahan, D., Weinberg, R.A., Hallmarks of cancer: the next generation. Cell 144 (2011), 646–674.
5. 5 Guillaumond, F., Leca, J., Olivares, O., Lavaut, M.N., Vidal, N., Berthezene, P., Dusetti, N.J., Loncle, C., Calvo, E., Turrini, O., et al. Strengthened glycolysis under hypoxia supports tumor symbiosis and hexosamine biosynthesis in pancreatic adenocarcinoma. Proc. Natl. Acad. Sci. U. S. A. 110 (2013), 3919–3924.
6. 13C-glucose infusion in NSCLC patients, which allows them to observe how differently perfused tumor areas use different carbon sources. The authors highlight the fact that poorly perfused areas use mainly glucose, while well perfused regions use other fuels such as fatty acids, aminoacids, ketones and lactate to produce Acetyl-CoA for the TCA.
7. 7 Sellers, K., Fox, M.P., Bousamra, M., 2nd Slone, S.P., Higashi, R.M., Miller, D.M., Wang, Y., Yan, J., Yuneva, M.O., Deshpande, R., et al. Pyruvate carboxylase is critical for non-small-cell lung cancer proliferation. J. Clin. Invest. 125 (2015), 687–698.
8. 8 Son, J., Lyssiotis, C.A., Ying, H., Wang, X., Hua, S., Ligorio, M., Perera, R.M., Ferrone, C.R., Mullarky, E., Shyh-Chang, N., et al. Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature 496 (2013), 101–105.
9. 9 Gao, P., Tchernyshyov, I., Chang, T.C., Lee, Y.S., Kita, K., Ochi, T., Zeller, K.I., De Marzo, A.M., Van Eyk, J.E., Mendell, J.T., et al. c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature 458 (2009), 762–765.
10. 10 Gundem, G., Van Loo, P., Kremeyer, B., Alexandrov, L.B., Tubio, J.M., Papaemmanuil, E., Brewer, D.S., Kallio, H.M., Hognas, G., Annala, M., et al. The evolutionary history of lethal metastatic prostate cancer. Nature 520 (2015), 353–357.
11. 11 Gerlinger, M., Rowan, A.J., Horswell, S., Larkin, J., Endesfelder, D., Gronroos, E., Martinez, P., Matthews, N., Stewart, A., Tarpey, P., et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N. Engl. J. Med. 366 (2012), 883–892.
12. G12D allelic enrichment in a p53 null background, the authors describe how gaining additional mutated copies of this oncogene promotes a metabolic switch that drives tumor progression.
13. 13 Joyce, J.A., Pollard, J.W., Microenvironmental regulation of metastasis. Nat. Rev. Cancer 9 (2009), 239–252.
14. 14 Kalluri, R., The biology and function of fibroblasts in cancer. Nat. Rev. Cancer 16 (2016), 582–598.
15. 15 Ward, P.S., Thompson, C.B., Metabolic reprogramming: a cancer hallmark even warburg did not anticipate. Cancer Cell 21 (2012), 297–308.
16. 16 Vander Heiden, M.G., Cantley, L.C., Thompson, C.B., Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324 (2009), 1029–1033.
17. 17 Martinez-Outschoorn, U.E., Trimmer, C., Lin, Z., Whitaker-Menezes, D., Chiavarina, B., Zhou, J., Wang, C., Pavlides, S., Martinez-Cantarin, M.P., Capozza, F., et al. Autophagy in cancer associated fibroblasts promotes tumor cell survival: role of hypoxia, HIF1 induction and NFkappaB activation in the tumor stromal microenvironment. ABBV Cell Cycle 9 (2010), 3515–3533.
18. 18 Liu, F.L., Mo, E.P., Yang, L., Du, J., Wang, H.S., Zhang, H., Kurihara, H., Xu, J., Cai, S.H., Autophagy is involved in TGF-beta1-induced protective mechanisms and formation of cancer-associated fibroblasts phenotype in tumor microenvironment. Oncotarget 7 (2016), 4122–4141.
19. 19 Wang, Q., Xue, L., Zhang, X., Bu, S., Zhu, X., Lai, D., Autophagy protects ovarian cancer-associated fibroblasts against oxidative stress. Cell Cycle 15 (2016), 1376–1385.
20. 20• Valencia, T., Kim, J.Y., Abu-Baker, S., Moscat-Pardos, J., Ahn, C.S., Reina-Campos, M., Duran, A., Castilla, E.A., Metallo, C.M., Diaz-Meco, M.T., et al. Metabolic reprogramming of stromal fibroblasts through p62-mTORC1 signaling promotes inflammation and tumorigenesis. Cancer Cell 26 (2014), 121–135 Activated CAFs play an important role in tumor progression. In this study, the authors find that p62 downregulation is a hallmark of activated CAFs of the prostate. Loss of p62 induces a metabolic reprogramming by inhibition of mTORC1 and c-Myc that ultimately leads to IL6 and TGFβ secretion, further contributing to inflammation of the TME and promoting tumor progression.
21. 21•• Sousa, C.M., Biancur, D.E., Wang, X., Halbrook, C.J., Sherman, M.H., Zhang, L., Kremer, D., Hwang, R.F., Witkiewicz, A.K., Ying, H., et al. Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. Nature 536 (2016), 479–483 PDAC is characterized by an extreme fibrotic response that is mostly driven by activated PSCs. Adding a new role for PSCs in PDAC, the authors describe how these stromal cells are able to mobilize free aminoacids from autophagic routes to supply nutrients to the tumor and maintain its metabolism.
22. 22 Mehrmohamadi, M., Liu, X., Shestov, A.A., Locasale, J.W., Characterization of the usage of the serine metabolic network in human cancer. Cell Rep. 9 (2014), 1507–1519.
23. 23 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. 24 (2016), 685–700.
24. 24 Zhao, H., Yang, L., Baddour, J., Achreja, A., Bernard, V., Moss, T., Marini, J.C., Tudawe, T., Seviour, E.G., San Lucas, F.A., et al. Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism. Elife, 5, 2016, e10250.
25. 25 Tape, C.J., Ling, S., Dimitriadi, M., McMahon, K.M., Worboys, J.D., Leong, H.S., Norrie, I.C., Miller, C.J., Poulogiannis, G., Lauffenburger, D.A., et al. Oncogenic KRAS regulates tumor cell signaling via stromal reciprocation. Cell, 165, 2016, 1818.
26. 26 Hansen, J.M., Coleman, R.L., Sood, A.K., Targeting the tumour microenvironment in ovarian cancer. Eur. J. Cancer 56 (2016), 131–143.
27. 27 Linares, J.F., Duran, A., Reina-Campos, M., Aza-Blanc, P., Campos, A., Moscat, J., Diaz-Meco, M.T., Amino acid activation of mTORC1 by a PB1-domain-driven kinase complex cascade. Cell Rep. 12 (2015), 1339–1352.
28. 28•• Umemura, A., He, F., Taniguchi, K., Nakagawa, H., Yamachika, S., Font-Burgada, J., Zhong, Z., Subramaniam, S., Raghunandan, S., Duran, A., et al. p62, upregulated during preneoplasia, induces hepatocellular carcinogenesis by maintaining survival of stressed HCC-initiating cells. Cancer Cell 29 (2016), 935–948 Oxidative stress and inflammation in the liver are conducive of HCC. The authors of this study found that p62 accumulation in the hepatocytes, caused by inhibited autophagy in the context or mTORC1 activation or induced genetic overexpression, is able to induce NRF2 activation that counteracts the oxidative stress and promotes the emergence of HCC.
29. 29•• Duran, A., Hernandez, E.D., Reina-Campos, M., Castilla, E.A., Subramaniam, S., Raghunandan, S., Roberts, L.R., Kisseleva, T., Karin, M., Diaz-Meco, M.T., et al. p62/SQSTM1 by binding to vitamin D receptor inhibits hepatic stellate cell activity, fibrosis, and liver cancer. Cancer Cell 30 (2016), 595–609 HSC activation is a hallmark of the fibrotic response in the liver that causes inflammation and profound ECM remodeling. Vitamin D has been showed to attenuate the fibrotic response by repress stellate cell activation. The authors of this study found that p62 acts as a scaffold for the VDR-RXR heterodimer formation, that is essential for the anti-fibrotic functions of Vitamin D. During HSC activation p62 is lost, which impairs RXR-VDR heterodimer formation and makes HSC, and liver tumors, insensitive to the beneficial effects of Vitamin D.
30. 30 Mathew, R., Karp, C.M., Beaudoin, B., Vuong, N., Chen, G., Chen, H.Y., Bray, K., Reddy, A., Bhanot, G., Gelinas, C., et al. Autophagy suppresses tumorigenesis through elimination of p62. Cell 137 (2009), 1062–1075.
31. 31 Duran, A., Linares, J.F., Galvez, A.S., Wikenheiser, K., Flores, J.M., Diaz-Meco, M.T., Moscat, J., The signaling adaptor p62 is an important NF-kappaB mediator in tumorigenesis. Cancer Cell 13 (2008), 343–354.
32. 32• Sherman, M.H., Yu, R.T., Engle, D.D., Ding, N., Atkins, A.R., Tiriac, H., Collisson, E.A., Connor, F., Van Dyke, T., Kozlov, S., et al. Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy. Cell 159 (2014), 80–93 Activated PSCs take part in the strong stromal response characteristic of PDAC. In this study, the authors reported how Vitamin D plays an anti-fibrotic role by blocking PSCs activation program. Combination of a Vitamin D analog, calcipotriol, is able to reduce markers of inflammation and fibrosis in the stromal compartment, and combined with gemcitabine, decrease tumor burden and increase overall survival in mice.
33. 33 Boon, T., Cerottini, J.C., Van den Eynde, B., van der Bruggen, P., Van Pel, A., Tumor antigens recognized by T lymphocytes. Annu. Rev. Immunol. 12 (1994), 337–365.
34. 34 Chen, D.S., Mellman, I., Oncology meets immunology: the cancer-immunity cycle. Immunity 39 (2013), 1–10.
35. 35 Schumacher, T.N., Schreiber, R.D., Neoantigens in cancer immunotherapy. Science 348 (2015), 69–74.
36. 36 Vinay, D.S., Ryan, E.P., Pawelec, G., Talib, W.H., Stagg, J., Elkord, E., Lichtor, T., Decker, W.K., Whelan, R.L., Kumara, H.M., et al. Immune evasion in cancer: mechanistic basis and therapeutic strategies. Semin. Cancer Biol. 35:Suppl (2015), S185–198.
37. 37 Ohta, A., Gorelik, E., Prasad, S.J., Ronchese, F., Lukashev, D., Wong, M.K., Huang, X., Caldwell, S., Liu, K., Smith, P., et al. A2A adenosine receptor protects tumors from antitumor T cells. Proc. Natl. Acad. Sci. U. S. A. 103 (2006), 13132–13137.
38. 38 Romero-Garcia, S., Moreno-Altamirano, M.M., Prado-Garcia, H., Sanchez-Garcia, F.J., Lactate contribution to the tumor microenvironment: mechanisms, effects on immune cells and therapeutic relevance. Front. Immunol., 7, 2016, 52.
39. 39 Doherty, J.R., Cleveland, J.L., Targeting lactate metabolism for cancer therapeutics. J. Clin. Invest. 123 (2013), 3685–3692.
40. 40 Walenta, S., Wetterling, M., Lehrke, M., Schwickert, G., Sundfor, K., Rofstad, E.K., Mueller-Klieser, W., High lactate levels predict likelihood of metastases, tumor recurrence, and restricted patient survival in human cervical cancers. Cancer Res. 60 (2000), 916–921.
41. 41 Fiaschi, T., Marini, A., Giannoni, E., Taddei, M.L., Gandellini, P., De Donatis, A., Lanciotti, M., Serni, S., Cirri, P., Chiarugi, P., Reciprocal metabolic reprogramming through lactate shuttle coordinately influences tumor-stroma interplay. Cancer Res. 72 (2012), 5130–5140.
42. 42 Haas, R., Smith, J., Rocher-Ros, V., Nadkarni, S., Montero-Melendez, T., D'Acquisto, F., Bland, E.J., Bombardieri, M., Pitzalis, C., Perretti, M., et al. Lactate regulates metabolic and pro-inflammatory circuits in control of T cell migration and effector functions. PLoS Biol., 13, 2015, e1002202.
43. 43 Vegran, F., Boidot, R., Michiels, C., Sonveaux, P., Feron, O., Lactate influx through the endothelial cell monocarboxylate transporter MCT1 supports an NF-kappaB/IL-8 pathway that drives tumor angiogenesis. Cancer Res. 71 (2011), 2550–2560.
44. 44 Sonveaux, P., Copetti, T., De Saedeleer, C.J., Vegran, F., Verrax, J., Kennedy, K.M., Moon, E.J., Dhup, S., Danhier, P., Frerart, F., et al. Targeting the lactate transporter MCT1 in endothelial cells inhibits lactate-induced HIF-1 activation and tumor angiogenesis. PLoS One, 7, 2012, e33418.
45. 45 Dietl, K., Renner, K., Dettmer, K., Timischl, B., Eberhart, K., Dorn, C., Hellerbrand, C., Kastenberger, M., Kunz-Schughart, L.A., Oefner, P.J., et al. Lactic acid and acidification inhibit TNF secretion and glycolysis of human monocytes. J. Immunol. 184 (2010), 1200–1209.
46. 46 Fischer, K., Hoffmann, P., Voelkl, S., Meidenbauer, N., Ammer, J., Edinger, M., Gottfried, E., Schwarz, S., Rothe, G., Hoves, S., et al. Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood 109 (2007), 3812–3819.
47. 47•• Colegio, O.R., Chu, N.Q., Szabo, A.L., Chu, T., Rhebergen, A.M., Jairam, V., Cyrus, N., Brokowski, C.E., Eisenbarth, S.C., Phillips, G.M., et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 513 (2014), 559–563 Macrophages surveil the TME and interact with its cellular components. The authors of this study describe how tumor-derived lactate is able to induce macrophage M2 polarization, that in turn, produces angiogenic factors (VEGF) and Arginase1 to promote tumor growth.
48. 48•• 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. 24 (2016), 657–671 Tumors consume high amounts of glucose and generate high amounts of lactate by converting pyruvate to lactate by the LDHA. The authors of this study found that LDHA-derived lactic acid is responsible to blunt NK and T cell functions by impairing NFAT activation and IFN-γ response.
49. 49 Peng, M., Yin, N., Chhangawala, S., Xu, K., Leslie, C.S., Li, M.O., Aerobic glycolysis promotes T helper 1 cell differentiation through an epigenetic mechanism. Science 354 (2016), 481–484.
50. 50 Doedens, A.L., Rubinstein, M.P., Gross, E.T., Best, J.A., Craig, D.H., Baker, M.K., Cole, D.J., Bui, J.D., Goldrath, A.W., Molecular programming of tumor-infiltrating CD8+ T cells and IL15 resistance. Cancer Immunol. Res. 4 (2016), 799–811.
51. 51 Tyrakis, P.A., Palazon, A., Macias, D., Lee, K.L., Phan, A.T., Velica, P., You, J., Chia, G.S., Sim, J., Doedens, A., et al. S-2-hydroxyglutarate regulates CD8+ T-lymphocyte fate. Nature 540 (2016), 236–241.
52. 52 Clever, D., Roychoudhuri, R., Constantinides, M.G., Askenase, M.H., Sukumar, M., Klebanoff, C.A., Eil, R.L., Hickman, H.D., Yu, Z., Pan, J.H., et al. Oxygen sensing by T cells establishes an immunologically tolerant metastatic niche. Cell 166 (2016), 1117–1131 e1114.
53. 53 Buck, M.D., O'Sullivan, D., Pearce, E.L., T cell metabolism drives immunity. J. Exp. Med. 212 (2015), 1345–1360.
54. 54 Chang, C.H., Qiu, J., O'Sullivan, D., Buck, M.D., Noguchi, T., Curtis, J.D., Chen, Q., Gindin, M., Gubin, M.M., van der Windt, G.J., et al. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162 (2015), 1229–1241.
55. 55•• Geiger, R., Rieckmann, J.C., Wolf, T., Basso, C., Feng, Y., Fuhrer, T., Kogadeeva, M., Picotti, P., Meissner, F., Mann, M., et al. L-arginine modulates T cell metabolism and enhances survival and anti-tumor activity. Cell 167 (2016), 829–842 e813 By using high-resolution mass spectrometry, the authors found that intracellular concentration of arginine is a key determinant of T cell fate. While low arginine concentration promotes T cell activation, intracellular arginine elevation fosters acquisition of a T cell memory-like phenotype that promotes anti-tumor activity in a mouse model.
56. 56• Peng, D., Kryczek, I., Nagarsheth, N., Zhao, L., Wei, S., Wang, W., Sun, Y., Zhao, E., Vatan, L., Szeliga, W., et al. Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. Nature 527 (2015), 249–253 The authors found an unexpected link between epigenetic reprogramming of the tumor epithelia and immune T cell infiltration. By studying human ovarian cancers, the authors described how PRC2/DNMT1-mediated silencing of two T cell recruiting chemokines, CXCL9 and CXCL10, is responsible for the lack of T cell recruitment to the tumor bulk. Additionally, the authors demonstrate that inhibition of the epigenetic machinery that leads to chemokine silencing removes the repression and enhances effector T cell responses.
57. 57 Janke, R., Dodson, A.E., Rine, J., Metabolism and epigenetics. Annu. Rev. Cell Dev. Biol. 31 (2015), 473–496.
58. 58 Lu, C., Thompson, C.B., Metabolic regulation of epigenetics. Cell Metab. 16 (2012), 9–17.
59. 59 Mentch, S.J., Mehrmohamadi, M., Huang, L., Liu, X., Gupta, D., Mattocks, D., Gomez Padilla, P., Ables, G., Bamman, M.M., Thalacker-Mercer, A.E., et al. Histone methylation dynamics and gene regulation occur through the sensing of one-carbon metabolism. Cell Metab. 22 (2015), 861–873.
60. 60 van der Knaap, J.A., Verrijzer, C.P., Undercover: gene control by metabolites and metabolic enzymes. Genes. Dev. 30 (2016), 2345–2369.
61. 61•• Pan, M., Reid, M.A., Lowman, X.H., Kulkarni, R.P., Tran, T.Q., Liu, X., Yang, Y., Hernandez-Davies, J.E., Rosales, K.K., Li, H., et al. Regional glutamine deficiency in tumours promotes dedifferentiation through inhibition of histone demethylation. Nat. Cell Biol. 18 (2016), 1090–1101 Nutrients are scarce in the TME. The authors of this study found that regional glutamine deficiency in melanoma tumors bearing BRAF mutations promotes epigenetic changes as a result of a drastic reduction in intracellular a-ketoglutarate levels, which are needed as cofactor for histone demethylases, in turn, this promotes cancer cell dedifferentiation and resistance to BRAF inhibitor treatment.
62. 62• Bindea, G., Mlecnik, B., Tosolini, M., Kirilovsky, A., Waldner, M., Obenauf, A.C., Angell, H., Fredriksen, T., Lafontaine, L., Berger, A., et al. Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer. Immunity 39 (2013), 782–795 In a large-scale approach, the authors explore the spatio-temporal dynamics of different immune cell types infiltrating tumors and provide a snapshot of the immune landscape in cancer. The authors observed a strong correlation between the composition and extent of specific immune cell types and tumor progression and verify their findings in a model of orthotopic colorectal cancer.
63. 63 Galon, J., Fox, B.A., Bifulco, C.B., Masucci, G., Rau, T., Botti, G., Marincola, F.M., Ciliberto, G., Pages, F., Ascierto, P.A., et al. Immunoscore and Immunoprofiling in cancer: an update from the melanoma and immunotherapy bridge 2015. J. Transl. Med., 14, 2016, 273.
64. 64 Galon, J., Pages, F., Marincola, F.M., Angell, H.K., Thurin, M., Lugli, A., Zlobec, I., Berger, A., Bifulco, C., Botti, G., et al. Cancer classification using the Immunoscore: a worldwide task force. J. Transl. Med., 10, 2012, 205.
65. 65• Spranger, S., Bao, R., Gajewski, T.F., Melanoma-intrinsic beta-catenin signalling prevents anti-tumour immunity. Nature 523 (2015), 231–235 Some melanoma tumors respond better than other to immune therapy. By comparing T cell infiltrated vs non-T cell-infiltrated tumors, the authors discovered that tumor beta-catenin signaling promotes an immunosuppressive state that prevent T cell infiltration and resistance to anti-CTLA4/anti-PD-L1 monoclonal antibody therapy.
66. 66 Vanharanta, S., Massague, J., Field cancerization: something new under the sun. Cell 149 (2012), 1179–1181.
67. 67 Baba, Y., Ishimoto, T., Kurashige, J., Iwatsuki, M., Sakamoto, Y., Yoshida, N., Watanabe, M., Baba, H., Epigenetic field cancerization in gastrointestinal cancers. Cancer Lett. 375 (2016), 360–366.