Table of Contents Author Guidelines Submit a Manuscript
PPAR Research
Volume 2016 (2016), Article ID 3082340, 7 pages
http://dx.doi.org/10.1155/2016/3082340
Review Article

PPARδ as a Metabolic Initiator of Mammary Neoplasia and Immune Tolerance

Department of Oncology, Georgetown University Medical Center and the Lombardi Comprehensive Cancer Center, 3970 Reservoir Rd, NW, Washington, DC 20007, USA

Received 19 July 2016; Accepted 3 November 2016

Academic Editor: Stefano Caruso

Copyright © 2016 Robert I. Glazer. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. C. Grommes, G. E. Landreth, and M. T. Heneka, “Antineoplastic effects of peroxisome proliferator-activated receptor γ agonists,” Lancet Oncology, vol. 5, no. 7, pp. 419–429, 2004. View at Publisher · View at Google Scholar · View at Scopus
  2. J. M. Olefsky and A. R. Saltiel, “PPARγ and the treatment of insulin resistance,” Trends in Endocrinology and Metabolism, vol. 11, no. 9, pp. 362–368, 2000. View at Publisher · View at Google Scholar · View at Scopus
  3. J. Berger and J. A. Wagner, “Physiological and therapeutic roles of peroxisome proliferator-activated receptors,” Diabetes Technology and Therapeutics, vol. 4, no. 2, pp. 163–174, 2002. View at Publisher · View at Google Scholar · View at Scopus
  4. J. Direnzo, M. Söderström, R. Kurokawa et al., “Peroxisome proliferator-activated receptors and retinoic acid receptors differentially control the interactions of retinoid X receptor heterodimers with ligands, coactivators, and corepressors,” Molecular and Cellular Biology, vol. 17, no. 4, pp. 2166–2176, 1997. View at Publisher · View at Google Scholar · View at Scopus
  5. R. M. Lavinsky, K. Jepsen, T. Heinzel et al., “Diverse signaling pathways modulate nuclear receptor recruitment of N- CoR and SMRT complexes,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 6, pp. 2920–2925, 1998. View at Publisher · View at Google Scholar · View at Scopus
  6. R. T. Nolte, G. B. Wisely, S. Westin et al., “Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-γ,” Nature, vol. 395, no. 6698, pp. 137–143, 1998. View at Publisher · View at Google Scholar · View at Scopus
  7. Y. Yin, H. Yuan, C. Wang et al., “3-Phosphoinositide-dependent protein kinase-1 activates the peroxisome proliferator-activated receptor- and promotes adipocyte differentiation,” Molecular Endocrinology, vol. 20, no. 2, pp. 268–278, 2006. View at Publisher · View at Google Scholar · View at Scopus
  8. J. P. Berger, T. E. Akiyama, and P. T. Meinke, “PPARs: therapeutic targets for metabolic disease,” Trends in Pharmacological Sciences, vol. 26, no. 5, pp. 244–251, 2005. View at Publisher · View at Google Scholar · View at Scopus
  9. R. M. Evans, G. D. Barish, and Y.-X. Wang, “PPARs and the complex journey to obesity,” Nature Medicine, vol. 10, no. 4, pp. 355–361, 2004. View at Publisher · View at Google Scholar · View at Scopus
  10. M. Lehrke and M. A. Lazar, “The many faces of PPARγ,” Cell, vol. 123, no. 6, pp. 993–999, 2005. View at Publisher · View at Google Scholar · View at Scopus
  11. L. Michalik, B. Desvergne, and W. Wahli, “Peroxisome-proliferator-activated receptors and cancers: complex stories,” Nature Reviews Cancer, vol. 4, no. 1, pp. 61–70, 2004. View at Publisher · View at Google Scholar · View at Scopus
  12. R. I. Glazer, H. Yuan, Z. Xie, and Y. Yin, “PPARγ and PPARδ as modulators of neoplasia and cell fate,” PPAR Research, vol. 2008, Article ID 247379, 8 pages, 2008. View at Publisher · View at Google Scholar · View at Scopus
  13. K.-D. Wagner and N. Wagner, “Peroxisome proliferator-activated receptor beta/delta (PPARβ/δ) acts as regulator of metabolism linked to multiple cellular functions,” Pharmacology and Therapeutics, vol. 125, no. 3, pp. 423–435, 2010. View at Publisher · View at Google Scholar · View at Scopus
  14. J. M. Peters, Y. M. Shah, and F. J. Gonzalez, “The role of peroxisome proliferator-activated receptors in carcinogenesis and chemoprevention,” Nature Reviews Cancer, vol. 12, no. 3, pp. 181–195, 2012. View at Publisher · View at Google Scholar · View at Scopus
  15. M. Xu, X. Zuo, and I. Shureiqi, “Targeting peroxisome proliferator-activated receptor-β/δ in colon cancer: how to aim?” Biochemical Pharmacology, vol. 85, no. 5, pp. 607–611, 2013. View at Publisher · View at Google Scholar · View at Scopus
  16. J. M. Peters, P. L. Yao, and F. J. Gonzalez, “Targeting peroxisome proliferator-activated receptor-β/Δ (PPARβ/Δ) for cancer chemoprevention,” Current Pharmacology Reports, vol. 1, no. 2, pp. 121–128, 2015. View at Publisher · View at Google Scholar
  17. G. M. Pighetti, W. Novosad, C. Nicholson et al., “Therapeutic treatment of DMBA-induced mammary tumors with PPAR ligands,” Anticancer Research, vol. 21, no. 2, pp. 825–830, 2001. View at Google Scholar · View at Scopus
  18. N. Suh, Y. Wang, C. R. Williams et al., “A new ligand for the peroxisome proliferator-activated receptor-γ (PPAR-γ), GW7845, inhibits rat mammary carcinogenesis,” Cancer Research, vol. 59, no. 22, pp. 5671–5673, 1999. View at Google Scholar · View at Scopus
  19. Y. Yin, R. G. Russell, L. E. Dettin et al., “Peroxisome proliferator-activated receptor delta and γ agonists differentially alter tumor differentiation and progression during mammary carcinogenesis,” Cancer Research, vol. 65, pp. 3950–3957, 2005. View at Google Scholar
  20. L. Patel, I. Pass, P. Coxon, C. P. Downes, S. A. Smith, and C. H. Macphee, “Tumor suppressor and anti-inflammatory actions of PPARγ agonists are mediated via upregulation of PTEN,” Current Biology, vol. 11, no. 10, pp. 764–768, 2001. View at Publisher · View at Google Scholar · View at Scopus
  21. H. Yuan, G. Upadhyay, Y. Yin, L. Kopelovich, and R. I. Glazer, “Stem cell antigen-1 deficiency enhances the chemopreventive effect of peroxisome proliferator–activated receptorγ activation,” Cancer Prevention Research, vol. 5, no. 1, pp. 51–60, 2012. View at Publisher · View at Google Scholar · View at Scopus
  22. M. Pignatelli, C. Cocca, A. Santos, and A. Perez-Castillo, “Enhancement of BRCA1 gene expression by the peroxisome proliferator-activated receptor γ in the MCF-7 breast cancer cell line,” Oncogene, vol. 22, pp. 5446–5450, 2003. View at Publisher · View at Google Scholar · View at Scopus
  23. A. J. Apostoli, J. M. Roche, M. M. Schneider et al., “Opposing roles for mammary epithelial-specific PPARγ signaling and activation during breast tumour progression,” Molecular Cancer, pp. 1–14, 2015. View at Publisher · View at Google Scholar · View at Scopus
  24. Y. Yin, H. Yuan, X. Zeng, L. Kopelovich, and R. I. Glazer, “Inhibition of peroxisome proliferator-activated receptor γ increases estrogen receptor-dependent tumor specification,” Cancer Research, vol. 69, no. 2, pp. 687–694, 2009. View at Publisher · View at Google Scholar · View at Scopus
  25. H. Yuan, L. Kopelovich, Y. Yin, J. Lu, and R. I. Glazer, “Drug-targeted inhibition of peroxisome proliferator-activated receptor-gamma enhances the chemopreventive effect of anti-estrogen therapy,” Oncotarget, vol. 3, no. 3, pp. 345–356, 2012. View at Publisher · View at Google Scholar · View at Scopus
  26. N. Di-Po, N. S. Tan, L. Michalik, W. Wahli, and B. Desvergne, “Antiapoptotic role of PPARβ in keratinocytes via transcriptional control of the Akt1 signaling pathway,” Molecular Cell, vol. 10, no. 4, pp. 721–733, 2002. View at Publisher · View at Google Scholar · View at Scopus
  27. N. Di-Poï, L. Michalik, N. S. Tan, B. Desvergne, and W. Wahli, “The anti-apoptotic role of PPARβ contributes to efficient skin wound healing,” Journal of Steroid Biochemistry and Molecular Biology, vol. 85, no. 2–5, pp. 257–265, 2003. View at Publisher · View at Google Scholar · View at Scopus
  28. R. L. Stephen, M. C. U. Gustafsson, M. Jarvis et al., “Activation of peroxisome proliferator-activated receptor δ stimulates the proliferation of human breast and prostate cancer cell lines,” Cancer Research, vol. 64, no. 9, pp. 3162–3170, 2004. View at Publisher · View at Google Scholar · View at Scopus
  29. C. B. Pollock, Y. Yin, H. Yuan et al., “PPARδ activation acts cooperatively with 3-phosphoinositide-dependent protein kinase-1 to enhance mammary tumorigenesis,” PLoS ONE, vol. 6, no. 1, Article ID e16215, 2011. View at Publisher · View at Google Scholar · View at Scopus
  30. M. Ghosh, Y. Ai, K. Narko, Z. Wang, J. M. Peters, and T. Hla, “PPARδ is pro-tumorigenic in a mouse model of COX-2-induced mammary cancer,” Prostaglandins and Other Lipid Mediators, vol. 88, no. 3-4, pp. 97–100, 2009. View at Publisher · View at Google Scholar · View at Scopus
  31. H. Yuan, J. Lu, J. Xiao et al., “PPARδ induces estrogen receptor-positive mammary neoplasia through an inflammatory and metabolic phenotype linked to mTOR activation,” Cancer Research, vol. 73, no. 14, pp. 4349–4361, 2013. View at Publisher · View at Google Scholar · View at Scopus
  32. A. Abdollahi, C. Schwager, J. Kleeff et al., “Transcriptional network governing the angiogenic switch in human pancreatic cancer,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 31, pp. 12890–12895, 2007. View at Publisher · View at Google Scholar · View at Scopus
  33. R. Kittler, J. Zhou, S. Hua et al., “A Comprehensive Nuclear Receptor Network for Breast Cancer Cells,” Cell Reports, vol. 3, no. 2, pp. 538–551, 2013. View at Publisher · View at Google Scholar · View at Scopus
  34. C. Sotiriou and L. Pusztai, “Gene-expression signatures in breast cancer,” New England Journal of Medicine, vol. 360, no. 8, pp. 752–800, 2009. View at Publisher · View at Google Scholar · View at Scopus
  35. R. L. Yamnik and M. K. Holz, “mTOR/S6K1 and MAPK/RSK signaling pathways coordinately regulate estrogen receptor α serine 167 phosphorylation,” FEBS Letters, vol. 584, no. 1, pp. 124–128, 2010. View at Publisher · View at Google Scholar · View at Scopus
  36. Y. Shi, M. Hon, and R. M. Evans, “The peroxisome proliferator-activated receptor δ, an integrator of transcriptional repression and nuclear receptor signaling,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 5, pp. 2613–2618, 2002. View at Publisher · View at Google Scholar · View at Scopus
  37. M. C. U. Gustafsson, D. Knight, and C. N. A. Palmer, “Ligand modulated antagonism of PPARγ by genomic and non-genomic actions of PPARδ,” PLoS ONE, vol. 4, no. 9, Article ID e7046, 2009. View at Publisher · View at Google Scholar · View at Scopus
  38. T. Adhikary, K. Kaddatz, F. Finkernagel et al., “Genomewide analyses define different modes of transcriptional regulation by peroxisome proliferator-activated receptor-β/δ (PPARβ/δ),” PLoS ONE, vol. 6, no. 1, Article ID e16344, 2011. View at Publisher · View at Google Scholar · View at Scopus
  39. M. I. Torres-Arzayus, J. Yuan, J. L. DellaGatta, H. Lane, A. L. Kung, and M. Brown, “Targeting the AIB1 oncogene through mammalian target of rapamycin inhibition in the mammary gland,” Cancer Research, vol. 66, no. 23, pp. 11381–11388, 2006. View at Publisher · View at Google Scholar · View at Scopus
  40. M. I. Torres-Arzayus, J. Font de Mora, J. Yuan et al., “High tumor incidence and activation of the PI3K/AKT pathway in transgenic mice define AIB1 as an oncogene,” Cancer Cell, vol. 6, no. 3, pp. 263–274, 2004. View at Publisher · View at Google Scholar · View at Scopus
  41. J. I. Herschkowitz, K. Simin, V. J. Weigman et al., “Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors,” Genome Biology, vol. 8, no. 5, article no. R76, 2007. View at Publisher · View at Google Scholar · View at Scopus
  42. M. Fant, A. Farina, R. Nagaraja, and D. Schlessinger, “PLAC1 (Placenta-specific 1): a novel, X-linked gene with roles in reproductive and cancer biology,” Prenatal Diagnosis, vol. 30, no. 6, pp. 497–502, 2010. View at Publisher · View at Google Scholar · View at Scopus
  43. M. Koslowski, U. Sahin, R. Mitnacht-Kraus, G. Seitz, C. Huber, and Ö. Türeci, “A placenta-specific gene ectopically activated in many human cancers is essentially involved in malignant cell processes,” Cancer Research, vol. 67, no. 19, pp. 9528–9534, 2007. View at Publisher · View at Google Scholar · View at Scopus
  44. W. A. Silva Jr., S. Gnjatic, E. Ritter et al., “PLAC1, a trophoblast-specific cell surface protein, is expressed in a range of human tumors and elicits spontaneous antibody responses,” Cancer Immunity, vol. 7, article 18, 2007. View at Google Scholar · View at Scopus
  45. X.-Y. Dong, J.-R. Peng, Y.-J. Ye et al., “PLAC1 is a tumor-specific antigen capable of eliciting spontaneous antibody responses in human cancer patients,” International Journal of Cancer, vol. 122, no. 9, pp. 2038–2043, 2008. View at Publisher · View at Google Scholar · View at Scopus
  46. F.-F. Liu, X.-Y. Dong, X.-W. Pang et al., “The specific immune response to tumor antigen CP1 and its correlation with improved survival in colon cancer patients,” Gastroenterology, vol. 134, no. 4, pp. 998–1006, 2008. View at Publisher · View at Google Scholar · View at Scopus
  47. L. Brunelli, K. A. Cieslik, J. L. Alcorn, M. Vatta, and A. Baldini, “Peroxisome proliferator-activated receptor-δ upregulates 14-3-3ε in human endothelial cells via CCAAT/enhancer binding protein-β,” Circulation Research, vol. 100, no. 5, pp. e59–e71, 2007. View at Publisher · View at Google Scholar · View at Scopus
  48. N. S. Tan, G. Icre, A. Montagner, B. Bordier-ten-Heggeler, W. Wahli, and L. Michalik, “The nuclear hormone receptor peroxisome proliferator-activated receptor β/δ potentiates cell chemotactism, polarization, and migration,” Molecular and Cellular Biology, vol. 27, no. 20, pp. 7161–7175, 2007. View at Publisher · View at Google Scholar · View at Scopus
  49. M. Romanowska, L. Reilly, C. N. A. Palmer, M. C. U. Gustafsson, and J. Foerster, “Activation of PPARβ/δ causes a psoriasis-like skin disease in vivo,” PLoS ONE, vol. 5, no. 3, Article ID e9701, 2010. View at Publisher · View at Google Scholar · View at Scopus
  50. S. A. Kliewer, S. S. Sundseth, S. A. Jones et al., “Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors α and γ,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 9, pp. 4318–4323, 1997. View at Publisher · View at Google Scholar · View at Scopus
  51. B. M. Forman, J. Chen, and R. M. Evans, “Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors α and δ,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 9, pp. 4312–4317, 1997. View at Publisher · View at Google Scholar · View at Scopus
  52. H. E. Xu, M. H. Lambert, V. G. Montana et al., “Molecular recognition of fatty acids by peroxisome proliferator- activated receptors,” Molecular Cell, vol. 3, no. 3, pp. 397–403, 1999. View at Publisher · View at Google Scholar · View at Scopus
  53. R. A. Gupta, J. Tan, W. F. Krause et al., “Prostacyclin-mediated activation of peroxisome proliferator-activated receptor δ in colorectal cancer,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 24, pp. 13275–13280, 2000. View at Publisher · View at Google Scholar · View at Scopus
  54. D. Wang, L. Fu, W. Ning et al., “Peroxisome proliferator-activated receptor δ promotes colonic inflammation and tumor growth,” Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 19, pp. 7084–7089, 2014. View at Publisher · View at Google Scholar · View at Scopus
  55. I. Shureiqi, W. Jiang, X. Zuo et al., “The 15-lipoxygenase-1 product 13-S-hydroxyoctadecadienoic acid down-regulates PPAR-δ to induce apoptosis in colorectal cancer cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 17, pp. 9968–9973, 2003. View at Publisher · View at Google Scholar · View at Scopus
  56. C. H. Liu, S.-H. Chang, K. Narko et al., “Overexpression of cyclooxygenase-2 is sufficient to induce tumorigenesis in transgenic mice,” Journal of Biological Chemistry, vol. 276, no. 21, pp. 18563–18569, 2001. View at Publisher · View at Google Scholar · View at Scopus
  57. S. Han, J. D. Ritzenthaler, B. Wingerd, and J. Roman, “Activation of peroxisome proliferator-activated receptor β/δ (PPARβ/δ) increases the expression of prostaglandin E2 receptor subtype EP4: the roles of phosphatidylinositol 3-kinase and CCAAT/enhancer-binding protein β,” The Journal of Biological Chemistry, vol. 280, no. 39, pp. 33240–33249, 2005. View at Publisher · View at Google Scholar · View at Scopus
  58. L. Xu, C. Han, K. Lim, and T. Wu, “Cross-talk between peroxisome proliferator-activated receptor δ and cytosolic phospholipase A2α/cyclooxygenase-2/prostaglandin E2 signaling pathways in human hepatocellular carcinoma cells,” Cancer Research, vol. 66, no. 24, pp. 11859–11868, 2006. View at Publisher · View at Google Scholar · View at Scopus
  59. J. Eswaran, D. Cyanam, P. Mudvari et al., “Transcriptomic landscape of breast cancers through mRNA sequencing,” Scientific Reports, vol. 2, article 264, 2012. View at Publisher · View at Google Scholar · View at Scopus
  60. B. L. Pierce, R. Ballard-Barbash, L. Bernstein et al., “Elevated biomarkers of inflammation are associated with reduced survival among breast cancer patients,” Journal of Clinical Oncology, vol. 27, no. 21, pp. 3437–3444, 2009. View at Publisher · View at Google Scholar · View at Scopus
  61. C. Gebhardt, J. Németh, P. Angel, and J. Hess, “S100A8 and S100A9 in inflammation and cancer,” Biochemical Pharmacology, vol. 72, no. 11, pp. 1622–1631, 2006. View at Publisher · View at Google Scholar · View at Scopus
  62. S. Ghavami, S. Chitayat, M. Hashemi et al., “S100A8/A9: a Janus-faced molecule in cancer therapy and tumorgenesis,” European Journal of Pharmacology, vol. 625, no. 1–3, pp. 73–83, 2009. View at Publisher · View at Google Scholar · View at Scopus
  63. C. B. Pollock, O. Rodriguez, P. L. Martin et al., “Induction of metastatic gastric cancer by peroxisome proliferator-activated receptorδ activation,” PPAR Research, vol. 2010, Article ID 571783, 12 pages, 2010. View at Publisher · View at Google Scholar · View at Scopus
  64. G. D. Barish, V. A. Narkar, and R. M. Evans, “PPARδ: a dagger in the heart of the metabolic syndrome,” Journal of Clinical Investigation, vol. 116, no. 3, pp. 590–597, 2006. View at Publisher · View at Google Scholar · View at Scopus
  65. J. Jonkers and W. H. Moolenaar, “Mammary tumorigenesis through LPA receptor signaling,” Cancer Cell, vol. 15, no. 6, pp. 457–459, 2009. View at Publisher · View at Google Scholar · View at Scopus
  66. N. Panupinthu, H. Y. Lee, and G. B. Mills, “Lysophosphatidic acid production and action: critical new players in breast cancer initiation and progression,” British Journal of Cancer, vol. 102, no. 6, pp. 941–946, 2010. View at Publisher · View at Google Scholar · View at Scopus
  67. D. A. Foster, “Phosphatidic acid signaling to mTOR: signals for the survival of human cancer cells,” Biochimica et Biophysica Acta (BBA)—Molecular and Cell Biology of Lipids, vol. 1791, no. 9, pp. 949–955, 2009. View at Publisher · View at Google Scholar · View at Scopus
  68. J. Storch and A. E. Thumser, “Tissue-specific functions in the fatty acid-binding protein family,” The Journal of Biological Chemistry, vol. 285, no. 43, pp. 32679–32683, 2010. View at Publisher · View at Google Scholar · View at Scopus
  69. P. Kannan-Thulasiraman, D. D. Seachrist, G. H. Mahabeleshwar, M. K. Jain, and N. Noy, “Fatty acid-binding protein 5 and PPARβ/δ are critical mediators of epidermal growth factor receptor-induced carcinoma cell growth,” Journal of Biological Chemistry, vol. 286, no. 41, pp. 19106–19115, 2011. View at Publisher · View at Google Scholar · View at Scopus
  70. L. Levi, G. Lobo, M. K. Doud et al., “Genetic ablation of the fatty acid-binding protein FABP5 suppresses HER2-induced mammary tumorigenesis,” Cancer Research, vol. 73, no. 15, pp. 4770–4780, 2013. View at Publisher · View at Google Scholar · View at Scopus
  71. K. M. Nieman, H. A. Kenny, C. V. Penicka et al., “Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth,” Nature Medicine, vol. 17, no. 11, pp. 1498–1503, 2011. View at Publisher · View at Google Scholar · View at Scopus
  72. K. Ito, A. Carracedo, D. Weiss et al., “A PML-PPAR-δ pathway for fatty acid oxidation regulates hematopoietic stem cell maintenance,” Nature Medicine, vol. 18, no. 9, pp. 1350–1358, 2012. View at Publisher · View at Google Scholar · View at Scopus
  73. L. M. Coussens, L. Zitvogel, and A. K. Palucka, “Neutralizing tumor-promoting chronic inflammation: a magic bullet?” Science, vol. 339, no. 6117, pp. 286–291, 2013. View at Publisher · View at Google Scholar · View at Scopus
  74. D. I. Gabrilovich and S. Nagaraj, “Myeloid-derived suppressor cells as regulators of the immune system,” Nature Reviews Immunology, vol. 9, no. 3, pp. 162–174, 2009. View at Publisher · View at Google Scholar · View at Scopus
  75. D. M. Pardoll, “The blockade of immune checkpoints in cancer immunotherapy,” Nature Reviews Cancer, vol. 12, no. 4, pp. 252–264, 2012. View at Publisher · View at Google Scholar · View at Scopus
  76. A. Sica and V. Bronte, “Altered macrophage differentiation and immune dysfunction in tumor development,” The Journal of Clinical Investigation, vol. 117, no. 5, pp. 1155–1166, 2007. View at Publisher · View at Google Scholar · View at Scopus
  77. K. Kang, S. M. Reilly, V. Karabacak et al., “Adipocyte-derived Th2 cytokines and myeloid PPARδ regulate macrophage polarization and insulin sensitivity,” Cell Metabolism, vol. 7, no. 6, pp. 485–495, 2008. View at Publisher · View at Google Scholar · View at Scopus
  78. J. I. Odegaard, R. R. Ricardo-Gonzalez, A. Red Eagle et al., “Alternative M2 activation of Kupffer cells by PPARδ ameliorates obesity-induced insulin resistance,” Cell Metabolism, vol. 7, no. 6, pp. 496–507, 2008. View at Publisher · View at Google Scholar · View at Scopus
  79. L. Mukundan, J. I. Odegaard, C. R. Morel et al., “PPAR-δ senses and orchestrates clearance of apoptotic cells to promote tolerance,” Nature Medicine, vol. 15, no. 11, pp. 1266–1272, 2009. View at Publisher · View at Google Scholar · View at Scopus
  80. P. Cheng, C. A. Corzo, N. Luetteke et al., “Inhibition of dendritic cell differentiation and accumulation of myeloid-derived suppressor cells in cancer is regulated by S100A9 protein,” Journal of Experimental Medicine, vol. 205, no. 10, pp. 2235–2249, 2008. View at Publisher · View at Google Scholar · View at Scopus
  81. S. Hiratsuka, A. Watanabe, Y. Sakurai et al., “The S100A8-serum amyloid A3-TLR4 paracrine cascade establishes a pre-metastatic phase,” Nature Cell Biology, vol. 10, no. 11, pp. 1349–1355, 2008. View at Publisher · View at Google Scholar · View at Scopus
  82. P. Sinha, V. K. Clements, A. M. Fulton, and S. Ostrand-Rosenberg, “Prostaglandin E2 promotes tumor progression by inducing myeloid-derived suppressor cells,” Cancer Research, vol. 67, no. 9, pp. 4507–4513, 2007. View at Publisher · View at Google Scholar · View at Scopus
  83. C.-H. Chang, J. Qiu, D. O'Sullivan et al., “Metabolic competition in the tumor microenvironment is a driver of cancer progression,” Cell, vol. 162, no. 6, pp. 1229–1241, 2015. View at Publisher · View at Google Scholar · View at Scopus
  84. A. J. Muller and P. A. Scherle, “Targeting the mechanisms of tumoral immune tolerance with small-molecule inhibitors,” Nature Reviews Cancer, vol. 6, no. 8, pp. 613–625, 2006. View at Publisher · View at Google Scholar · View at Scopus