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Review

Epigenetic Control of the Tumor Microenvironment

, &
Pages 1671-1687 | Received 24 Aug 2016, Accepted 21 Sep 2016, Published online: 04 Oct 2016

References

  • Hansen JM , ColemanRL , SoodAK . Targeting the tumour microenvironment in ovarian cancer . Eur. J. Cancer56 , 131 – 143 ( 2016 ).
  • Iijima J , KonnoK , ItanoN . Inflammatory alterations of the extracellular matrix in the tumor microenvironment . Cancers (Basel)3 ( 3 ), 3189 – 3205 ( 2011 ).
  • Neesse A , AlgulH , TuvesonDA , GressTM . Stromal biology and therapy in pancreatic cancer: a changing paradigm . Gut64 ( 9 ), 1476 – 1484 ( 2015 ).
  • Nielsen MF , MortensenMB , DetlefsenS . Key players in pancreatic cancer-stroma interaction: cancer-associated fibroblasts, endothelial and inflammatory cells . World J. Gastroenterol.22 ( 9 ), 2678 – 2700 ( 2016 ).
  • Gascard P , TlstyTD . Carcinoma-associated fibroblasts: orchestrating the composition of malignancy . Genes Dev.30 ( 9 ), 1002 – 1019 ( 2016 ).
  • Feig C , GopinathanA , NeesseA , ChanDS , CookN , TuvesonDA . The pancreas cancer microenvironment . Clin. Cancer Res.18 ( 16 ), 4266 – 4276 ( 2012 ).
  • Houghton AN . LIGHTing the way for tumor immunity . Nat. Immunol.5 ( 2 ), 123 – 124 ( 2004 ).
  • Hinz B , PhanSH , ThannickalVJet al. Recent developments in myofibroblast biology: paradigms for connective tissue remodeling . Am. J. Pathol.180 ( 4 ), 1340 – 1355 ( 2012 ).
  • Schober M , JesenofskyR , FaissnerRet al. Desmoplasia and chemoresistance in pancreatic cancer . Cancers (Basel)6 ( 4 ), 2137 – 2154 ( 2014 ).
  • Shiga K , HaraM , NagasakiT , SatoT , TakahashiH , TakeyamaH . Cancer-associated fibroblasts: their characteristics and their roles in tumor growth . Cancers (Basel)7 ( 4 ), 2443 – 2458 ( 2015 ).
  • Buchsbaum RJ , OhSY . Breast cancer-associated fibroblasts: where we are and where we need to go . Cancers (Basel)8 ( 2 ), pii: E19 ( 2016 ).
  • Karagiannis GS , PoutahidisT , ErdmanSE , KirschR , RiddellRH , DiamandisEP . Cancer-associated fibroblasts drive the progression of metastasis through both paracrine and mechanical pressure on cancer tissue . Mol. Cancer Res.10 ( 11 ), 1403 – 1418 ( 2012 ).
  • Xing Y , ZhaoS , ZhouBP , MiJ . Metabolic reprogramming of the tumour microenvironment . FEBS J.282 ( 20 ), 3892 – 3898 ( 2015 ).
  • Pitt JM , MarabelleA , EggermontA , SoriaJC , KroemerG , ZitvogelL . Targeting the tumor microenvironment: removing obstruction to anticancer immune responses and immunotherapy . Ann. Oncol.27 ( 8 ), 1482 – 1492 ( 2016 ).
  • Yu J , WalterK , OmuraNet al. Unlike pancreatic cancer cells pancreatic cancer associated fibroblasts display minimal gene induction after 5-aza-2′-deoxycytidine . PLoS ONE7 ( 9 ), e43456 ( 2012 ).
  • Chung I , KarpfAR , MuindiJRet al. Epigenetic silencing of CYP24 in tumor-derived endothelial cells contributes to selective growth inhibition by calcitriol . J. Biol. Chem.282 ( 12 ), 8704 – 8714 ( 2007 ).
  • Tyan SW , HsuCH , PengKLet al. Breast cancer cells induce stromal fibroblasts to secrete ADAMTS1 for cancer invasion through an epigenetic change . PLoS ONE7 ( 4 ), e35128 ( 2012 ).
  • Hellebrekers DM , MelotteV , VireEet al. Identification of epigenetically silenced genes in tumor endothelial cells . Cancer Res.67 ( 9 ), 4138 – 4148 ( 2007 ).
  • Mitra AK , ZillhardtM , HuaYet al. MicroRNAs reprogram normal fibroblasts into cancer-associated fibroblasts in ovarian cancer . Cancer Discov.2 ( 12 ), 1100 – 1108 ( 2012 ).
  • Yamada N , TsujimuraN , KumazakiMet al. Colorectal cancer cell-derived microvesicles containing microRNA-1246 promote angiogenesis by activating Smad 1/5/8 signaling elicited by PML down-regulation in endothelial cells . Biochim. Biophys. Acta1839 ( 11 ), 1256 – 1272 ( 2014 ).
  • Yang M , ChenJ , SuFet al. Microvesicles secreted by macrophages shuttle invasion-potentiating microRNAs into breast cancer cells . Mol. Cancer10 , 117 ( 2011 ).
  • Fukino K , ShenL , PatocsA , MutterGL , EngC . Genomic instability within tumor stroma and clinicopathological characteristics of sporadic primary invasive breast carcinoma . JAMA297 ( 19 ), 2103 – 2111 ( 2007 ).
  • Patocs A , ZhangL , XuYet al. Breast-cancer stromal cells with TP53 mutations and nodal metastases . N. Engl. J. Med.357 ( 25 ), 2543 – 2551 ( 2007 ).
  • Weber F , XuY , ZhangLet al. Microenvironmental genomic alterations and clinicopathological behavior in head and neck squamous cell carcinoma . JAMA297 ( 2 ), 187 – 195 ( 2007 ).
  • Corver WE , Ter HaarNT , FleurenGJ , OostingJ . Cervical carcinoma-associated fibroblasts are DNA diploid and do not show evidence for somatic genetic alterations . Cell. Oncol. (Dordr.)34 ( 6 ), 553 – 563 ( 2011 ).
  • Hosein AN , WuM , ArcandSLet al. Breast carcinoma-associated fibroblasts rarely contain p53 mutations or chromosomal aberrations . Cancer Res.70 ( 14 ), 5770 – 5777 ( 2010 ).
  • Qiu W , HuM , SridharAet al. No evidence of clonal somatic genetic alterations in cancer-associated fibroblasts from human breast and ovarian carcinomas . Nat. Genet.40 ( 5 ), 650 – 655 ( 2008 ).
  • Madar S , GoldsteinI , RotterV . ‘Cancer associated fibroblasts’ – more than meets the eye . Trends Mol. Med.19 ( 8 ), 447 – 453 ( 2013 ).
  • Ostman A , AugstenM . Cancer-associated fibroblasts and tumor growth – bystanders turning into key players . Curr. Opin. Genet. Dev.19 ( 1 ), 67 – 73 ( 2009 ).
  • Bird A . Perceptions of epigenetics . Nature447 ( 7143 ), 396 – 398 ( 2007 ).
  • Easwaran H , TsaiHC , BaylinSB . Cancer epigenetics: tumor heterogeneity, plasticity of stem-like states, and drug resistance . Mol. Cell54 ( 5 ), 716 – 727 ( 2014 ).
  • Schlesinger Y , StraussmanR , KeshetIet al. Polycomb-mediated methylation on Lys27 of histone H3 pre-marks genes for de novo methylation in cancer . Nat. Genet.39 ( 2 ), 232 – 236 ( 2007 ).
  • Jin B , RobertsonKD . DNA methyltransferases, DNA damage repair, and cancer . Adv. Exp. Med. Biol.754 , 3 – 29 ( 2013 ).
  • Jeschke J , CollignonE , FuksF . DNA methylome profiling beyond promoters – taking an epigenetic snapshot of the breast tumor microenvironment . FEBS J.282 ( 9 ), 1801 – 1814 ( 2015 ).
  • Yang X , HanH , De CarvalhoDD , LayFD , JonesPA , LiangG . Gene body methylation can alter gene expression and is a therapeutic target in cancer . Cancer Cell26 ( 4 ), 577 – 590 ( 2014 ).
  • Cheishvili D , BoureauL , SzyfM . DNA demethylation and invasive cancer: implications for therapeutics . Br. J. Pharmacol.172 ( 11 ), 2705 – 2715 ( 2015 ).
  • Mummaneni P , ShordSS . Epigenetics and oncology . Pharmacotherapy34 ( 5 ), 495 – 505 ( 2014 ).
  • Klutstein M , NejmanD , GreenfieldR , CedarH . DNA methylation in cancer and aging . Cancer Res.76 ( 12 ), 3446 – 3450 ( 2016 ).
  • Vincent A , OmuraN , HongSM , JaffeA , EshlemanJ , GogginsM . Genome-wide analysis of promoter methylation associated with gene expression profile in pancreatic adenocarcinoma . Clin. Cancer Res.17 ( 13 ), 4341 – 4354 ( 2011 ).
  • Esteller M . Cancer epigenomics: DNA methylomes and histone-modification maps . Nat. Rev. Genet.8 ( 4 ), 286 – 298 ( 2007 ).
  • Jiang L , GondaTA , GambleMVet al. Global hypomethylation of genomic DNA in cancer-associated myofibroblasts . Cancer Res.68 ( 23 ), 9900 – 9908 ( 2008 ).
  • Vizoso M , PuigM , CarmonaFJet al. Aberrant DNA methylation in non-small cell lung cancer-associated fibroblasts . Carcinogenesis36 ( 12 ), 1453 – 1463 ( 2015 ).
  • Gotze S , SchumacherEC , KordesC , HaussingerD . Epigenetic changes during hepatic stellate cell activation . PLoS ONE10 ( 6 ), e0128745 ( 2015 ).
  • Xiao Q , ZhouD , RuckiAAet al. Cancer associated fibroblasts in pancreatic cancer are reprogrammed by tumor-induced alterations in genomic DNA methylation . Cancer Res.76 ( 18 ), 5395 – 5404 ( 2016 ).
  • Albrengues J , BerteroT , GrassetEet al. Epigenetic switch drives the conversion of fibroblasts into proinvasive cancer-associated fibroblasts . Nat. Commun.6 , 10204 ( 2015 ).
  • Bian EB , HuangC , MaTTet al. DNMT1-mediated PTEN hypermethylation confers hepatic stellate cell activation and liver fibrogenesis in rats . Toxicol. Appl. Pharmacol.264 ( 1 ), 13 – 22 ( 2012 ).
  • Janson PC , MaritsP , ThornM , OhlssonR , WinqvistO . CpG methylation of the IFNG gene as a mechanism to induce immunosuppression [correction of immunosupression] in tumor-infiltrating lymphocytes . J. Immunol.181 ( 4 ), 2878 – 2886 ( 2008 ).
  • Ashcroft GS , YangX , GlickABet al. Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory response . Nat. Cell Biol.1 ( 5 ), 260 – 266 ( 1999 ).
  • Flanders KC . Smad3 as a mediator of the fibrotic response . Int. J. Exp. Pathol.85 ( 2 ), 47 – 64 ( 2004 ).
  • Wang Z , GaoZ , ShiYet al. Inhibition of Smad3 expression decreases collagen synthesis in keloid disease fibroblasts . J. Plast. Reconstr. Aesthet. Surg.60 ( 11 ), 1193 – 1199 ( 2007 ).
  • Iba K , AlbrechtsenR , GilpinBJ , LoechelF , WewerUM . Cysteine-rich domain of human ADAM 12 (meltrin alpha) supports tumor cell adhesion . Am. J. Pathol.154 ( 5 ), 1489 – 1501 ( 1999 ).
  • Walter K , OmuraN , HongSMet al. Overexpression of smoothened activates the sonic hedgehog signaling pathway in pancreatic cancer-associated fibroblasts . Clin. Cancer Res.16 ( 6 ), 1781 – 1789 ( 2010 ).
  • De Wever O , DemetterP , MareelM , BrackeM . Stromal myofibroblasts are drivers of invasive cancer growth . Int. J. Cancer123 ( 10 ), 2229 – 2238 ( 2008 ).
  • Franco OE , ShawAK , StrandDW , HaywardSW . Cancer associated fibroblasts in cancer pathogenesis . Semin. Cell Dev. Biol.21 ( 1 ), 33 – 39 ( 2010 ).
  • Bronisz A , GodlewskiJ , WallaceJAet al. Reprogramming of the tumour microenvironment by stromal PTEN-regulated miR-320 . Nat. Cell Biol.14 ( 2 ), 159 – 167 ( 2012 ).
  • Trimboli AJ , Cantemir-StoneCZ , LiFet al. Pten in stromal fibroblasts suppresses mammary epithelial tumours . Nature461 ( 7267 ), 1084 – 1091 ( 2009 ).
  • Bedi U , MishraVK , WasilewskiD , ScheelC , JohnsenSA . Epigenetic plasticity: a central regulator of epithelial-to-mesenchymal transition in cancer . Oncotarget5 ( 8 ), 2016 – 2029 ( 2014 ).
  • Sharma S , KellyTK , JonesPA . Epigenetics in cancer . Carcinogenesis31 ( 1 ), 27 – 36 ( 2010 ).
  • Kim KH , RobertsCW . Targeting EZH2 in cancer . Nat. Med.22 ( 2 ), 128 – 134 ( 2016 ).
  • Shilatifard A . The COMPASS family of histone H3K4 methylases: mechanisms of regulation in development and disease pathogenesis . Annu. Rev. Biochem.81 , 65 – 95 ( 2012 ).
  • Lim S , MetzgerE , SchuleR , KirfelJ , BuettnerR . Epigenetic regulation of cancer growth by histone demethylases . Int. J. Cancer127 ( 9 ), 1991 – 1998 ( 2010 ).
  • Simon RP , RobaaD , AlhalabiZ , SipplW , JungM . KATching-up on small molecule modulators of lysine acetyltransferases . J. Med. Chem.59 ( 4 ), 1249 – 1270 ( 2016 ).
  • Benedetti R , ConteM , AltucciL . Targeting histone deacetylases in diseases: where are we?Antioxid. Redox. Signal.23 ( 1 ), 99 – 126 ( 2015 ).
  • Wagner EJ , CarpenterPB . Understanding the language of Lys36 methylation at histone H3 . Nat. Rev. Mol. Cell Biol.13 ( 2 ), 115 – 126 ( 2012 ).
  • Yi X , JiangXJ , LiXY , JiangDS . Histone methyltransferases: novel targets for tumor and developmental defects . Am. J. Transl. Res.7 ( 11 ), 2159 – 2175 ( 2015 ).
  • Perugorria MJ , WilsonCL , ZeybelMet al. Histone methyltransferase ASH1 orchestrates fibrogenic gene transcription during myofibroblast transdifferentiation . Hepatology56 ( 3 ), 1129 – 1139 ( 2012 ).
  • Alicea-Velazquez NL , ShinskySA , LohDM , LeeJH , SkalnikDG , CosgroveMS . Targeted disruption of the interaction between WD-40 repeat protein 5 (WDR5) and mixed lineage leukemia (MLL)/SET1 family proteins specifically inhibits MLL1 and SETd1A methyltransferase complexes . J. Biol. Chem. doi:10.1074/jbc.M116.752626 ( 2016 ) ( Epub ahead of print ).
  • Tsai CT , SoCW . Epigenetic therapies by targeting aberrant histone methylome in AML: molecular mechanisms, current preclinical and clinical development . Oncogene doi:10.1038/onc.2016.315 ( 2016 ) ( Epub ahead of print ).
  • Nagarsheth N , PengD , KryczekIet al. PRC2 epigenetically silences Th1-Type chemokines to suppress effector T-cell trafficking in colon cancer . Cancer Res.76 ( 2 ), 275 – 282 ( 2016 ).
  • Peng D , KryczekI , NagarshethNet al. Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy . Nature527 ( 7577 ), 249 – 253 ( 2015 ).
  • Alvarez-Errico D , Vento-TormoR , SiewekeM , BallestarE . Epigenetic control of myeloid cell differentiation, identity and function . Nat. Rev. Immunol.15 ( 1 ), 7 – 17 ( 2015 ).
  • Mehta S , JeffreyKL . Beyond receptors and signaling: epigenetic factors in the regulation of innate immunity . Immunol. Cell Biol.93 ( 3 ), 233 – 244 ( 2015 ).
  • Suarez-Alvarez B , Baragano RanerosA , OrtegaF , Lopez-LarreaC . Epigenetic modulation of the immune function: a potential target for tolerance . Epigenetics8 ( 7 ), 694 – 702 ( 2013 ).
  • Frediani JN , FabbriM . Essential role of miRNAs in orchestrating the biology of the tumor microenvironment . Mol. Cancer15 ( 1 ), 42 ( 2016 ).
  • Gallach S , Calabuig-FarinasS , Jantus-LewintreE , CampsC . MicroRNAs: promising new antiangiogenic targets in cancer . Biomed. Res. Int.2014 , 878450 ( 2014 ).
  • Chou J , ShahiP , WerbZ . microRNA-mediated regulation of the tumor microenvironment . Cell Cycle12 ( 20 ), 3262 – 3271 ( 2013 ).
  • Kohlhapp FJ , MitraAK , LengyelE , PeterME . MicroRNAs as mediators and communicators between cancer cells and the tumor microenvironment . Oncogene34 ( 48 ), 5857 – 5868 ( 2015 ).
  • Kuninty PR , SchnittertJ , StormG , PrakashJ . MicroRNA targeting to modulate tumor microenvironment . Front. Oncol.6 , 3 ( 2016 ).
  • Svoronos AA , EngelmanDM , SlackFJ . OncomiR or tumor suppressor? The duplicity of microRNAs in cancer . Cancer Res.76 ( 13 ), 3666 – 3670 ( 2016 ).
  • Aprelikova O , YuX , PallaJet al. The role of miR-31 and its target gene SATB2 in cancer-associated fibroblasts . Cell Cycle9 ( 21 ), 4387 – 4398 ( 2010 ).
  • Doldi V , CallariM , GiannoniEet al. Integrated gene and miRNA expression analysis of prostate cancer associated fibroblasts supports a prominent role for interleukin-6 in fibroblast activation . Oncotarget6 ( 31 ), 31441 – 31460 ( 2015 ).
  • Shen H , YuX , YangFet al. Reprogramming of normal fibroblasts into cancer-associated fibroblasts by miRNAs-mediated CCL2/VEGFA signaling . PLoS Genet.12 ( 8 ), e1006244 ( 2016 ).
  • Wang L , SteeleI , KumarJDet al. Distinct miRNA profiles in normal and gastric cancer myofibroblasts and significance in Wnt signaling . Am. J. Physiol. Gastrointest. Liver Physiol.310 ( 9 ), G696 – G704 ( 2016 ).
  • Yang TS , YangXH , ChenXet al. MicroRNA-106b in cancer-associated fibroblasts from gastric cancer promotes cell migration and invasion by targeting PTEN . FEBS Lett.588 ( 13 ), 2162 – 2169 ( 2014 ).
  • Musumeci M , CoppolaV , AddarioAet al. Control of tumor and microenvironment cross-talk by miR-15a and miR-16 in prostate cancer . Oncogene30 ( 41 ), 4231 – 4242 ( 2011 ).
  • Aprelikova O , PallaJ , HiblerBet al. Silencing of miR-148a in cancer-associated fibroblasts results in WNT10B-mediated stimulation of tumor cell motility . Oncogene32 ( 27 ), 3246 – 3253 ( 2013 ).
  • Bullock MD , PickardKM , NielsenBSet al. Pleiotropic actions of miR-21 highlight the critical role of deregulated stromal microRNAs during colorectal cancer progression . Cell Death Dis.4 , e684 ( 2013 ).
  • Ali S , SureshR , BanerjeeSet al. Contribution of microRNAs in understanding the pancreatic tumor microenvironment involving cancer associated stellate and fibroblast cells . Am. J. Cancer Res.5 ( 3 ), 1251 – 1264 ( 2015 ).
  • Kuninty PR , BojmarL , TjomslandVet al. MicroRNA-199a and -214 as potential therapeutic targets in pancreatic stellate cells in pancreatic tumor . Oncotarget7 ( 13 ), 16396 – 16408 ( 2016 ).
  • Chen Y , DuM , WangJet al. MiRNA-200a expression is inverse correlation with hepatocyte growth factor expression in stromal fibroblasts and its high expression predicts a good prognosis in patients with non-small cell lung cancer . Oncotarget doi:10.18632/oncotarget.10302 ( 2016 ) ( Epub ahead of print ).
  • Baroni S , Romero-CordobaS , PlantamuraIet al. Exosome-mediated delivery of miR-9 induces cancer-associated fibroblast-like properties in human breast fibroblasts . Cell Death Dis.7 ( 7 ), e2312 ( 2016 ).
  • Lopatina T , GaiC , DeregibusMC , KholiaS , CamussiG . Cross talk between cancer and mesenchymal stem cells through extracellular vesicles carrying nucleic acids . Front. Oncol.6 , 125 ( 2016 ).
  • Pang W , SuJ , WangYet al. Pancreatic cancer-secreted miR-155 implicates in the conversion from normal fibroblasts to cancer-associated fibroblasts . Cancer Sci.106 ( 10 ), 1362 – 1369 ( 2015 ).
  • Paggetti J , HaderkF , SeiffertMet al. Exosomes released by chronic lymphocytic leukemia cells induce the transition of stromal cells into cancer-associated fibroblasts . Blood126 ( 9 ), 1106 – 1117 ( 2015 ).
  • Lin HK , BergmannS , PandolfiPP . Cytoplasmic PML function in TGF-beta signalling . Nature431 ( 7005 ), 205 – 211 ( 2004 ).
  • Kim J , MorleyS , LeMet al. Enhanced shedding of extracellular vesicles from amoeboid prostate cancer cells: potential effects on the tumor microenvironment . Cancer Biol. Ther.15 ( 4 ), 409 – 418 ( 2014 ).
  • Yin Y , CaiX , ChenXet al. Tumor-secreted miR-214 induces regulatory T cells: a major link between immune evasion and tumor growth . Cell Res.24 ( 10 ), 1164 – 1180 ( 2014 ).
  • Zhou M , ChenJ , ZhouL , ChenW , DingG , CaoL . Pancreatic cancer derived exosomes regulate the expression of TLR4 in dendritic cells via miR-203 . Cell. Immunol.292 ( 1–2 ), 65 – 69 ( 2014 ).
  • Josson S , GururajanM , SungSYet al. Stromal fibroblast-derived miR-409 promotes epithelial-to-mesenchymal transition and prostate tumorigenesis . Oncogene34 ( 21 ), 2690 – 2699 ( 2015 ).
  • Shah SH , MillerP , Garcia-ContrerasMet al. Hierarchical paracrine interaction of breast cancer associated fibroblasts with cancer cells via hMAPK-microRNAs to drive ER-negative breast cancer phenotype . Cancer Biol. Ther.16 ( 11 ), 1671 – 1681 ( 2015 ).
  • Zhao E , MajT , KryczekIet al. Cancer mediates effector T cell dysfunction by targeting microRNAs and EZH2 via glycolysis restriction . Nat. Immunol.17 ( 1 ), 95 – 103 ( 2016 ).
  • Amsen D , HelbigC , BackerRA . Notch in T cell differentiation: all things considered . Trends Immunol.36 ( 12 ), 802 – 814 ( 2015 ).
  • Li P , ShanJX , ChenXHet al. Epigenetic silencing of microRNA-149 in cancer-associated fibroblasts mediates prostaglandin E2/interleukin-6 signaling in the tumor microenvironment . Cell Res.25 ( 5 ), 588 – 603 ( 2015 ).
  • Erez N , GlanzS , RazY , AviviC , BarshackI . Cancer associated fibroblasts express pro-inflammatory factors in human breast and ovarian tumors . Biochem. Biophys. Res. Commun.437 ( 3 ), 397 – 402 ( 2013 ).
  • Gao J , WangD , LiuDet al. Tumor necrosis factor-related apoptosis-inducing ligand induces the expression of proinflammatory cytokines in macrophages and re-educates tumor-associated macrophages to an antitumor phenotype . Mol. Biol. Cell26 ( 18 ), 3178 – 3189 ( 2015 ).
  • Chiappinelli KB , ZahnowCA , AhujaN , BaylinSB . Combining Epigenetic and Immunotherapy to Combat Cancer . Cancer Res.76 ( 7 ), 1683 – 1689 ( 2016 ).
  • Falahi F , Van KruchtenM , MartinetN , HospersGA , RotsMG . Current and upcoming approaches to exploit the reversibility of epigenetic mutations in breast cancer . Breast Cancer Res.16 ( 4 ), 412 ( 2014 ).
  • Simo-Riudalbas L , EstellerM . Targeting the histone orthography of cancer: drugs for writers, erasers and readers . Br. J. Pharmacol.172 ( 11 ), 2716 – 2732 ( 2015 ).
  • Strauss J , FiggWD . Using epigenetic therapy to overcome chemotherapy resistance . Anticancer Res.36 ( 1 ), 1 – 4 ( 2016 ).
  • Van Kampen JG , Marijnissen-Van ZantenMA , SimmerF , Van Der GraafWT , LigtenbergMJ , NagtegaalID . Epigenetic targeting in pancreatic cancer . Cancer Treat. Rev.40 ( 5 ), 656 – 664 ( 2014 ).
  • Pleyer L , GreilR . Digging deep into “dirty” drugs – modulation of the methylation machinery . Drug Metab. Rev.47 ( 2 ), 252 – 279 ( 2015 ).
  • Bian EB , HuangC , WangHet al. Repression of Smad7 mediated by DNMT1 determines hepatic stellate cell activation and liver fibrosis in rats . Toxicol. Lett.224 ( 2 ), 175 – 185 ( 2014 ).
  • Mann J , OakleyF , AkiboyeF , ElsharkawyA , ThorneAW , MannDA . Regulation of myofibroblast transdifferentiation by DNA methylation and MeCP2: implications for wound healing and fibrogenesis . Cell Death Differ.14 ( 2 ), 275 – 285 ( 2007 ).
  • Niki T , RomboutsK , De BleserPet al. A histone deacetylase inhibitor, trichostatin A, suppresses myofibroblastic differentiation of rat hepatic stellate cells in primary culture . Hepatology29 ( 3 ), 858 – 867 ( 1999 ).
  • Rombouts K , NikiT , WielantA , HellemansK , GeertsA . Trichostatin A, lead compound for development of antifibrogenic drugs . Acta Gastroenterol. Belg.64 ( 3 ), 239 – 246 ( 2001 ).
  • Bulow R , FitznerB , SparmannG , EmmrichJ , LiebeS , JasterR . Antifibrogenic effects of histone deacetylase inhibitors on pancreatic stellate cells . Biochem. Pharmacol.74 ( 12 ), 1747 – 1757 ( 2007 ).
  • Liu Y , WangZ , WangJet al. A histone deacetylase inhibitor, largazole, decreases liver fibrosis and angiogenesis by inhibiting transforming growth factor-beta and vascular endothelial growth factor signalling . Liver Int.33 ( 4 ), 504 – 515 ( 2013 ).
  • Park KC , ParkJH , JeonJYet al. A new histone deacetylase inhibitor improves liver fibrosis in BDL rats through suppression of hepatic stellate cells . Br. J. Pharmacol.171 ( 21 ), 4820 – 4830 ( 2014 ).
  • Zhu S , DenmanCJ , CobanogluZSet al. The narrow-spectrum HDAC inhibitor entinostat enhances NKG2D expression without NK cell toxicity, leading to enhanced recognition of cancer cells . Pharm. Res.32 ( 3 ), 779 – 792 ( 2015 ).
  • Italiano A . Role of the EZH2 histone methyltransferase as a therapeutic target in cancer . Pharmacol. Ther.165 , 26 – 31 ( 2016 ).
  • Yin J , LeavenworthJW , LiYet al. Ezh2 regulates differentiation and function of natural killer cells through histone methyltransferase activity . Proc. Natl Acad. Sci. USA112 ( 52 ), 15988 – 15993 ( 2015 ).
  • Bantikassegn A , SongX , PolitiK . Isolation of epithelial, endothelial, and immune cells from lungs of transgenic mice with oncogene-induced lung adenocarcinomas . Am. J. Respir. Cell Mol. Biol.52 ( 4 ), 409 – 417 ( 2015 ).
  • Galvan JA , HelblingM , KoelzerVHet al. TWIST1 and TWIST2 promoter methylation and protein expression in tumor stroma influence the epithelial-mesenchymal transition-like tumor budding phenotype in colorectal cancer . Oncotarget6 ( 2 ), 874 – 885 ( 2015 ).
  • Massani M , SteccaT , FabrisLet al. Isolation and characterization of biliary epithelial and stromal cells from resected human cholangiocarcinoma: a novel in vitro model to study tumor-stroma interactions . Oncol. Rep.30 ( 3 ), 1143 – 1148 ( 2013 ).
  • Luo W , HuQ , WangDet al. Isolation and genome-wide expression and methylation characterization of CD31+ cells from normal and malignant human prostate tissue . Oncotarget4 ( 9 ), 1472 – 1483 ( 2013 ).
  • Apte MV , HaberPS , ApplegateTLet al. Periacinar stellate shaped cells in rat pancreas: identification, isolation, and culture . Gut43 ( 1 ), 128 – 133 ( 1998 ).
  • Friedman SL . Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver . Physiol. Rev.88 ( 1 ), 125 – 172 ( 2008 ).
  • Grupp C , TrocheI , KlassC , KohlerM , MullerGA . A novel model to study renal myofibroblast formation in vitro . Kidney Int.59 ( 2 ), 543 – 553 ( 2001 ).
  • Wilson BG , RobertsCW . SWI/SNF nucleosome remodellers and cancer . Nat. Rev. Cancer11 ( 7 ), 481 – 492 ( 2011 ).
  • Arina A , IdelC , HyjekEMet al. Tumor-associated fibroblasts predominantly come from local and not circulating precursors . Proc. Natl Acad. Sci. USA113 ( 27 ), 7551 – 7556 ( 2016 ).
  • Lund PK . The alpha-smooth muscle actin promoter: a useful tool to analyse autocrine and paracrine roles of mesenchymal cells in normal and diseased bowel . Gut42 ( 3 ), 320 – 322 ( 1998 ).
  • Santos AM , JungJ , AzizN , KissilJL , PureE . Targeting fibroblast activation protein inhibits tumor stromagenesis and growth in mice . J. Clin. Invest.119 ( 12 ), 3613 – 3625 ( 2009 ).
  • Banerjee S , ModiS , McginnOet al. Impaired synthesis of stromal components in response to minnelide improves vascular function, drug delivery, and survival in pancreatic cancer . Clin. Cancer Res.22 ( 2 ), 415 – 425 ( 2016 ).
  • Murakami M , ErnstingMJ , UndzysE , HolwellN , FoltzWD , LiSD . Docetaxel conjugate nanoparticles that target alpha-smooth muscle actin-expressing stromal cells suppress breast cancer metastasis . Cancer Res.73 ( 15 ), 4862 – 4871 ( 2013 ).
  • Sumida T , KitadaiY , ShinagawaKet al. Anti-stromal therapy with imatinib inhibits growth and metastasis of gastric carcinoma in an orthotopic nude mouse model . Int. J. Cancer128 ( 9 ), 2050 – 2062 ( 2011 ).
  • Carr RM , Fernandez-ZapicoME . Pancreatic cancer microenvironment, to target or not to target?EMBO Mol. Med.8 ( 2 ), 80 – 82 ( 2016 ).
  • Javle M , GolanT , MaitraA . Changing the course of pancreatic cancer–Focus on recent translational advances . Cancer Treat. Rev.44 , 17 – 25 ( 2016 ).
  • Catenacci DV , JunttilaMR , KarrisonTet al. Randomized Phase Ib/II study of gemcitabine plus placebo or vismodegib, a hedgehog pathway inhibitor, in patients with metastatic pancreatic cancer . J. Clin. Oncol.33 ( 36 ), 4284 – 4292 ( 2015 ).
  • Liu K , LiuY , LauJL , MinJ . Epigenetic targets and drug discovery part 2: histone demethylation and DNA methylation . Pharmacol. Ther.151 , 121 – 140 ( 2015 ).

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