Similar articles

Abstract: The tumor microenvironment (TME) plays an important role in supporting cancer progression. The TME is composed of tumor cells, the surrounding tumor-associated stromal cells, and the extracellular matrix (ECM). Crosstalk between the TME components contributes to tumorigenesis. Recently, one of our studies showed that pancreatic ductal adenocarcinoma (PDAC) cells can induce DNA methylation in cancer-associated fibroblasts (CAFs), thereby modifying tumor-stromal interactions in the TME, and subsequently creating a TME that supports tumor growth. Here we summarize recent studies about how DNA methylation affects tumorigenesis through regulating tumor-associated stromal components including fibroblasts and immune cells. We also discuss the potential for targeting DNA methylation for the treatment of cancers.

肿瘤微环境中的甲基化调节机制

[1]Ahmed, S.F., Farquharson, C., 2010. The effect of GH and IGF1 on linear growth and skeletal development and their modulation by SOCS proteins. J. Endocrinol., 206(3): 249-259.

[2]Albrengues, J., Bertero, T., Grasset, E., et al., 2015. Epigenetic switch drives the conversion of fibroblasts into proinvasive cancer-associated fibroblasts. Nat. Commun., 6:10204.

[3]Amodio, N., Bellizzi, D., Leotta, M., et al., 2013. miR-29b induces SOCS-1 expression by promoter demethylation and negatively regulates migration of multiple myeloma and endothelial cells. Cell Cycle, 12(23):3650-3662.

[4]Batarseh, K.I., 2013. Antineoplastic activities, apoptotic mechanism of action and structural properties of a novel silver(I) chelate. Curr. Med. Chem., 20(18):2363-2373.

[5]Berraondo, P., Minute, L., Ajona, D., et al., 2016. Innate immune mediators in cancer: between defense and resistance. Immunol. Rev., 274(1):290-306.

[6]Bian, E.B., Huang, C., Ma, T.T., et al., 2012. DNMT1-mediated PTEN hypermethylation confers hepatic stellate cell activation and liver fibrogenesis in rats. Toxicol. Appl. Pharmacol., 264(1):13-22.

[7]Bird, A., 2007. Perceptions of epigenetics. Nature, 447(7143): 396-398.

[8]Bock, C., Beerman, I., Lien, W.H., et al., 2012. DNA methylation dynamics during in vivo differentiation of blood and skin stem cells. Mol. Cell, 47(4):633-647.

[9]Broske, A.M., Vockentanz, L., Kharazi, S., et al., 2009. DNA methylation protects hematopoietic stem cell multipotency from myeloerythroid restriction. Nat. Genet., 41(11): 1207-1215.

[10]Cheung, P., Allis, C.D., Sassone-Corsi, P., 2000. Signaling to chromatin through histone modifications. Cell, 103(2): 263-271.

[11]Chiappinelli, K.B., Zahnow, C.A., Ahuja, N., et al., 2016. Combining epigenetic and immunotherapy to combat cancer. Cancer Res., 76(7):1683-1689.

[12]Cui, H., Onyango, P., Brandenburg, S., et al., 2002. Loss of imprinting in colorectal cancer linked to hypomethylation of H19 and IGF2. Cancer Res., 62(22):6442-6446.

[13]Dedeurwaerder, S., Desmedt, C., Calonne, E., et al., 2011. DNA methylation profiling reveals a predominant immune component in breast cancers. EMBO Mol. Med., 3(12):726-741.

[14]de Wever, O., Demetter, P., Mareel, M., et al., 2008. Stromal myofibroblasts are drivers of invasive cancer growth. Int. J. Cancer, 123(10):2229-2238.

[15]Easwaran, H., Tsai, H.C., Baylin, S.B., 2014. Cancer epigenetics: tumor heterogeneity, plasticity of stem-like states, and drug resistance. Mol. Cell, 54(5):716-727.

[16]El Taghdouini, A., Sorensen, A.L., Reiner, A.H., et al., 2015. Genome-wide analysis of DNA methylation and gene expression patterns in purified, uncultured human liver cells and activated hepatic stellate cells. Oncotarget, 6(29):26729-26745.

[17]Esteller, M., 2007. Cancer epigenomics: DNA methylomes and histone-modification maps. Nat. Rev. Genet., 8(4): 286-298.

[18]Feig, C., Gopinathan, A., Neesse, A., et al., 2012. The pancreas cancer microenvironment. Clin. Cancer Res., 18(16): 4266-4276.

[19]Garzon, R., Calin, G.A., Croce, C.M., 2009. MicroRNAs in Cancer. Annu. Rev. Med., 60(1):167-179.

[20]Gascard, P., Tlsty, T.D., 2016. Carcinoma-associated fibroblasts: orchestrating the composition of malignancy. Genes Dev., 30(9):1002-1019.

[21]Gibb, E.A., Brown, C.J., Lam, W.L., 2011. The functional role of long non-coding RNA in human carcinomas. Mol. Cancer, 10(1):38.

[22]Gotze, S., Schumacher, E.C., Kordes, C., et al., 2015. Epigenetic changes during hepatic stellate cell activation. PLoS ONE, 10(6):e0128745.

[23]Gronbaek, K., Hother, C., Jones, P.A., 2007. Epigenetic changes in cancer. APMIS, 115(10):1039-1059.

[24]Hanahan, D., Weinberg, R.A., 2011. Hallmarks of cancer: the next generation. Cell, 144(5):646-674.

[25]Hinz, B., Phan, S.H., Thannickal, V.J., et al., 2007. The myofibroblast: one function, multiple origins. Am. J. Pathol., 170(6):1807-1816.

[26]Iba, K., Albrechtsen, R., Gilpin, B.J., et al., 1999. Cysteine-rich domain of human ADAM 12 (meltrin α) supports tumor cell adhesion. Am. J. Pathol., 154(5):1489-1501.

[27]Iorio, M.V., Piovan, C., Croce, C.M., 2010. Interplay between microRNAs and the epigenetic machinery: an intricate network. Biochim. Biophys. Acta, 1799(10-12):694-701.

[28]Ishii, G., Ochiai, A., Neri, S., 2016. Phenotypic and functional heterogeneity of cancer-associated fibroblast within the tumor microenvironment. Adv. Drug Deliv. Rev., 99(Pt B): 186-196.

[29]Janson, P.C., Marits, P., Thorn, M., et al., 2008. CpG methylation of the IFNG gene as a mechanism to induce immunosuppression in tumor-infiltrating lymphocytes. J. Immunol., 181(4):2878-2886.

[30]Jiang, L., Gonda, T.A., Gamble, M.V., et al., 2008. Global hypomethylation of genomic DNA in cancer-associated myofibroblasts. Cancer Res., 68(23):9900-9908.

[31]Karagiannis, G.S., Poutahidis, T., Erdman, S.E., et al., 2012. Cancer-associated fibroblasts drive the progression of metastasis through both paracrine and mechanical pressure on cancer tissue. Mol. Cancer Res., 10(11):1403-1418.

[32]Ke, X., Zhang, S., Xu, J., et al., 2016. Non-small-cell lung cancer-induced immunosuppression by increased human regulatory T cells via Foxp3 promoter demethylation. Cancer Immunol. Immunother., 65(5):587-599.

[33]Kouzarides, T., 2007. Chromatin modifications and their function. Cell, 128(4):693-705.

[34]Ling, H., Spizzo, R., Atlasi, Y., et al., 2013. CCAT2, a novel noncoding RNA mapping to 8q24, underlies metastatic progression and chromosomal instability in colon cancer. Genome Res., 23(9):1446-1461.

[35]Liu, H.X., Li, X.L., Dong, C.F., 2015. Epigenetic and metabolic regulation of breast cancer stem cells. J. Zhejiang Univ.-Sci. B (Biomed. & Biotechnol.), 16(1):10-17.

[36]Luperchio, T.R., Wong, X., Reddy, K.L., 2014. Genome regulation at the peripheral zone: lamina associated domains in development and disease. Curr. Opin. Genet. Dev., 25: 50-61.

[37]Mann, J., Chu, D.C., Maxwell, A., et al., 2010. MeCP2 controls an epigenetic pathway that promotes myofibroblast transdifferentiation and fibrosis. Gastroenterology, 138(2): 705-714.

[38]Mueller, M.M., Fusenig, N.E., 2004. Friends or foes—bipolar effects of the tumour stroma in cancer. Nat. Rev. Cancer, 4(11):839-849.

[39]Neesse, A., Algul, H., Tuveson, D.A., et al., 2015. Stromal biology and therapy in pancreatic cancer: a changing paradigm. Gut, 64(9):1476-1484.

[40]Page, A., Paoli, P., Moran, S.E., et al., 2016. Hepatic stellate cell transdifferentiation involves genome-wide remodeling of the DNA methylation landscape. J. Hepatol., 64(3): 661-673.

[41]Peric-Hupkes, D., Meuleman, W., Pagie, L., et al., 2010. Molecular maps of the reorganization of genome-nuclear lamina interactions during differentiation. Mol. Cell, 38(4):603-613.

[42]Pinzani, M., Rombouts, K., Colagrande, S., 2005. Fibrosis in chronic liver diseases: diagnosis and management. J. Hepatol., 42(Suppl. 1):S22-S36.

[43]Pleyer, L., Greil, R., 2015. Digging deep into “dirty” drugs— modulation of the methylation machinery. Drug Metab. Rev., 47(2):252-279.

[44]Rabinovich, E.I., Kapetanaki, M.G., Steinfeld, I., et al., 2012. Global methylation patterns in idiopathic pulmonary fibrosis. PLoS ONE, 7(4):e33770.

[45]Rucki, A.A., Zheng, L., 2014. Pancreatic cancer stroma: understanding biology leads to new therapeutic strategies. World J. Gastroenterol., 20(9):2237-2246.

[46]Schuyler, R.P., Merkel, A., Raineri, E., et al., 2016. Distinct trends of DNA methylation patterning in the innate and adaptive immune systems. Cell Rep., 17(8):2101-2111.

[47]Sharma, S., Kelly, T.K., Jones, P.A., 2010. Epigenetics in cancer. Carcinogenesis, 31(1):27-36.

[48]Sido, J.M., Yang, X., Nagarkatti, P.S., et al., 2015. Δ⁹-Tetrahydrocannabinol-mediated epigenetic modifications elicit myeloid-derived suppressor cell activation via STAT3/S100A8. J. Leukoc. Biol., 97(4):677-688.

[49]Smith, Z.D., Meissner, A., 2013. DNA methylation: roles in mammalian development. Nat. Rev. Genet., 14:204-220.

[50]Sorensen, A.L., Timoskainen, S., West, F.D., et al., 2010. Lineage-specific promoter DNA methylation patterns segregate adult progenitor cell types. Stem Cells Dev., 19(8):1257-1266.

[51]Sukari, A., Nagasaka, M., Al-Hadidi, A., et al., 2016. Cancer immunology and immunotherapy. Anticancer Res., 36(11): 5593-5606.

[52]Tampe, B., Tampe, D., Muller, C.A., et al., 2014. Tet3-mediated hydroxymethylation of epigenetically silenced genes contributes to bone morphogenic protein 7-induced reversal of kidney fibrosis. J. Am. Soc. Nephrol., 25(5): 905-912.

[53]Trikha, P., Carson, W.R., 2014. Signaling pathways involved in MDSC regulation. Biochim. Biophys. Acta, 1846(1): 55-65.

[54]Trimboli, A.J., Cantemir-Stone, C.Z., Li, F., et al., 2009. Pten in stromal fibroblasts suppresses mammary epithelial tumours. Nature, 461(7267):1084-1091.

[55]van Kampen, J.G.M., Marijnissen-van Zanten, M.A.J., Simmer, F., et al., 2014. Epigenetic targeting in pancreatic cancer. Cancer Treat. Rev., 40(5):656-664.

[56]Vincent, A., Omura, N., Hong, S.M., et al., 2011. Genome-wide analysis of promoter methylation associated with gene expression profile in pancreatic adenocarcinoma. Clin. Cancer Res., 17(13):4341-4354.

[57]Vizoso, M., Puig, M., Carmona, F.J., et al., 2015. Aberrant DNA methylation in non-small cell lung cancer-associated fibroblasts. Carcinogenesis, 36(12):1453-1463.

[58]Wang, Z., Gao, Z., Shi, Y., et al., 2007. Inhibition of Smad3 expression decreases collagen synthesis in keloid disease fibroblasts. J. Plast. Reconstr. Aesthet. Surg., 60(11): 1193-1199.

[59]Wieczorek, G., Asemissen, A., Model, F., et al., 2009. Quantitative DNA methylation analysis of FOXP3 as a new method for counting regulatory T cells in peripheral blood and solid tissue. Cancer Res., 69(2):599-608.

[60]Xiang, J.F., Yin, Q.F., Chen, T., et al., 2014. Human colorectal cancer-specific CCAT1-L lncRNA regulates long-range chromatin interactions at the MYC locus. Cell Res., 24(5):513-531.

[61]Xiao, Q., Zhou, D., Rucki, A.A., et al., 2016. Cancer-associated fibroblasts in pancreatic cancer are reprogrammed by tumor-induced alterations in genomic DNA methylation. Cancer Res., 76(18):5395-5404.

[62]Xing, Y., Zhao, S., Zhou, B.P., et al., 2015. Metabolic reprogramming of the tumour microenvironment. Febs. J., 282(20):3892-3898.

[63]Yu, J., Walter, K., Omura, N., et al., 2012. Unlike pancreatic cancer cells pancreatic cancer associated fibroblasts display minimal gene induction after 5-Aza-2'-deoxycytidine. PLoS ONE, 7(9):e43456.

[64]Zhi, K., Shen, X., Zhang, H., et al., 2010. Cancer-associated fibroblasts are positively correlated with metastatic potential of human gastric cancers. J. Exp. Clin. Cancer Res., 29(1):66.