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Year : 2011  |  Volume : 48  |  Issue : 4  |  Page : 507--512

Epigenetic changes in tumor microenvironment

P Dey 
 Department of Cytology, Post Graduate Institute of Medical Education and Research, Chandigarh, India

Correspondence Address:
P Dey
Department of Cytology, Post Graduate Institute of Medical Education and Research, Chandigarh


The drama of cancer is not the solo performance of the malignant cells. Microenvironment of the tumor has significant contribution in carcinogenesis. Recent evidences show distinct gene promoter methylation in stromal cells of various malignant and pre-malignant tumors. These changes probably create unique tumor microenvironment, which is responsible for initiation, proliferation, invasion, and metastasis of tumor cells. In this mini review the role of epigenetic changes of tumor microenvironment in carcinogenesis has been discussed.

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Dey P. Epigenetic changes in tumor microenvironment.Indian J Cancer 2011;48:507-512

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Dey P. Epigenetic changes in tumor microenvironment. Indian J Cancer [serial online] 2011 [cited 2022 May 18 ];48:507-512
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Cancer is commonly viewed as a group of diseases that are evolved due to progressive genomic abnormalities caused by factors, which are either inherited due to germ line mutation or acquired due to somatic mutation. [1] Cancer cells are significantly influenced by the surrounding stromal tissues for the initiation, nutrition, proliferation, and distant colony formation. Presently, it has been shown that surrounding stromal tissue that means tumor microenvironment shows distinct genetic abnormalities. [2],[3] It was also shown that carcinoma associated stromal cells can transform non tumorus epithelial cells into neoplasm. [4],[5] Every times, there may not be any distinct phenotypic and gentetic changes of the tumor microenvironment. The changes may be subtle and epigenetics. The term epigenetics means the altered gene expression without any change of DNA base pair arrangement. [6] Methylation of promoter gene and post translational modification of histone is predominantly responsible for epigenetic changes. [7],[8] There are growing evidences of distinct epigenetic changes of stromal cells in various malignancies with intense focus of attention. [9],[10],[11],[12] Thorough knowledge in this area may provide us understanding of tumor biology, applications of effective chemotherapeutic drugs, and even reversal of tumor. In this review, I focus on the role of epigenetic changes of tumor microenvironment in carcinogenesis and its possible clinical impact.

Tumor microenvironment: Genetic changes and beyond

The tumor microenvironment is composed of stromal fibroblasts, myofibroblasts, myoepithelial cells, macrophages, endothelial cells, leucocytes, and extracellular matrix (ECM). Macrophages are one of the most important components of the tumor microenvironment (TME). These cells are derived from CD34-positive bone marrow progenitor cells. These progenitor cells continually proliferate and shed their progeny in the blood stream as promonocytes that successively develop into monocytes and extravasate into the tissue as tissue macrophages. The tumor derived chemoattractants are probably responsible for the recruitment of macrophages in the tumor tissue. [13] The stromal fibroblasts and myofibroblasts are morphologically identical. These cells show oval to elongated nuclei with mild to moderate cytoplasm. Unlike stromal fibroblasts, myofibroblasts are positive for laminin, beta 4 integrin, and maspin. Fibroblasts are positive for HGFr and type IV collagen. [14]

ECM consists of basement membrane and interstitial matrix. This is produced by resident cell population of the tissue particularly fibroblasts. ECM is composed of proteins and glycosaminoglycans. There are various fibers in ECM such as collagen, elastin, fibronectin, and laminin.

Mutual and reciprocal interactions of epithelial and mesenchyhemal components are very important for organogenesis. [15],[16],[17] It has been well documented that microenvironment modulates tissue specific growth, proliferation, and invasive behavior of the tumor. [18],[19]

For many decades, the focus of carcinogenesis was predominantly on epithelial cells rather than surrounding stromal tissue. It was proposed that the target epithelial cells have oncogenic potential. There may be already a mutation in the target cells and a second mutation or loss of heterozygosity produces tumor. [20] Presently this epitheliocentric view of carcinogenesis has been slowly replaced by tumour microenvironment concept of carcinogenesis. Epithelial tissue are multicellular and resides in a three dimensional space within the stroma. The complex spatial and temporal relation of stromal microenvironment and epithelial cells is responsible to maintain the tissue development, remodelling of tissue and proper homeostais. Alteration or disturbance of epithelial and stromal interaction may cause malignancy. It has been shown that genetic mutation need not pre-exist in the target epithelial cells and tumor may arise because of pre-existing genetic mutation in the stromal tissue itself. Monifer et al[21] have excised normal appearing stromal tissue adjacent to breast carcinoma and have shown distinct genetic alteration and loss of heterozygosity in the stromal tissue. Haggie et al have also shown tumor like phenotype in so called normal looking fibroblast in the breast tissue of relative of patients with familial breast disease. Zhu et al have shown that Nf1 heterozygosisty in the stromal fibroblasts, mast cells and perinurial cells is needed for neurofibroma formation. [22]

Many studies have shown that there is a concurrent and independent genetic alteration in stromal and epithelial cells of breast and colonic carcinomas. [21],[23] Various genetic alterations in the breast stroma have been recorded such as loss of heterozygosity (LOH), microsatellite instability, and point mutations of tumor suppressor genes. [24],[25],[26],[27],[28] LOH has also been noted in micro-dissected stroma adjacent to bladder carcinoma. [29] Therefore, these mounting evidences favor the genetic alteration of TME responsible for carcinogenesis.

Allinen et al [30] purified all major cell types from normal breast tissue, in situ carcinoma and invasive carcinoma. They analyzed comprehensive gene expression and genetic profiles of normal breast tissue, in situ and invasive carcinoma cases using serial analysis of gene expression (SAGE) and SNP arrays, respectively. They noted significant gene expression changes in tumor epithelial cell, endothelial cells, leucocytes, fibroblasts, and myofibroblasts during tumor progression. The CXCL2 and CXCL12 chemokines were overexpressed in tumor myoepithelial cells and myofibroblasts. These chemokines bind to receptors on the epithelial cells and enhance their proliferation and invasion. However, it is interesting to note that with the help of comparative genomic hybridization technique, the clonally selected genetic alterations could not be demonstrated in the stromal cells and these were restricted only in tumor epithelial cells. [30] The missing link between alterations of gene expression without much alteration of genetic changes in stromal cells can best be explained by epigenetic changes.

Epigenetic changes and carcinogenesis

Epigenetic changes of the tumor microenvironment may affect initiation, proliferation, and metastasis of the primary tumor [Figure 1]. {Figure 1}

Initiation of tumor

Distinct epigenetic change of the tumor microenvironment first has been highlighted by Hu et al [9] They performed a novel technique of methylation based digital karyotyping (MSDK) to characterize the comprehensive unbiased DNA methylation profile of the epithelial, myoepithelial cells, and stromal fibroblasts from normal breast tissue, and in situ and invasive breast carcinomas. Distinct epigenetic changes were shown in myoepithelial cells and tumor epithelial cells in normal, in situ and invasive carcinoma. Epithelial and myoepithelial cells are supposed to originate from a common bi-potential progenitor cells. [31] Based on methylation differences between the two groups of cell they suggest that the stromal cells and epithelial cells are probably originated from two different clones or may have undergone epigenetic modification during differentiation. They also noted that the transcription factors with known developmental functions are preferentially affected by DNA methylation in each cell type in different breast lesions. This suggests that the epigenetic changes in stromal cells may affect the abnormal cell differentiation in the tumor. Fiegl et al did laser capture micro-dissection of the tumor epithelial cells and stromal tissue of HER 2-positive breast carcinoma cases. They showed gene promoter methylation (PGR, HSD1734, and CDH 13) in both tumor epithelial cells and tumor stromal cell simultaneously. [12] In a recent study by Hanson et al in prostatic carcinoma, distinct promoter gene methylation (GSTP1, RAR BETA 2) was also demonstrated in prostate cancer epithelial cells and stroma. [10] Glutathione S-transferase P1 (GSTP1) gene promoter is methylated in tumor cells of the prostate. Rodriguez-Canales et al [11] measured the extent and location of tumor and stromal cell methylation throughout an entire prostate specimen with cancer by using pyrosequencing quantification of GSTP1 promoter methylation. Normal epithelium and stroma, tumor epithelium, and tumor-associated stromal cells were collected by laser capture micro-dissection from multiple locations within the gland. The methylation was quantified and mapped back by an anatomical three-dimensional reconstruction of the entire prostate. Tumor-associated stromal cells were found to be methylated only in a localized and distinct anatomical sub-field of the tumor. This suggests the presence of an epigenetically unique microenvironment within the cancer.

Probably, the characteristic epigenetic changes provided the necessary microenvironment for initiation of the prostatic adenocarcinoma.

Growth induction

Transforming growth factor beta 1 (TGF-β) is one of the most well-known and potent inhibitors of epithelial cell growth. [32] Perturbation of TGF-β type II receptor in mouse mammary fibroblasts promotes the growth and invasion of mammary carcinoma through up regulation of TGF β, macrophage stimulating protein (MSP), and hepatocyte growth factor (HGF)-mediated signalling network. [33] This indicates that there is a dynamic interaction between stromal fibroblasts and tumor epithelial cells. TGF-β receptor is a key mediator of transforming growth factor-beta (TGF-beta) signaling. Marked down regulation of TGF-β receptor (TGFBR) has been demonstrated in invasive prostate carcinomas. [34] There was no demonstrable DNA methylation, whereas decreased expression of human TGFBR2 was mainly due to decreased transcription activity, related to histone deacetylation and H3 lysine 27 trimethylation. Till now, there is no evidence of epigenetic changes of TGF-β or TGF-β receptor in stromal fibroblasts. However, the role of chromatin remodeling involving the TGF-β or TGF-β receptor genes of stromal fibroblast in promoting tumor can not be excluded.

Invasion and metastasis

Invasion and metastasis are two important events in any cancer progression. Rupture of basement membrane of the glandular epithelial cells and penetration to the adjacent stroma are essential for tumor invasion and metastasis. It has been shown that the myoepithelial cells in the glandular lining of ductal carcinoma of breast are distinctly abnormal in gene expression and DNA methylation profiles. [21],[30] These myoepithelial cells are pro-angiogenic and loss many of their differentiation markers. The disruption of the basement membrane of the gland, decreased number of myoepithelial cells and loss of polarity of the tumor epithelial cells are the inevitable consequence of the progression of carcinoma in situ to invasive carcinoma [Figure 1].

Similarly the epigenetic changes in stromal cells may have significant role in metastatic deposition of tumor [Figure 1]. In metastatic prostatic carcinoma cases a phenomenon known as "osteomimicry" is noted. [35] Here, the carcinoma cells in metastatic site induce epigenetic changes of the bone marrow stromal cells and favor genetic alteration in local micro-environment for proliferation. [35],[36] The malignant prostate epithelial cells induce the differentiation of osteogenic progenitor cells to osteoclast. It helps in resorption of bone and facilitates the carcinoma cells in colonization of bone matrix.

Why aberrant methylation?

The exact cause of aberrant promoter methylation in the cancer cells or stroma is not known. Aberrant gene promoter methylation in the region of cancer may be due to the machinery that is responsible for the methylation of DNA. Initiation and maintenance of gene methylation happens due to the combined action of two DNA methyltransferases enzymes (DNMT1 and DNAMT 3b). Both these enzymes are raised in tumor epithelial cells and are suspected as the main factor in maintaining abnormal gene promoter methylation in cancer. [37],[38],[39],[40],[41],[42],[43] However, it is still not known whether these enzymes are raised in stromal cells or not. Somatic mutation of DNMT1 has been reported in occasional cases of colorectal carcinoma. [44] However, no mutation of DNA methyltransferase genes has been identified in stromal cells. It may be possible that environmental factors directly affect the stromal cells to have detrimental epigenetic changes. More research is needed in this area.

Epithelial mesenchymal transformation

Epithelial mesenchymal transition (EMT) plays a vital role in tumor invasion and metastasis. [45],[46] EMT is a process whereby the epithelial cells undergo morphological, functional and molecular changes and transform to mesenchymal cells. [47] EMT helps in the loss of cell polarity and reduced intracellular adhesion of the epithelial cells. The transformed malignant cells gain certain functional properties of mesenchymal cells such as increased cell motility and enhanced property of invasiveness. It has been suggested that the carcinoma cells may undergo transformation to mesenchymal phenotype and these mesenchymal cells have increased malignant potential. [14] So it is possible that the tumor-associated stromal cells may be due to the transformation of malignant epithelial cells into mesenchymal cells with the identical epigenetic changes. However, identical epigenetic changes have not been noted always in prostate stromal cells and epithelial cells in prostate carcinoma. [10]

Histone modification

Post translation modification of histones indicates acetylation, methylation, and phosphorylation of core histones of chromatin. Acetylation of histones causes conformational change of chromatin and expression of gene, whereas deacetylation and methylation of histones are responsible for gene silencing. [7] Post-translation modification of histone is one of the major components of epigenetic changes/ [7] . Modification of histone tails by utilizing histone code controls various gene expression. In lower organisms, DNA methylation depends on H3K9 methylation and it is assumed that both DNA methylation and histone modification are interdependent. [48],[49] Till now, there are no studies on histone modification and chromatin remodeling of cellular compartments of tumor microenvironment.

Gene promoter hypomethylation

In cancer, both global and gene specific hypermethylation and hypomethylation occurs. Hypermethylation of promoter region of tumor suppressor gene causes gene silencing and tumorogenesis, [50] whereas, growth promoter genes are activated by hypomethylation. [51] In fact, tissue-specific hypomethylation is equally important as hypermethylation in cancer. Gene promoter hypomethylation of the cells of tumor microenvironment has not been explored so far. This may provide us further clues about the influence of tumor microenvironment on the cell proliferation of cancer cells.

Reversal of epigenetic changes and cancer control

Cancer is a highly heterogeneous disease and the most of the malignant cells rapidly acquire the resistance against chemotherapeutic drugs. Chemotherapeutic resistance of cancer cell can not be blamed upon a single gene. [52],[53] The transcriptional profile of pre and post chemotherapeutic colonic cancer shows the change of expression of several hundred genes. [54] Epigenetic reprogramming probably takes important role in chemotherapy resistance of tumor cell. [55] A remarkable important feature of epigenetic changes is that its dynamicity. [56] Epigenetic alterations are essentially reversible and allow plasticity. So without removal of oncogenes, gene deletion or mutations, it is possible to revert cancer cells into normal phenotype with the help of epigenetic reversion. [57] In a recent study, DNA methyltransferase and histone deactylase inhibitors were used to up regulate the epigenetically silenced ICAM-1 in tumor endothelial cells. [58] There may be unique expression of the gene and proteomic profiling of the individual cell types of tumor microenvironment. [59],[60] The determination of the molecular profile of different so called "normal cells" related to tumor progression will be extremely important to design the plan of epigenetic modification.


In summary, epigenetic changes of various components of tumor microenvironment play significant role in tumor initiation, progression and metastasis. Data on DNA methylation pattern and gene expression profile of cells of tumor microenvironment in various stages of carcinogenesis may be helpful to modify the epigenetic changes and reversal of cancer. DNA hypomethylation pattern and histone modification of the stromal cells have not been well studied so far. The information may show additional evidences of epigenetic control of tumor microenvironment on tumor.


1Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100:57-70.
2Barcellos-Hoff MH, Ravani SA. Irradiated mammary gland stroma promotes the expression of tumorigenic potential by unirradiated epithelial cells. Cancer Res 2000;60:1254-60.
3Maffini MV, Soto AM, Calabro JM, Ucci AA, Sonnenschein C. The stroma as a crucial target in rat mammary gland carcinogenesis. J Cell Sci 2004;117:1495-502.
4Barclay WW, Woodruff RD, Hall MC, Cramer SD. A system for studying epithelial-stromal interactions reveals distinct inductive abilities of stromal cells from benign prostatic hyperplasia and prostate cancer. Endocrinology 2005;146:13-8.
5Hayward SW, Wang Y, Cao M, Hom YK, Zhang B, Grossfeld GD, et al. Malignant transformation in a nontumorigenic human prostatic epithelial cell line. Cancer Res 2001;61:8135-42.
6Lund AH, Lohuizen MV. Epigenetics and cancer. Genes Dev 2004;18:2315-35.
7Dey P. Chromatin Remodeling, Cancer and Chemotherapy. Curr Med Chem 2006;13;2909-19.
8Feinberg AP, Tycko B. The history of cancer epigenetics. Nat Rev Cancer 2004;4:143-53.
9Hu M, Yao J, Cai L, Bachman KE, van den Brûle F, Velculescu V, et al. Distinct epigenetic changes in the stromal cells of breast cancers. Nat Genet 2005;37:899-905.
10Hanson JA, Gillespie JW, Grover A, Tangrea MA, Chuaqui RF, Emmert-Buck MR, et al. Gene promoter methylation in prostate tumor-associated stromal cells. J Natl Cancer Inst 2006;98:255-61.
11Rodriguez-Canales J, Hanson JC, Tangrea MA, Erickson HS, Albert PS, Wallis BS, et al. Identification of a unique epigenetic sub-microenvironment in prostate cancer. J Pathol 2007;211:410-9.
12Fiegl H, Millinger S, Goebel G, Müller-Holzner E, Marth C, Laird PW, et al. Breast cancer DNA methylation profiles in cancer cells and tumor stroma: Association with HER-2/neu status in primary breast cancer. Cancer Res 2006;66:29-33.
13Murdoch C, Giannoudis A, Lewis CE. Mechanisms regulating the recruitment of macrophages into hypoxic areas of tumors and other ischemic tissues. Blood 2004;104:2224-34.
14Petersen OW, Nielsen HL, Gudjonsson T, Villadsen R, Rank F, Niebuhr E, et al. Epithelial to mesenchymal transition in human breast cancer can provide a nonmalignant stroma. Am J Pathol 2003;162:391-402.
15Isaacs JT. The biology of hormone refractory prostate cancer. Why does it develop? Uro Clin North Am 1999;26:263-73.
16Bissell MJ, Barcellos-Hoff MH. The influence of extracellular matrix on gene expression: Is structure the message? J Cell Sci 1987;8:327-43.
17Cunha GR, Alaird ET, Turner T, Donjaccour AA, Boutin EL, Foster BA. Normal and abnormal development of the male urogenital tract: Role of androgen, mesenchymal-epithelial interactions and growth factors. J Androl 1992;13:465-75.
18Bissell M J, Radisky D. Putting tumors in the context. Nat Rev Cancer 2001;1:46-54.
19Elenbaas B, Weinberg RA. Heterotypic signaling between epithelial tumor cells and fibroblasts in carcinoma formation. Exp Cell Res 2001;264:169-84.
20Knudson A. "Mutation and cancer: Statistical study of retinoblastoma". Proc Natl Acad Sci U S A 1971;68:820-3.
21Moinfar F, Man YG, Arnould L, Bratthauer GL, Ratschek M, Tavassoli FA. Concurrent and independent genetic alterations in the stromal and epithelial cells of mammary carcinoma: Implications for tumorigenesis. Cancer Res 2000;60:2562-6.
22Zhu Y, Ghosh P, Charnay P, Burns DK, Parada LF. Neurofibromas in NF1: Schwann cell origin and role of tumor environment. Science 2002;296:920-2.
23Wernert N, Locherbah C, Wellmann A, Behrens P, Hugel A. Presence of genetic alterations in microdissected stroma of human colon and breast cancers. Anticancer Res 2001;21:2259-64.
24Fukino K, Shen L, Matsumoto S, Morrison CD, Mutter GL, Eng C. Combined total genome loss of heterozygosity scan of breast cancer stroma and epithelium reveals multiplicity of stromal targets. Cancer Res 2004;64:7231-6.
25Fukino K, Shen L, Patocs A, Mutter GL, Eng C. Genomic instability within tumor stroma and clinicopathological characteristics of sporadic primary invasive breast carcinoma. JAMA 2007;297:2103-11.
26Kurose K, Hoshaw-Woodard S, Adeyinka A, Lemeshow S, Watson PH, Eng C, Genetic model of multi-step breast carcinogenesis involving the epithelium and stroma: Clues to tumour-microenvironment interactions. Hum Mol Genet 2001;10:1907-13.
27Weber F, Fukino K, Sawada T, Williams N, Sweet K, Brena RM, et al. Variability in organ-specific EGFR mutational spectra in tumour epithelium and stroma may be the biological basis for differential responses to tyrosine kinase inhibitors. Br J Cancer 2005;92:1922-6.
28Fukino K, Shen L, Patocs A, Mutter GL, Eng C, Caldes T, et al. Total-genome analysis of BRCA1/2-related invasive carcinomas of the breast identifies tumor stroma as potential landscaper for neoplastic initiation. Am J Hum Genet. 2006;78:961-72.
29Paterson RF, Ulbright TM, Maclenan GT, Zhang S, Pan CX, Sweeney CJ, et al. Molecular genetic alterations in the laser capture microdissected stroma adjacent to bladder carcinoma. Cancer 2003;98:1830-6.
30Allinen M, Beroukhim R, Cai L, Brennan C, Lahti-Domenici J, Huang H, et al. Molecular characterization of the tumor microenvironment in breast cancer. Cancer cell 2004;6:17-32.
31Böcker W, Moll R, Poremba C, Holland R, Van Diest PJ, Dervan P, et al. Common adult stem cells in the human breast give rise to glandular and myoepithelial cell lineages: A new cell biological concept. Lab Invest 2002;82:737-46.
32Moses H, Yang E, Pietonpol J. TGF-ß stimulation and inhibition of cell proliferation: New mechanistic insights. Cell 1990;63:245-7.
33Cheng N, Bhowmick NA, Chytil A, Gorksa AE, Brown KA, Muraoka R, et al. Loss of TGF-beta type II receptor in fibroblasts promotes mammary carcinoma growth and invasion through upregulation of TGF-alpha-MSP- and HGF-mediated signaling networks, Oncogene 2005;24:5053-68.
34Yamashita S, Takahashi S, McDonell N, Watanabe N, Niwa T, Hosoya K, et al. Methylation silencing of transforming growth factor-beta receptor type II in rat prostate cancers. Cancer Res 2008;68:2112-21.
35Koeneman KS, Yeung F, Chung LW. Osteomimetic properties of prostate cancer cells: A hypothesis supporting the predilection of prostate cancer metastasis and growth in the bone environment. Prostate 1999;39:246-61.
36Chung LW, Baseman A, Assikis V, Zhau HE. Molecular insights into prostate cancer progression: The missing link of tumor microenvironment. J Urol 2005;173:10-20.
37Rhee I, Bachman KE, Park BH, Jair KW, Yen RW, Schuebel KE, et al. DNMT1 and DNMT3b cooperate to silence genes in human cancer cells. Nature 2002;416:552-6.
38Robertson KD, Uzvolgyi E, Liang G, Talmadge C, Sumegi J, Gonzales FA, et al. The human DNA methyltransferases (DNMTs) 1, 3a and 3b: Coordinate mRNA expression in normal tissues and overexpression in tumors. Nucleic Acids Res 1999;27:2291-8.
39Girault I, Tozlu S, Lidereau R, Bieche I. Expression analysis of DNA methyltransferases 1, 3A, and 3B in sporadic breast carcinomas. Clin Cancer Res 2003;9:4415-22.
40Agoston AT, Argani P, Yegnasubramanian S, De Marzo AM, Ansari-Lari MA, Hicks JL, et al. Increased protein sstability causes DNA methyltransferase1 dysregulation in breeast cancer. J Biol Chem 2005;280:18302-10.
41ShiehYS, Shiah SG, Jeng HH, Lee HS, Wu CW, Chang LC. DNA methyltransferase 1 expression and promoter methylation of E-cadherin in mucoepidermoid carcinoma. Cancer 2005;104:1013-21.
42Arai E, Kanai Y, Ushijima S, Fujimoto H, Mukai K, Hirohashi S. Regional DNA hypermethylation and DNA methyltransferase (DNMT) 1 protein overexpression in both renal tumors and corresponding nontumorous renal tissues. Int J Cancer 2006;119:288-96.
43Peng DF, Kanai Y, Sawada M, Ushijima S, Hiraoka N, Kitazawa S, et al. DNA methylation of multiple tumor-related genes in association with overexpression of DNA methyltransferase 1 (DNMT1) during multistage carcinogenesis in the pancreas. Carcinogenesis 2006;27:1160-8.
44Kanai Y, Ushijima S, Nakanishi Y, Sakamoto M, Hirohashi S. Mutation of the DNA methyltransferase (DNMT) 1 gene in human colorectal cancers. Cancer Lett 2003;192:75-82
45Wu Y, Zhou BP. New insights of epithelial-mesenchymal transition in cancer metastasis. Acta Biochim Biophys Sin 2008;40:643-50.
46De Wever O, Pauwels P, De Craene B, Sabbah M, Emami S, Redeuilh G, et al. Molecular and pathological signatures of epithelial-mesenchymal transitions at the cancer invasion front. Histochem Cell Biol 2008;130:481-94.
47Shook D, Keller R. Mechanism, mechanics and function of epithelial-mesenchymal transitions in early development. Mech Dev 2003;120:1351-83.
48Tamaru H, Selker EU. A histone H3 methyltransferases controls DNA methylation in Neurospora crossa. Nature 2001;414:273-83.
49Jackson JP, Lindroth AM, Cao X, Jacobsen SE. Control of CpNpG DNA methylation by the KRYPTONITE histone H3methy transferase. Nature 2002;416:556-60.
50Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer. Nature Rev Genet 2002;3:415-28.
51Wilson AS, Power BE, Molloy PL. DNA hypomethylation and human diseases. Biochem Biophys Acta 2007;1775:138-62.
52Oza AM. Clinical development of p glycoprotein modulators in oncology. Novartis Found Symp 2002;243:103-15.
53Choi CH. ABC transporters as multidrug resistance mechanisms and the development of chemosensitizers for their reversal. Cancer Cell Int 2005;5:30.
54Graudens E, Boulanger V, Mollard C, Mariage-Samson R, Barlet X, Gremy G, et al. Deciphering cellular states of innate tumor drug responses. Genome Biol 2006;7: R19.
55Perez-Plasencia C, Duenas-Gonzalez A. Can the state of cancer chemotherapy resistance be reverted by epigenetic therapy? Molecular Cancer 2006;5:27.
56Ohisson R, Kanduri C, Whitehead J, Pfeifer S, Lobanenkov V, Feinberg AP. Epigenetic variability and the evolution of human cancer. Adv Cancer Res 2003;88:145-68.
57Sandal T, Valyi-Nagy K, Spencer VA, Folberg R, Bissell MJ, Maniotis AJ. Epigenetic reversion of breast carcinoma phenotype is accompanied by changes in DNA sequestration as measured by Alul restriction enzyme. Am J Pathol 2007;170:1739-49.
58Hellebrekers DM, Castermans K, Vire E, Dings RP, Hoebers NT, Mayo KH, et al. Epigenetic regulation of tumor endothelial cell anergy: Silencing of intercellular adhesion molecule-1 by histone modifications. Cancer Res 2006;66:10770-7.
59Oh P, Li Y, Yu J, Durr E, Krasinska KM, Carver LA, et al. Subtractive proteomic mapping of the endothelial surface in lung and solid tumors for tissue specific therapy. Nature 2004;429:629-35.
60St Croix B, Rago C, Velculescu V, Traverso G, RomansKE, Montgomery E, et al. Genes expressed in human tumor endothelium. Science 2000;289:1197-202.