|MOLECULAR BIOLOGY - REVIEW ARTICLE
|Year : 2011 | Volume
| Issue : 4 | Page : 507-512
Epigenetic changes in tumor microenvironment
Department of Cytology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
|Date of Web Publication||25-Jan-2012|
Department of Cytology, Post Graduate Institute of Medical Education and Research, Chandigarh
Source of Support: None, Conflict of Interest: None
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.
Keywords: Carcinogenesis, epigenetics, microenvironment, stroma, tumor
|How to cite this article:|
Dey P. Epigenetic changes in tumor microenvironment. Indian J Cancer 2011;48:507-12
| » Introduction|| |
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.  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. , It was also shown that carcinoma associated stromal cells can transform non tumorus epithelial cells into neoplasm. , 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.  Methylation of promoter gene and post translational modification of histone is predominantly responsible for epigenetic changes. , There are growing evidences of distinct epigenetic changes of stromal cells in various malignancies with intense focus of attention. ,,, 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.  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. 
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. ,, It has been well documented that microenvironment modulates tissue specific growth, proliferation, and invasive behavior of the tumor. ,
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.  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 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. 
Many studies have shown that there is a concurrent and independent genetic alteration in stromal and epithelial cells of breast and colonic carcinomas. , 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. ,,,, LOH has also been noted in micro-dissected stroma adjacent to bladder carcinoma.  Therefore, these mounting evidences favor the genetic alteration of TME responsible for carcinogenesis.
Allinen et al  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.  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: Schematic view shows possible effects of epigenetic changes of tumor microenvironment|
Click here to view
Initiation of tumor
Distinct epigenetic change of the tumor microenvironment first has been highlighted by Hu et al  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.  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.  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.  Glutathione S-transferase P1 (GSTP1) gene promoter is methylated in tumor cells of the prostate. Rodriguez-Canales et al  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.
Transforming growth factor beta 1 (TGF-β) is one of the most well-known and potent inhibitors of epithelial cell growth.  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.  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.  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. , 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.  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. , 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. ,,,,,, 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.  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. , EMT is a process whereby the epithelial cells undergo morphological, functional and molecular changes and transform to mesenchymal cells.  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.  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. 
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.  Post-translation modification of histone is one of the major components of epigenetic changes/  . 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. , 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,  whereas, growth promoter genes are activated by hypomethylation.  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. , The transcriptional profile of pre and post chemotherapeutic colonic cancer shows the change of expression of several hundred genes.  Epigenetic reprogramming probably takes important role in chemotherapy resistance of tumor cell.  A remarkable important feature of epigenetic changes is that its dynamicity.  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.  In a recent study, DNA methyltransferase and histone deactylase inhibitors were used to up regulate the epigenetically silenced ICAM-1 in tumor endothelial cells.  There may be unique expression of the gene and proteomic profiling of the individual cell types of tumor microenvironment. , 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.
| » Conclusions|| |
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.
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