Implications For Cancer Progression Research Articles

Distinct responses to reduplicated chromosomes require distinct Mad2 responses.

Duplicating chromosomes once each cell cycle produces sister chromatid pairs, which separate accurately at anaphase. In contrast, reduplicating chromosomes without separation frequently produces polytene chromosomes, a barrier to accurate mitosis. Chromosome reduplication occurs in many contexts, including: polytene tissue development, polytene tumors, and following treatment with mitosis-blocking chemotherapeutics. However, mechanisms responding to or resolving polyteny during mitosis are poorly understood. Here, using Drosophila, we uncover two distinct reduplicated chromosome responses. First, when reduplicated polytene chromosomes persist into metaphase, an anaphase delay prevents tissue malformation and apoptosis. Second, reduplicated polytene chromosomes can also separate prior to metaphase through a spindle-independent mechanism termed Separation-Into-Recent-Sisters (SIRS). Both reduplication responses require the spindle assembly checkpoint protein Mad2. While Mad2 delays anaphase separation of metaphase polytene chromosomes, Mad2's control of overall mitotic timing ensures efficient SIRS. Our results pinpoint mechanisms enabling continued proliferation after genome reduplication, a finding with implications for cancer progression and prevention.

Molecular regulation of galectin-3 expression and therapeutic implication in cancer progression.

Galectin-3, a multifunctional protein, distributes inside and outside cells and plays an important role in tumor cell adhesion, proliferation, differentiation, angiogenesis, and metastasis in multiple tumors. Changes in galectin-3 expression are commonly seen in cancer and pre-cancerous conditions. Therefore, to understand the molecular regulation of galectin-3 expression could aid the development of new approach for cancer treatment. This review summarizes different expression of galectin-3 in cancer cells and patients' serum, the regulation mechanism and the potential therapeutic targets of galectin-3 in cancer progression.

Negative regulation of Bmi-1 by AMPK and implication in cancer progression.

Bmi-1 is a transcriptional regulator that promotes tumor cell self-renewal and epithelial to mesenchymal transition and its upregulation is associated with tumor progression, AMPK is an intracellular fuel-sensing enzyme and plays important roles in tumor cell growth and progression. Thus, the present study aims to examine the regulation of Bmi-1 by AMPK. First, our data revealed that, as compared to adjacent normal tissue, Bmi-1 was highly expressed in gastric cancer, whereas phosphorylation of AMPK (p-AMPK) was reduced. Similar findings were observed in lung adenocarcinomas and appeared that the expression of Bmi-1 was correlated with pathological grades of the cancer, where opposite changes were found in p-AMPK. Second, Metformin, a pharmacological AMPK activator and anti-diabetic drug, or ectopic expression of LKB1, diminished expression of Bmi-1 in cancer cells, an event that was reversed by silencing LKB1. Third, knockdown of LITAF, previously identified as a downstream target of AMPK, upregulated Bmi-1, associated with increased cell viability, colony formation, and migration of cancer cells in vitro. Fourth, metformin increased the abundance of miR-15a, miR-128, miR-192, and miR-194, which was prevented by knockdown of LITAF. Accordingly, transfection of these individual miRNAs downregulated Bmi-1. Altogether, our data for the first time suggest a regulatory axis in cancer cells: AMPK upregulates LITAF, which in turn increases miRNAs, leading to attenuation of Bmi-1 expression.

Snail interacts with hPLSCR1 promoter and down regulates its expression in IMR-32

Human phospholipid scramblase 1 (hPLSCR1) is a proapoptotic protein whose expression is deregulated in a variety of cancers cells. However till date the transcription regulation of hPLSCR1 is unknown. Transcriptional regulation of hPLSCR1 was studied by cloning the 5′-flanking region of hPLSCR1. Luciferase assays revealed that −1525 to −1244 region of hPLSCR1 was found to regulate its promoter activity. A putative Snail transcription factor (TF) binding site was found within the regulatory region of the promoter. Snail binding was found to down regulate the expression of hPLSCR1 both at the transcriptional and translational levels. Snail knock down using Snail-shRNA confirmed that down regulation of hPLSCR1 by Snail was specific. Point mutation studies confirm that the predicted Snail TF binds to −1123 to −1117 site. ChIP assay further confirms the physical interaction of Snail with hPLSCR1 promoter. This is the first report showing the transcriptional regulation of hPLSCR1 expression by Snail TF and its possible implications in cancer progression.

The role of chemokines in breast cancer pathology and its possible use as therapeutic targets.

Chemokines are small proteins that primarily regulate the traffic of leukocytes under homeostatic conditions and during specific immune responses. The chemokine-chemokine receptor system comprises almost 50 chemokines and approximately 20 chemokine receptors; thus, there is no unique ligand for each receptor and the binding of different chemokines to the same receptor might have disparate effects. Complicating the system further, these effects depend on the cellular milieu. In cancer, although chemokines are associated primarily with the generation of a protumoral microenvironment and organ-directed metastasis, they also mediate other phenomena related to disease progression, such as angiogenesis and even chemoresistance. Therefore, the chemokine system is becoming a target in cancer therapeutics. We review the emerging data and correlations between chemokines/chemokine receptors and breast cancer, their implications in cancer progression, and possible therapeutic strategies that exploit the chemokine system.

Involvement of liver-intestine cadherin in cancer progression

Cadherins constitute a superfamily of Ca(2+)-dependent cell adhesion molecules that play critical roles in the maintenance of tissue structure and morphogenesis. Their dysregulation is commonly observed in a variety of cancers. Liver-intestine cadherin (LI-cadherin), which was so named in view of its sole expression in the liver and intestine of the rat, is a structurally unique member of the cadherin superfamily, possessing seven cadherin repeats within the extracellular cadherin domain and only 25 amino acids in the cytoplasmic domain. Its adhesive property does not require any interaction with cytoplasmic components such as catenins, and it responds to small changes in extracellular Ca(2+) below the physiological plasma concentration. In humans, the distribution of LI-cadherin is limited to the duodenum, jejunum, ileum, colon, and part of the pancreatic duct. Data accumulated from studies of the biological characteristics of LI-cadherin have shown that it plays an important role in the pathophysiology of human cancers. Here, we review recent information about LI-cadherin and its implications for cancer progression.

Targeting Axl With an High-affinity Inhibitory Aptamer

Axl is a tyrosine kinase receptor that was first identified as a transforming gene in human myeloid leukemia. Recent converging evidence suggests its implication in cancer progression and invasion for several solid tumors, including lung, breast, brain, thyroid, and pancreas. In the last decade, Axl has thus become an attractive target for therapeutic development of more aggressive cancers. An emerging class of therapeutic inhibitors is now represented by short nucleic acid aptamers. These molecules act as high affinity ligands with several advantages over conventional antibodies for their use in vivo, including their small size and negligible immunogenicity. Furthermore, these molecules can easily form conjugates able to drive the specific delivery of interfering RNAs, nanoparticles, or chemotherapeutics. We have thus generated and characterized a selective RNA-based aptamer, GL21.T that binds the extracellular domain of Axl at high affinity (12 nmol/l) and inhibits its catalytic activity. GL21.T blocked Axl-dependent transducing events in vitro, including Erk and Akt phosphorylation, cell migration and invasion, as well as in vivo lung tumor formation in mice xenografts. In this respect, the GL21.T aptamer represents a promising therapeutic molecule for Axl-dependent cancers whose importance is highlighted by the paucity of available Axl-specific inhibitory molecules.

FOXP3 expression in tumor cells and implications for cancer progression

FOXP3 is a member of the forkhead/winged-helix family of transcriptional regulators. Defects in the FOXP3 gene cause an X-linked autoimmune/immunodeficiency syndrome in humans and the Scurfy phenotype in mice. FOXP3 acts mainly in regulating the development and function of CD4+CD25+ regulatory T cells. Although initially thought to be specific for these cells, FOXP3 expression has recently been described in non-hematopoietic cells, including epithelial cells of multiple lineages and of different tissue origins. Moreover, FOXP3 expression has been detected in tumor cells of both epithelial and non-epithelial tissues. The role of FOXP3 expression by tumor cells remains controversial, with in vitro studies pointing to an onco-suppressive action, whereas studies conducted on human samples associate FOXP3 expression by tumor cells with metastatic spread. Here, we review evidence for the multi-faceted role of FOXP3 in cancer cells.

Abstract 3081: Crosstalk between Runx2 regulatory network and PI3K/Akt signaling pathway in breast cancer cells

Abstract The Runt-related transcription factor Runx2 is essential for skeletal development but is also aberrantly expressed in several cancers (e.g., breast, prostate and osteosarcoma) where it promotes cell migration, invasive and growth properties of cancer cells. The phosphatidylinositol 3′ kinase (PI3K)/Akt signaling pathway is linked to Runx2-dependent skeletogenesis, however, the mechanisms of Runx2 role in PI3K-Akt signaling in breast cancers, and its implication in cancer progression remains under investigated. To mechanistically determine the function of Runx2 in epidermal growth factor (EGF)-induced PI3K/Akt signaling and concomitantly ensuing downstream signaling events, we modulated Runx2 expression levels in immortalized normal MCF-10A and invasive MDA-MB-231 cells via lentiviral vector-mediated gene delivery. The Runx2 over-expression in EGF-stimulated MCF-10A cells increased the cellular response towards PI3K inhibitor LY294002 as indicated by a decline in Akt (Serine 473) phosphorylation (pAkt) levels. This effect could be restored by Runx2 suppression indicating the specificity of Runx2 function in Akt regulation. In MDA-MB-231 cells, Runx2 over-expression and, surprisingly, suppression profoundly inhibited pAkt suggesting that a threshold level of Runx2 is required for phosphorylation of Akt. The Runx2-mediated decline in pAkt was completely reversed by the Runx2-DNA binding mutant over-expression indicating that Runx2 DNA binding domain is essential for Akt inhibition. To further dissect the mechanism of Runx2-mediated regulation of pAkt levels in MDA-MB-231 cells, we examined the protein levels of phosphatases and kinases associated with PI3K/Akt signaling pathway. These analyses revealed that PH domain and leucine rich repeat protein phosphatase 1 (PHLPP1) levels were directly responsive to Runx2. Chromatin immunoprecipitation studies showed Runx2 recruitment on the proximal promoter of PHLPP1 suggesting that Runx2 mediates its effect on Akt activity, in part by regulating PHLPP1 expression. Furthermore, Runx2 overexpression increased nuclear translocation of a forkhead box transcription factor FoxO1, a downstream molecule of PI3K/Akt signaling indicating an indirect Runx2 affect on FoxO1 transcriptional activity in MDA-MB-231 cells as examined by western blot analysis and immunofluorescence studies. Together, our results identified clinically relevant and novel mechanisms of Runx2 regulatory network in PI3K/Akt signaling pathway that could have important consequences in targeting breast cancer-associated cell survival and invasive properties. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3081. doi:1538-7445.AM2012-3081

Differential Expression of Chemokine Receptors and their Roles in Cancer Imaging

Chemokine/chemokine receptor interactions play diverse roles in cell migration and homeostasis. Emerging evidence suggests that cancer cells co-opt chemokine networks for survival, proliferation, immune evasion, and metastasis. Most of the chemokine receptors are reported to be involved in tumor progression. Given their extensive implication in cancer progression, several chemokine receptor/ligand axes are considered as potential therapeutic targets. This review provides a survey of chemokine receptor expression in cancer and evaluates the potential of chemokine receptor imaging as a tool for molecular characterization of cancer.

Tissue transglutaminase, inflammation, and cancer: how intimate is the relationship?

Despite significant advances in surgery and biology, cancer remains a major health problem. It is now well accepted that metastasis and cancer cells' acquired or inherent resistance to conventional therapies are major roadblocks to successful treatment. Chronic inflammation is an important driving force that provides a favorable platform for cancer's progression and development and suggests a link between inflammation and metastatic transformation. However, how chronic inflammation contributes to metastatic cell transformation is not well understood. According to the current theory of cancer progression, a small subpopulation of cancer stem cells (CSCs) in tumors is responsible for their metastasis, resistance, and sustenance. Whether CSCs originate from normal stem cells or from dedifferentiation of terminally differentiated cells remains unknown. Recent evidence indicates that stem cells are not unique; malignant or nonmalignant cells can reprogram and de-differentiate to acquire a stemness phenotype. Thus, phenotypic plasticity may exist between stem cells and non-stem cells, and a dynamic equilibrium may exist between the two phenotypes. Moreover, this equilibrium may shift in one direction or another on the basis of contextual signals in the microenvironment that influence the interconversion between stem and non-stem cell compartments. Whether the inflammatory microenvironment influences this interconversion and shifts the dynamic equilibrium towards stem cell compartments remains unknown. We recently found that aberrant tissue transglutaminase (TG2) expression induces the mesenchymal transition (EMT) and stem cell characteristics in epithelial cells. This finding, in conjunction with the observation that inflammatory signals (e.g., TGFβ, TNFα, and NF-κB) which induce EMT, also induce TG2 expression, suggests a possible link between TG2, inflammation, and cancer progression. In this review, we summarize TG2-driven processes in inflammation and their implications in cancer progression.

Abstract 73: PELP1 is a novel reader of chromatin modifications: Implications in cancer progression

Abstract Cancer is caused by abnormalities of the genome and epigenome including the frequently occurring epigenetic changes of histone modifications. Specifically, estrogen-induced breast carcinogenesis is characterized by alterations in histone modifications. Reader proteins that recognize these modifications facilitate modulation of genes and their resulting biological actions. In addition to regulation by several coregulators, estrogen receptor alpha (ERα) transcriptional activation or repression depends on the modulation of histone methylation at target promoters. The ERα coregulator PELP1 plays an important role in ERα signaling, is a proto-oncogene with aberrant expression in hormone-related cancers and a prognostic indicator of decreased survival in breast cancer patients. The molecular mechanisms by which PEPL1 promotes oncogenesis remain unknown; however, previous studies from our lab have shown that PELP1 interacts with histones and is a novel reader of chromatin modifications. To explore the PELP1 epigenetic interactome, we used a histone peptide array containing 384 unique combinations of histone modifications including methylation, phosphorylation, acetylation and citrullination. Our results show that PELP1 uniquely recognizes histones modified by arginine dimethylation, arginine citrullination and lysine dimethylation. Phosphorylation of residues adjacent to a methyl modification affects the ability of PELP1 to recognize histone methylation. Using various deletions of PELP1 peptides, we have found that PELP1 acts as a module for recognition of a specific histone modification through the carboxyl-terminal glutamic acid rich region. Reporter gene assays showed that PELP1 functionally interacts with arginine methyltransferases including CARM1 and PRMT6, both shown to be dysregulated in human cancers, and synergistically enhances ERα-transactivation. Chromatin immunoprecipitation assays revealed that PELP1 has the potential to alter histone H3 arginine methylation status at ERα target gene promoters. The critical role of PELP1 status in modulating arginine methylation status was also observed through in vivo studies which show PELP1 knockdown results in decreased tumorigenesis and arginine dimethylation. Our findings suggest that PELP1 is a reader of histone methyl modifications and deregulation may have implications on tumor proliferation via epigenetic alterations at ERα target promoters. Targeting these epigenetic alterations through inhibition of PELP1 and the arginine methyltransferases could be a promising cancer therapeutic. This study was funded by NIH grant CA095681. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 73. doi:10.1158/1538-7445.AM2011-73

Laminin‐332 cleavage by matriptase alters motility parameters of prostate cancer cells

Matriptase, a type II transmembrane serine protease, has been linked to initiation and promotion of epidermal carcinogenesis in a murine model, suggesting that deregulation of its role in epithelia contributes to transformation. In human prostate cancer, matriptase expression correlates with progression. It is therefore of interest to determine how matriptase may contribute to epithelial neoplastic progression. One approach for studying this is to identify potential matriptase substrates involved in epithelial integrity and/or transformation like the extracellular matrix macromolecule, laminin-332 (Ln-332), which is found in the basement membrane of many epithelia, including prostate. Proteolytic processing of Ln-332 regulates cell motility of both normal and transformed cells, which has implications in cancer progression. In vitro cleavage experiments were performed with purified Ln-332 protein and matriptase. Western blotting, enzyme inhibition assays, and mass spectrometry were used to confirm cleavage events. Matriptase overexpressing LNCaP prostate cancer cells were generated and included in Transwell migration assays and single cell motility assays, along with other prostate cells. We report that matriptase proteolytically cleaves Ln-332 in the β3 chain. Substrate specificity was confirmed by blocking cleavage with the matriptase inhibitor, Kunitz domain-1. Transwell migration assays showed that DU145 cell motility was significantly enhanced when plated on matriptase-cleaved Ln-332. Similarly, Transwell migration of matriptase-overexpressing LNCaP cells was significantly increased on Ln-332 and, as determined by live single-cell microscopy, two motility parameters of this cell line, speed and directional persistence, were also higher. Proteolytic processing of Ln-332 by matriptase enhances speed and directional persistence of prostate cancer cells.

Transforming growth factor-(beta)s and mammary gland involution; functional roles and implications for cancer progression.

During rodent mammary gland involution there is a dramatic increase in the expression of the transforming growth factor-beta isoform, TGF-beta3. The TGF-betas are multifunctional cytokines which play important roles in wound healing and in carcinogenesis. The responses that are activated in the remodeling of the gland during involution have many similarities with the wound healing process and have been postulated to generate a mammary stroma that provides a microenvironment favoring tumor progression. In this review we will discuss the putative role of TGF-beta during involution, as well as its effects on the mammary microenvironment and possible implications for pregnancy-associated tumorigenesis.

Regulation of Autophagy by Reactive Oxygen Species (ROS): Implications for Cancer Progression and Treatment

Reactive oxygen species (ROS) have been identified as signaling molecules in various pathways regulating both cell survival and cell death. Autophagy, a self-digestion process that degrades intracellular structures in response to stress, such as nutrient starvation, is also involved in both cell survival and cell death. Alterations in both ROS and autophagy regulation contribute to cancer initiation and progression, and both are targets for developing therapies to induce cell death selectively in cancer cells. Many stimuli that induce ROS generation also induce autophagy, including nutrient starvation, mitochondrial toxins, hypoxia, and oxidative stress. Some of these stimuli are under clinical investigation as cancer treatments, such as 2-methoxyestrodial and arsenic trioxide. Recently, it was demonstrated that ROS can induce autophagy through several distinct mechanisms involving Atg4, catalase, and the mitochondrial electron transport chain (mETC). This leads to both cell-survival and cell-death responses and could be selective toward cancer cells. In this review, we give an overview of the roles ROS and autophagy play in cell survival and cell death, and their importance to cancer. Furthermore, we describe how autophagy is mediated by ROS and the implications of this regulation to cancer treatments.

Expression and clinical significance of Glucose Regulated Proteins GRP78 (BiP) and GRP94 (GP96) in human adenocarcinomas of the esophagus

BackgroundGlucose regulated proteins (GRPs) are main regulators of cellular homeostasis due to their role as molecular chaperones. Moreover, the functions of GRPs suggest that they also may play important roles in cancer biology. In this study we investigated the glucose regulated proteins GRP78 (BiP) and GRP94 (GP96) in a series of human esophageal adenocarcinomas to determine their implications in cancer progression and prognosis.MethodsFormalin-fixed, paraffin-embedded tissues of primary resected esophageal (Barrett) adenocarcinomas (n = 137) and corresponding normal tissue were investigated. mRNA-gene expression levels of GRP78 and GRP94 were determined by quantitative real-time RT-PCR after mRNA extraction. Protein expression analysis was performed with immunohistochemical staining of the cases, assembled on a tissue micorarray. The results were correlated with pathologic features (pT, pN, G) and overall survival.ResultsGRP78 and GRP94 mRNA were expressed in all tumors. The relative gene expression of GRP78 was significantly higher in early cancers (pT1m and pT1sm) as compared to more advanced stages (pT2 and pT3) and normal tissue (p = 0.031). Highly differentiated tumors showed also higher GRP78 mRNA levels compared to moderate and low differentiated tumors (p = 0.035). In addition, patients with higher GRP78 levels tended to show a survival benefit (p = 0.07). GRP94 mRNA-levels showed no association to pathological features or clinical outcome.GRP78 and GRP94 protein expression was detectable by immunohistochemistry in all tumors. There was a significant correlation between a strong GRP78 protein expression and early tumor stages (pT1m and pT1sm, p = 0.038). For GRP94 low to moderate protein expression was significantly associated with earlier tumor stage (p = 0.001) and less lymph node involvement (p = 0.036). Interestingly, the patients with combined strong GRP78 and GRP94 protein expression exclusively showed either early (pT1m or pT1sm) or advanced (pT3) tumor stages and no pT2 stage (p = 0.031).ConclusionWe could demonstrate an association of GRP78 and GRP94 mRNA and protein expression with tumor stage and behaviour in esophageal adenocarcinomas. Increased expression of GRP78 may be responsible for controlling local tumor growth in early tumor stages, while high expression of GRP78 and GRP94 in advanced stages may be dependent from other factors like cellular stress reactions due to glucose deprivation, hypoxia or the hosts' immune response.

The helicase-like transcription factor and its implication in cancer progression.

The helicase-like transcription factor (HLTF) belongs to the SWI/SNF family of chromatin-remodeling factors. Several SWI/SNF genes are disrupted in cancer, suggesting their possible role as tumor suppressors. Similarly, the HLTF gene was found to be inactivated by hypermethylation in a significant number of colon, gastric and uterine tumors, indicating that HLTF silencing may confer a growth advantage and that HLTF could be considered as a tumor suppressor gene. However, 20-fold HLTF overexpression was detected in various transformed cell lines, suggesting that HLTF could be associated with neoplastic transformation and act more like an oncogene. Moreover, HLTF activation was recently linked to the initial steps of carcinogenesis in an experimental model of estrogen-induced kidney tumors. Those apparently contradictory observations suggest that HLTF might play various roles in cancer. In this review, we will try to reconcile all these data in order to specify the role of HLTF in cancer progression.

Targeting platelet-derived endothelial cell growth factor/thymidine phosphorylase for cancer therapy

Thymidine phosphorylase (TP) is a key enzyme in the pyrimidine nucleoside salvage pathway, but it also recognizes and inactivates various anti-cancer chemotherapeutic agents. Moreover, TP is identical to platelet-derived endothelial cell growth factor (PD-ECGF), an angiogenic factor with anti-apoptotic properties. Increased expression of PD-ECGF/TP is found in many tumor and stromal cells, and elevated TP levels are associated with aggressive disease and/or poor prognosis. Thus, progression and metastasis of TP-expressing tumors might be abrogated by TP inhibitors that are used as single agents or in combination with (TP-sensitive) nucleoside analogues. On the other hand, increased TP activity in tumors may be exploited for the tumor-specific activation of fluoropyrimidine prodrugs, such as capecitabine. This review will focus on the different biological activities of PD-ECGF/TP and their implications for cancer progression and treatment.

The secretory leukocyte protease inhibitor gene is a target of epidermal growth factor receptor action in endometrial epithelial cells

The over-expression of epidermal growth factor receptor (EGFR) and its ligands, epidermal growth factor (EGF) and transforming growth factor-alpha, is a common feature of epithelial carcinomas and correlates with neoplastic progression. Secretory leukocyte protease inhibitor (SLPI), a member of the Kazal superfamily of serine anti-proteases, induces proliferation and promotes malignancy of epithelial cells and is expressed at high levels in multiple tumor types. In the present study, we have demonstrated that EGF increases SLPI expression in the human endometrial epithelial cell line Ishikawa in a dose- and time-dependent manner. We have shown that this effect of EGF occurs, in part, at the level of the SLPI promoter and involves the MAP kinase signaling pathway. We have further shown that EGF promotion of cell proliferation, but not induction of cyclin D1 gene expression, involves SLPI. Our results suggest that the regulation of SLPI expression by EGFR ligand(s) may represent a 'feed-forward' mechanism by which the enhanced proliferative and migratory properties of EGFR over-expressing cancer cells are sustained. Increased SLPI expression is likely an important component of altered EGFR signaling in human tumors and may have significant therapeutic implications in cancer progression.

Methylation profiling of human cancers in blood: Molecular monitoring and prognostication (Review)

Cancer is a polygenetic and polyepigenetic disease. Circulating tumor cells in peripheral blood have been demonstrated to reflect the biological characteristics of tumors including the potential of metastasis development and tumor recurrence. Aberrant promoter methylation has emergingly become a fundamental molecular abnormality leading to transcriptional silencing of tumor suppressor genes, DNA repair genes and metastasis inhibitor genes, and is linked to the predisposition of genetic alterations of other cancer-associated genes. This epigenetic inheritance has significant biological implications for cancer progression and metastasis formation. Of significance, DNA hypermethylation of multiple genes successfully detected in circulating tumor cells from cancer patients may prove valuable for disease monitoring. A number of epigenetic markers may feasibly enable the detection of circulating tumor cells from patients with different cancer types. The prognostic and therapeutic implications of aberrant DNA methylation could eventually bring forth improved outcome of cancer patients. A growing body of evidence and future advances in understanding cancer epigenetics may fuel us to monitor and treat cancers in alternative ways.