Current Cancer Drug Targets - Volume 13, Issue 9, 2013

Epithelial-to-Mesenchymal transition (EMT) is a phenomenon in which cancer cells loose their polarity, undergo morphological changes from epithelial to mesenchymal thereby achieving plasticity that confers an invasive and metastatic behavior. A large number of signaling molecules (Wnt/β-Catenin, TGF-β, notch, EGF, HGF and hypoxia) have been implicated in the EMT process. The EMT signaling molecules are localized either extracellularly, in the cytosol, or in the nucleus. The Wnt, TGF-β, notch, EGF and HGF signaling initiates from receptors on the cell surface through the cytoplasm and ultimately to the cell's nucleus where the signaling cascade leads to the expression of EMT genes. No matter what the source is, the ultimate effector molecules from each one of these signaling pathways need to reach cell nucleus, aligning on DNA in a sequence specific manner and initiating the transcription of EMT promoting genes. In essence cellular transport, particularly the nuclear transport that is regulated by specialized proteins called Karyopherins, in a way controls the majority of EMT promoting pathways either directly or indirectly. Nevertheless, there have been no attempts to understand the consequence of alterations in the nuclear transport machinery that is often times aberrantly expressed in cancer, on EMT development. This review poses important questions on the role of nuclear transporters (Importins and Exportins) in the development of EMT and provides an in depth understanding of the underappreciated cellular transport based regulation of EMT signaling molecules and also discusses the possibility of targeting the nuclear import and export proteins to rein in EMT.

Overcoming intrinsic and acquired drug resistance is a major challenge in treating cancer. Poor responses to drug treatment can result in metastasis, cancer dissemination and death. Recently, the epithelial-mesenchymal transition (EMT) has been found to play a critical role in cancer drug resistance, but the nature of this intrinsic link remains unclear. This review summarizes recent advances in the understanding of drug resistance and focuses especially on the association between EMT and drug resistance. We discuss the roles of EMT in regulating drug resistance across different types of cancer, focusing simultaneously on the molecular mechanisms and potential pathways involved in the regulation of drug resistance by EMT. In addition, we discuss potential therapeutic strategies to target EMT to reverse drug resistance.

Epithelial-mesenchymal transition (EMT) is a developmental process that converts epithelial cells into migratory and invasive cells. This process also plays an important role in cancer progression and metastasis by enabling tumor cells to leave primary sites. EMT is regulated by complex transcription networks and post-transcriptional modulators. MicroRNAs are single-stranded non-coding RNAs that represent a novel class of gene regulators. It has been shown that microRNAs are critical regulators of EMT process. The molecular mechanisms of EMT modulation by microRNAs include the suppression of transcription factors that directly regulate EMT and the down-regulation of cellular genes and pathways that are indirectly involved in EMT process. The expressions of microRNAs that control EMT process are dysregulated in cancer. In this review, we summarize the recent progress of microRNAs in EMT regulation.

The epithelial-mesenchymal transition (EMT) is a fundamental biological process that is involved in normal embryogenesis, would healing, and tissue repair, as well as numerous pathologies, including organ fibrosis, malignant transformation, and cancer progression. Both transcriptional and post-transcriptional regulatory mechanisms contribute to a complex and tightly controlled regulatory network during the EMT process, and a growing body of evidence now demonstrates that microRNAs (miRNAs) are crucial regulators of this network. miRNAs are a class of small non-coding RNAs that regulate gene expression through translational repression or mRNA degradation. A set of miRNAs have been discovered that have the potential to target multiple components of the signaling pathways and downstream effectors of the EMT. Our understanding of the roles that miRNAs play during the EMT process suggests that these miRNAs may eventually serve as novel biomarkers and therapeutic targets for various EMT-based pathological conditions. This review summarizes the current knowledge concerning how miRNAs mechanistically regulate the EMT and discusses the specific roles that miRNAs play in three EMT subtypes. We hope that a more comprehensive understanding of the functions of miRNAs in the EMT process will lead to the rapid development of novel diagnostic techniques and molecular-based strategies for controlling EMT.

Epithelial to mesenchymal transition (EMT) is an important and complex phenomenon that determines the aggressiveness of cancer cells. The morphological transformation of cancerous cells is accompanied by various cellular processes such as alterations in cell-cell adhesion, cell matrix degradation, down regulation of epithelial marker Ecadherin and upregulation of mesenchymal markers N-cadherin and Vimentin. Besides these markers several other important tumor antigens/mucins are also involved in the EMT process. Mainly high molecular weight glycoproteins such as mucin molecules (MUC1, MUC4 and MUC16) play a major role in the cellular transformation and signaling alteration in EMT process. In addition to these factors, EMT may be an essential process triggering the emergence or expansion of the CSC population, which slowly results in the initiation of tumor at metastatic sites. Furthermore, mucins have been demonstrated to be involved in the EMT process and also in the enrichment of cancer stem cell population. Mucin mediated EMT is very complex since the key components of tumor microenvironment are also regulating mucin molecules. In this review, we have discussed all the aforementioned factors and their mechanistic involvement for EMT process.

Notch signaling pathway has been reported to play critical roles in the development and progression of human cancers because Notch signaling pathway is critically involved in many cellular processes including cell proliferation, survival, apoptosis, migration, invasion, angiogenesis, and metastasis. Emerging evidence suggests that Notch regulates EMT (Epithelial-to-Mesenchymal Transition), leading to tumor invasion and metastasis. Thus, this mini-review is focused on discussing the novel role of Notch signaling pathway in the regulation of EMT. Moreover, we summarized that Notch signaling pathway could be down-regulated by its inhibitors or natural compounds, resulting in the reversal of EMT to MET (Mesenchymal-to-Epithelial Transition), which could be a promising strategy for achieving better treatment outcome in patients diagnosed with cancer.

Epithelial-mesenchymal transition (EMT) is a highly conserved process in which polarized, immobile epithelial cells lose tight junctions, associated adherence, and become migratory mesenchymal cells. Several transcription factors, including the Snail/Slug family, Twist, δEF1/ZEB1, SIP1/ZEB2 and E12/E47 respond to microenvironmental stimuli and function as molecular switches for the EMT program. Snail is a zinc-finger transcriptional repressor controlling EMT during embryogenesis and tumor progression. Through its N-terminal SNAG domain, Snail interacts with several corepressors and epigenetic remodeling complexes to repress specific target genes, such as the E-cadherin gene (CDH1). An integrated and complex signaling network, including the RTKs, TGF-β, Notch, Wnt, TNF-α, and BMPs pathways, activates Snail, thereby inducing EMT. Snail expression correlates with the tumor grade, nodal metastasis of many types of tumor and predicts a poor outcome in patients with metastatic cancer. Emerging evidences indicate that Snail causes a metabolic reprogramming, bestows tumor cells with cancer stem cell-like traits, and additionally, promotes drug resistance, tumor recurrence and metastasis. Despite many new and exciting developments, several challenges remain to be addressed in order to understand more thoroughly the role of Snail in metastasis. Additional investigations are required to disclose the contribution of microenvironmental factors on tumor progression. This information will lead to a comprehensive understanding of Snail in cancer and will provide us with novel approaches for preventing and treating metastatic cancers.

Epithelial-mesenchymal transition (EMT) is a vital process implemented in embryo development, organ fibrosis, and cancer metastasis. Several transcription factors and signaling pathways impinge on the transcriptional program of the cell, leading to the change of cell phenotype without alteration of genotype. Accumulating evidence suggests that epigenetic mechanisms play important roles in inducing EMT and orchestrating the heredity and reversibility of EMT. In this review, we discuss how DNA methylation, histone modifications, and microRNAs (miRNAs) act in a concerted manner to regulate EMT. ‘Epigenetic therapies’—inhibitors of DNA methyltransferases and histone deacetylases as well as microRNAs are emerging as promising agents for cancer intervention.

Gastrointestinal (GI) cancer is characterized by its aggressiveness, but the underlying mechanism is not fully understood. Studies reveal that epithelial to mesenchymal transition (EMT), which is regulated by a series of transcription factors and signaling pathways, is strongly associated with GI cancer cell proliferation, invasion and metastasis. Importantly, EMT is a product of crosstalk between signaling pathways. Kruppel-like factor 4 (KLF4), a zinc finger-type transcription factor, is decreased or lost in most GI cancers. By transcriptionally regulating its downstream target genes, KLF4 plays important roles of GI cancer tumorigenesis, proliferation and differentiation. In this review, we focus on the mechanism of KLF4 in GI cancer EMT, and demonstrate that through crosstalk with TGF-β, Notch, and Wnt signaling pathways, KLF4 negatively regulates EMT of GI cancers. Finally, we indicate the challenging new frontiers for KLF4 which contributes to better understanding of the mechanism of GI cancer aggressiveness.

Oncogenic epithelial-mesenchymal transition (oncEMT) plays important roles in the genesis of cancer stem cells (CSCs), malignant tumor initiation and progression, cancer metastasis, and drug resistance. Although the role of oncEMT in tumorigenesis has recently been extensively studied, the initiation of oncEMT is not clearly understood, and its mechanisms of action are still unknown. Emerging evidence suggests that oncEMT is a complex process, which involves multiple endogenous and exogenous factors. Overexpression of several oncogenes and reprogramming factors in precancerous and cancerous cells, including Ras, Myc, Bmi-1, Oct4, Nanog, Slug, Twist, Zeb1, and Zeb2, may initiate oncEMT and tumorigenesis. Defects in key tumor suppressors, such as p53, PTEN, CCN6 protein, and p21 also are associated with oncEMT. MicroRNA (miRNA) may also play a role in the oncEMT. Furthermore, exogenous factors, including chemical carcinogens, viruses, radiation, hypoxia, and acidic microenvironment, can drive oncEMT. Moreover, various growth factors derived from either malignant tumor cells or tumor-associated non-tumor cells in the cancer microenvironment can promote oncEMT. Together, the endogenous and exogenous factors, as well as a hostile cancer microenvironment, initiate the oncEMT program through diverse signaling pathways and networks. However, the dynamic process of initiating oncEMT and the mechanisms are still incompletely understood. Further characterization of the dynamics and mechanisms of the oncEMT will provide new insights into oncogenesis, as well as identify specific oncEMT markers and targets for early diagnosis of cancer and novel anti-cancer drug discovery.