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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

EMT and MET in carcinoma-clinical observations, regulatory pathways and new models.
Clin Exp Metastasis 2008
PMID:EMT and MET in carcinoma--clinical observations, regulatory pathways and new models. 1856 98

Cancer metastasis follows a sequential series of events, and many of the critical steps are distinctly similar to EMT-like transformations that occur during normal embryonic development. A current area of focus is the similarities between how cancer cells interact with the ectopic parenchyma after metastatic spread, and secondary developmental MET events that occur in epithelial tissues that have re-assembled within the embryo from mesenchymal cells. Accumulating evidence suggests a critical role for these secondary events, termed mesenchymal-epithelial transitions (MET) in development and mesenchymal-epithelial reverting transitions (MErT) in cancer. In this situation, metastatic seed cancer cells may inertly become part of the ectopic tissue and therefore surmount the metastatic inefficiencies to which most disseminated cancer cells succumb. Just as a critical EMT event is the downregulation or silencing of E-cadherin, we discuss the role of E-cadherin in cancer-associated MErT at distant metastatic sites and speculate on the implications for the fate of micrometastases that undergo a transition to being E-cadherin positive.
Clin Exp Metastasis 2008
PMID:E-cadherin as an indicator of mesenchymal to epithelial reverting transitions during the metastatic seeding of disseminated carcinomas. 1860 Mar 5

NSCLC cells with a mesenchymal phenotype have shown a marked reduction in sensitivity to EGFR inhibitors, though the molecular rationale has remained obscure. Here we find that in mesenchymal-like tumor cells both tyrosine phosphorylation of EGFR, ErbB2, and ErbB3 signaling networks and expression of EGFR family ligands were decreased. While chronic activation of EGFR can promote an EMT-like transition, once having occurred EGFR family signaling was attenuated. We investigated the mechanisms by which mesenchymal-like cells bypass EGFR signaling and acquire alternative routes of proliferative and survival signaling. Mesenchymal-like NSCLC cells exhibit aberrant PDGFR and FGFR expression and autocrine signaling through these receptors can activate the MEK-ERK and PI3K pathways. Selective pharmacological inhibition of PDGFR or FGFR receptor tyrosine kinases reduced cell proliferation in mesenchymal-like but not epithelial NSCLC cell lines. A metastable, reversible EMT-like transition in the NSCLC line H358 was achieved by exogenous TGFbeta, which served as a model EMT system. The H358/TGFbeta cells showed many of the attributes of established mesenchymal-like NSCLC cells including a loss of cell-cell junctions, a loss of EGF-family ligand expression, a loss of ErbB3 expression, increased EGFR-independent Mek-Erk pathway activation and reduced sensitivity to EGFR inhibition. Notably an EMT-dependent acquisition of PDGFR, FGFR and TGFbeta receptors in H358/TGFbeta cells was also observed. In H358/TGFbeta cells both PDGFR and FGFR showed functional ligand stimulation of their intrinsic tyrosine kinase activities. The findings of kinase switching and acquired PDGFR and FGFR signaling suggest investigation of new inhibitor combinations to target NSCLC metastases.
Clin Exp Metastasis 2008
PMID:Kinase switching in mesenchymal-like non-small cell lung cancer lines contributes to EGFR inhibitor resistance through pathway redundancy. 1869 32

Sporadic colorectal cancer is a major cause of death worldwide. Development takes place in a sequential manner from benign adenomas leading to carcinomas. In 90% of tumours bearing a Ras mutation it is Ki-Ras that is mutated. We have developed a model cell system to study oncogenic Ras mutations in colorectal cancer cell lines. In this analysis two Caco-2 derived cell lines expressing Ha-RasV12 (Caco-H) and Ki-RasV12 (Caco-K), respectively, have been used in large-scale microarray profiling against a Caco-2 control. This was carried out using an Illumina microarray containing 24,000 genes. Genes have been identified as differentially expressed in each isoform as well as commonly regulated. In addition the Caco-H cell line has a strong epithelial-mesenchymal phenotype that is reflected in many of its differentially expressed genes. These include the known EMT markers Vimentin, E-cadherin and Slug. Other genes of interest include several members of the Claudin family, Forkhead transcription factors and GATA-factors. The Caco-K cell line shows strong downregulation of the Dickkopf transcriptional repressor implicating it in WNT signalling. Pathway and functional analysis has also been carried out for the differentially expressed genes for both cell lines using Ingenuity software. This genome wide microarray analysis has provided a molecular signature for EMT in a Caco-H colon cancer cell line. It has also revealed a number of key genes for Caco-K expression and identified novel markers for Ras expression that have been verified by PCR analysis.
Clin Exp Metastasis 2009
PMID:A molecular signature for Epithelial to Mesenchymal transition in a human colon cancer cell system is revealed by large-scale microarray analysis. 1934 May 93

According to recently published data, the epithelial-mesenchymal transition--a process important for embryonic development, may be involved in many pathological processes such as wound healing, tissue fibrosis or cancer progression. The EMT process in cell is driven by growth factors (EGF, PDGF, HGF) or other signaling proteins such as TGF-beta, sonic hedgehog (Shh), Wnt/beta-catenin and extracellular matrix (ECM) components that may stimulate cellular growth and migration. During cancer progression, the EMT process is necessary to the conversion of benign tumor to aggressive and highly invasive cancer. This is due to complex changes in cancer cells and their microenvironment that lead to dissolution of intracellular junctions and their detachment from basolateral membrane, and changes in the interactions between cancer cells and ECM. The loss of adhesion is accompanied by molecular and morphologic changes in cancer cells that are essential for the phenotypic change from epithelial to mesenchymal one, and the acquirement of higher migration and invasion potential. During the colonization of distant sites, a reverse process mesenchymal-epithelial transition (MET) takes place and metastatic cancer cells again acquire the epithelial phenotype. The EMT in cancer progression is not only specific for cancer cells. It has been suggested that also cells within tumor microenvironment e.g. cancer associated fibroblasts (CAF) are generated in part from normal epithelial cells in EMT process. The understanding of the role of EMT and MET processes in cancer progression and their relationship with cancer stem cells, cancer associated fibroblasts and other stroma cells might lead to the discovery of new, targeted cancer therapies.
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PMID:[Epithelial-mesenchymal transition in cancer progression]. 1982 67

The activating mutation BRAF(V600E) is a frequent genetic event in papillary thyroid carcinomas (PTC) that predicts a poor prognosis, leading to loss of sodium/iodide symporter (NIS) expression and subsequent radioiodide-refractory metastatic disease. The molecular basis of such an aggressive behavior induced by BRAF remains unclear. Here, we show a mechanism through which BRAF induces NIS repression and promotes epithelial to mesenchimal transition and invasion based on the operation of an autocrine transforming growth factor (TGF)beta loop. BRAF induces secretion of functional TGFbeta and blocking TGFbeta/Smad signaling at multiple levels rescues BRAF-induced NIS repression. Although this mechanism is MAP/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK independent, secreted TGFbeta cooperates with MEK-ERK signaling in BRAF-induced cell migration, Matrigel invasion, and EMT. Consistent with this process, TGFbeta and other key components of TGFbeta signaling, such as TbetaRII and pSmad2, are overexpressed in human PTC, suggesting a widespread activation of this pathway by locally released TGFbeta. Moreover, this high TGFbeta/Smad activity is associated with PTC invasion, nodal metastasis, and BRAF status. Interestingly, TGFbeta is overexpressed in the invasive front, whereas NIS is preferentially expressed in the central regions of the tumors, suggesting that this negative correlation between TGFbeta and NIS occurs locally inside the tumor. Our study describes a novel mechanism of NIS repression in thyroid cancer and provides evidence that TGFbeta may play a key role in promoting radioiodide resistance and tumor invasion during PTC progression.
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PMID:The BRAFV600E oncogene induces transforming growth factor beta secretion leading to sodium iodide symporter repression and increased malignancy in thyroid cancer. 1986 38

The cancer stem cell (CSC) hypothesis provides an attractive model of tumour development and progression, holding that solid tumours are hierarchically organized and sustained by a minority of the tumour cell population with stem cell properties, such as self-renewal, tumorigenicity and multilineage differentiation capacity. Therapeutic resistance, underlying tumour recurrence and the lack of curative treatments in metastatic disease, raise the question if conventional anticancer therapies target the right cells. Indeed, these treatments might miss CSCs, which represent a more chemoresistant and radioresistant subpopulation within cancer. Recently, a direct link between the epithelial-mesenchymal transition process and the gain of stem cell competence were demonstrated in cultured breast cells. In particular, it was shown that the induction of EMT program not only allow cancer cells to disseminate from the primary tumor, but also promotes their self-renewal capability. Furthermore, the expression of stemness and EMT markers in CTCs were associated with resistance to conventional anti-cancer therapies and treatment failure, highlighting the urgency of improving tools for detecting and eliminating minimal residual disease.
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PMID:Cancer stem cells and epithelial-mesenchymal transition: revisiting minimal residual disease. 2038 75

Currently stem cells are hypothesized to play a central role in the origin, spread and resistance to treatment of breast cancer. Common anticancer therapy is effective but transient, with tumor relapse and metastatic disease often occurring. For therapy to be more effective, debulking of differentiated tumors must occur followed by targeting of the remaining surviving often quiescent tumor stem cells. New therapeutics aimed at cancer stem cells are achieved through non immunological and immunological methods. The former include elective ABC drug transporters or the heat shock protein 90 inhibition, targeting the self-renewal signalling pathways or the EMT program, differentiation therapy, or other interventions to eliminate BrCSCs. The latter include targeting specific antigens expressed on BrCSCs, dendritic cells (DCs) based vaccination and blockers of the extrinsic signals at CSC niche. Here all these novel approaches related to breast cancer stem cells are described.
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PMID:Cancer stem cells: perspectives of new therapeutical approaches for breast cancer. 2162 84

The principal problem arising from prostate cancer (PCa) is its propensity to metastasize to bone. MicroRNAs (miRNAs) play a crucial role in many tumor metastases. The importance of miRNAs in bone metastasis of PCa has not been elucidated to date. We investigated whether the expression of certain miRNAs was associated with bone metastasis of PCa. We examined the miRNA expression profiles of 6 primary and 7 bone metastatic PCa samples by miRNA microarray analysis. The expression of 5 miRNAs significantly decreased in bone metastasis compared with primary PCa, including miRs-508-5p, -145, -143, -33a and -100. We further examined other samples of 16 primary PCa and 13 bone metastases using real-time PCR analysis. The expressions of miRs-143 and -145 were verified to down-regulate significantly in metastasis samples. By investigating relationship of the levels of miRs-143 and -145 with clinicopathological features of PCa patients, we found down-regulations of miRs-143 and -145 were negatively correlated to bone metastasis, the Gleason score and level of free PSA in primary PCa. Over-expression miR-143 and -145 by retrovirus transfection reduced the ability of migration and invasion in vitro, and tumor development and bone invasion in vivo of PC-3 cells, a human PCa cell line originated from a bone metastatic PCa specimen. Their upregulation also increased E-cadherin expression and reduced fibronectin expression of PC-3 cells which revealed a less invasive morphologic phenotype. These findings indicate that miRs-143 and -145 are associated with bone metastasis of PCa and suggest that they may play important roles in the bone metastasis and be involved in the regulation of EMT Both of them may also be clinically used as novel biomarkers in discriminating different stages of human PCa and predicting bone metastasis.
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PMID:Identification of miRs-143 and -145 that is associated with bone metastasis of prostate cancer and involved in the regulation of EMT. 2164 77

Despite the therapeutic advances, lung cancer remains the leading cause of cancer-related death in the United States and worldwide. Metastasis and recurrence are considered to be responsible for the failure of treatment. Recent studies indicate Epithelial mesenchymal transition, an evolutionarily conserved process, plays an important role in the embryonic development and cancer progression and is involved in the metastasis, drug resistance and correlated with progression of many tumors. Of importance, EMT is also involved in the acquisition of stemness phenotype of tumor cells. Although a growing body of evidence supports the role of EMT in the progression of many cancers, and a number of signal pathways, transcriptional factors and microRNAs involved in EMT process have been identified. However, the role of EMT in lung cancer is elusive. In this review, we present the recent findings in EMT including the molecular mechanisms of EMT, and the involvement of EMT in cancer progression, cancer stem cells and drug resistance, especially focusing on the correlation of EMT and lung cancer.
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PMID:Epithelial mesenchymal transition and lung cancer. 2226 37


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