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epithelial-mesenchymal transition

Wednesday 29 October 2003

EMT, EMP; epithelial-mesenchymal plasticity

Definition: Conversion from an epithelial to a mesenchymal phenotype, which is a normal process of embryonic development. In carcinomas, this transformation results in altered cell morphology, the expression of mesenchymal proteins and increased invasiveness.

EMTs in tumors

Epithelial-mesenchymal transitions (EMTs) occur as key steps during embryonic morphogenesis, and are now implicated in the progression of primary tumors towards metastases. Recent advances have fostered a more detailed understanding of molecular mechanisms and networks governing EMT in tumor progression.

Besides TGFbeta and RTK/Ras signaling, autocrine factors and Wnt-, Notch-, Hedgehog- and NF-kappaB-dependent pathways were found to contribute to EMT.

Repression of E-cadherin by transcriptional regulators such as Snail or Twist emerges as one critical step driving EMT, and this stage is currently being molecularly linked with many of the new players.

Increasing evidence suggests that EMT plays a specific role in the migration of cells from a primary tumor into the circulation and may provide a rationale for developing more effective cancer therapies.

EM plasticity

Epithelial cells adhere to their neighboring cells through, among others, adherens junctions via binding of cadherins. Carcinoma cells are of epithelial origin and experience the same cell–cell interaction through adhesion molecules such as cadherins (CDHs), claudins (CLDNs), or plakoglobin; these interactions prevent them from spreading in the first place.

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EMBO Mol Med
v.7(1); 2015 Jan
PMC4309663

Logo of emmolmed
EMBO Mol Med. 2015 Jan; 7(1): 1–11.
Published online 2014 Nov 14. doi : 10.15252/emmm 201303698
PMCID: PMC4309663
Biology, detection, and clinical implications of circulating tumor cells
Simon A Joosse,† Tobias M Gorges,† and Klaus Pantel*
Author information ► Article notes ► Copyright and License information ►
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Abstract

Cancer metastasis is the main cause of cancer-related death, and dissemination of tumor cells through the blood circulation is an important intermediate step that also exemplifies the switch from localized to systemic disease. Early detection and characterization of circulating tumor cells (CTCs) is therefore important as a general strategy to monitor and prevent the development of overt metastatic disease. Furthermore, sequential analysis of CTCs can provide clinically relevant information on the effectiveness and progression of systemic therapies (e.g., chemo-, hormonal, or targeted therapies with antibodies or small inhibitors). Although many advances have been made regarding the detection and molecular characterization of CTCs, several challenges still exist that limit the current use of this important diagnostic approach. In this review, we discuss the biology of tumor cell dissemination, technical advances, as well as the challenges and potential clinical implications of CTC detection and characterization.
Keywords: Disseminating tumor cells (DTC), EMT, metastasis, tumor cell dormancy, tumor cell plasticity
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Biology of circulating tumor cells
Introduction

The ability of a malignant tumor to become metastatic begins with the hallmarks of motility and invasiveness (Hanahan & Weinberg, 2011). When individual cells or clusters of cancer cells acquire the ability to separate and move away from the primary tumor mass, migrate through the surrounding tissue, and enter the lymphatic system and/or blood circulation, the metastatic trait of a given tumor becomes manifest (Fig​(Fig1).1). Tumor cells that escape their primary microenvironment need to escape anoikis and might be challenged by the host’s immunologic defenses. Although the rate of tumor cell release in cancer patients is unknown, experimental models indicate that millions of tumor cells are continuously dispersed through the body, although only few of these cells might reach a distant organ, survive in a dormant state, evade the immune system and systemic therapy, and eventually grow into an overt metastasis (Chambers et al, 2002; Kang & Pantel, 2013). Adaption to a new microenvironment and proliferation of a single tumor cell in a distant site requires special traits (plasticity) that the cell must already have or acquire in order to develop to an overt metastasis detectable by clinical procedures. Tumor cells may stop cell division processes after dissemination but may persist in a quiescent status until environmental conditions provide appropriate signals to start proliferation again. This quiescent state, for which the underlying mechanisms are largely unknown, is called clinical cancer dormancy (Uhr & Pantel, 2011; Kang & Pantel, 2013) and may last more than 10 years. There is now increasing evidence that the microenvironment plays a critical role in this process (e.g., osteoclasts as regulators of osteolytic bone metastases (Lu et al, 2011; Ell et al, 2013)), in addition to changes in the tumor cells themselves (e.g., acquisition of new mutations).
Figure 1
Figure 1
Metastatic cascade
CTC migration: mobility and motility

Cancer metastasis has been correlated with specific genetic biomarkers such as mutations, chromosomal aberrations, and gene expression patterns (Nguyen & Massague, 2007; Wrage et al, 2009; Wikman et al, 2012; Hohensee et al, 2013). Nevertheless, whether CTCs enter the blood circulation through an active migration process, by passive means, or both, remains clinically and scientifically an unresolved question (Joosse & Pantel, 2013). In this review, we employ the terms motile and mobile cells to describe the differences between active and passive migration of the tumor cells.

Motile cancer cells are cells that are able to move on their own accord and that has thus gained the ability to move through the extracellular matrix and penetrate basement membranes and endothelial walls upon intravasation and extravasation. These active migration mechanisms imply modification of cell morphology, position, and surrounding tissue (Friedl & Alexander, 2011). Furthermore, cancer cells may infiltrate as single entities, in clusters, in strands, or in single (Indian) files as observed in lobular breast carcinoma. Single cells must weaken or completely lose their adhesive bonds with neighboring tumor cells for infiltration, whereas collective migration requires stable cell–cell adhesion and multicellular coordinated movement (Friedl & Gilmour, 2009). These clusters frequently comprise of different cell morphologies, that is, both epithelial-and mesenchymal-like. Collective migration may require a leader cell with mesenchymal features, able to create a path for the trailing tumor cells through the surrounding tissue (Friedl & Wolf, 2009).

Mobile cancer cells are moved by external forces such as growth of the tumor, mechanical forces, or friction which cause them to be dragged or pushed out of place (Camara et al, 2006; Fornvik et al, 2013). Although a vast amount of literature is available about the processes involved in active migration of cancer cells through the extracellular matrix, less is known concerning the passive dissemination of cancer cells and how they may be forced into the blood circulation. Carcinomas induce the formation of new blood vessels by the secretion of the vascular endothelial growth factor (VEGF) to facilitate the supply of nutrients and oxygen for growth. This process called angiogenesis, often results in leaky vessels caused by weak interconnections of the vessel’s endothelial cells and intercellular openings (McDonald & Baluk, 2002). Due to outward pushing of the tumor during growth, single or clusters of tumor cells can be forced through the leaky vessels, thus ending up in the blood circulation as ‘accidental CTCs’. Furthermore, tumor cells may be passively moved through the micro-tracks created by other tumor cells by proteolysis or through other pre-existing tissue structures (Friedl & Wolf, 2009).

Because the ‘accidental CTCs’ from epithelial malignancies are more likely to have retained their original phenotype, detection with epithelial-specific markers such as the epithelial cell adhesion molecule (EpCAM) would be feasible. On the other hand, tumor cells that have transformed to a more mesenchymal-like phenotype, and thus exhibit greater plasticity, may prove to be less easily detected by conventional EpCAM-based detection methods (Brabletz, 2012; Joosse & Pantel, 2013). Nevertheless, new evidence shows that a phenotypical transformation is not always required for tumor cell motility (Aceto et al, 2014; Godinho et al, 2014).
Epithelial–mesenchymal plasticity

Epithelial cells adhere to their neighboring cells through, among others, adherens junctions via binding of cadherins. Carcinoma cells are of epithelial origin and experience the same cell–cell interaction through adhesion molecules such as cadherins, claudins, or plakoglobin; these interactions prevent them from spreading in the first place (Pantel et al, 1998).

Normal epithelial cells show remarkable plasticity as they are able to reprogram and undergo dynamic and reversible transitions between the epithelial and mesenchymal cell phenotype. This de-differentiation process known as epithelial-to-mesenchymal transition (EMT) occurs frequently throughout embryogenesis because cells continuously migrate to form tissues and organs.

EMT also plays an important role in wound healing and tissue regeneration. Not surprisingly, carcinoma cells also make use of EMT as they become invasive. Indeed, they typically feature loss of cell–cell adherence proteins such as cadherin, followed by loss of apico-basal polarity, and finally, gaining the ability to migrate and invade.

EMT can be triggered by paracrine signaling of TGF-beta, WNT, platelet-derived growth factors, or interleukin-6 (IL-6) but can also be induced by nicotine, alcohol, and ultraviolet light. These triggers activate transcription factors such as Snail, Twist, and Zeb that maintain the mesenchymal phenotype by autocrine signaling (Tam & Weinberg, 2013).

Because of the loss of tight and adherens junctions, as well as cytoskeletal changes, typical epithelial markers such as EpCAM and E-cadherin are down-regulated, keratin expression is altered, and finally, up-regulation of mesenchymal markers such as vimentin is observed during EMT (Joosse et al, 2012).

Consequently, mesenchymal-like CTC subpopulations are difficult to identify in the hematopoietic cell environment which is also of mesenchymal origin (Joosse & Pantel, 2013).

Of note, single tumor cells found in the blood of breast cancer patients exhibit EMT-associated changes, while cell clusters appear to require a partial EMT so that these cells possess the migratory abilities of a mesenchymal cell but retain the cell–cell interaction profile of an epithelial cell (Yu et al, 2013).

EMT-Related Biomarkers

Single-cell approaches are used to study EMT-related markers of CTCs for metastatic prostate cancer detection and prediction. Markers are identified using microfluidics and atomic force microscope (AFM) for molecular profiling and nanomechanical and nanochemical phenotypes of CTCs, respectively.

SRC and FAK

SRC kinase controls cellular adhesions, including cadherin-based intercellular adhesions and integrin-mediated cell-matrix adhesions.

In epithelial cells, SRC activation, or increased signalling from migratory growth factor receptors via SRC, induces an adhesion switch that enhances dynamic cell-matrix adhesions and migratory capacity while suppressing intercellular contact.

Moreover, SRC and the associated tyrosine kinase FAK are at the heart of the recently identified crosstalk between integrin- and cadherin-mediated adhesions of epithelial cells, particularly during the epithelial-to-mesenchymal transition.

See also

- centrosome amplification

References

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