Target cell movement in tumor and cardiovascular diseases based on the epithelial–mesenchymal transition concept

Chua, Koon Jiew; Poon, Kar Lai; Lim, Jormay; Sim, Wen-Jing; Huang, Ruby Yun‐Ju; Thiery, Jean Paul

doi:10.1016/j.addr.2011.02.003

Cited by 41 publications

(37 citation statements)

References 111 publications

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Section: Primermentioning

confidence: 99%

“…Subsequently, in the fourth cycle of EMT, a group of epicardial cells delaminates and gives rise to epicardial-derived cells (EPDCs), the mesenchymal cells that populate the subepicardium and form coronary smooth muscle, endothelial cells and cardiac fibroblasts (Fig. 4B) (Chua et al, 2011).The first cycle of EMT at gastrulation involves induction of Snail1/2, which contributes to the formation of mesenchymal cells; part of this cell population rapidly acquires myogenic properties in response to a complex signaling pathway mediated by TGF family members (Ladd et al, 1998). The formation of the endocardium in the second cycle also involves TGF family members (Sugi and Markwald, 2003), although the detailed mechanisms remain to be explored.…”

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confidence: 99%

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Epithelial-mesenchymal transitions: insights from development

2012

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Epithelial-mesenchymal transition (EMT) is a crucial, evolutionarily conserved process that occurs during development and is essential for shaping embryos. Also implicated in cancer, this morphological transition is executed through multiple mechanisms in different contexts, and studies suggest that the molecular programs governing EMT, albeit still enigmatic, are embedded within developmental programs that regulate specification and differentiation. As we review here, knowledge garnered from studies of EMT during gastrulation, neural crest delamination and heart formation have furthered our understanding of tumor progression and metastasis.Key words: Epithelial-mesenchymal transition, Gastrulation, Neural crest, Heart morphogenesis Introduction Epithelial-mesenchymal transition (EMT) is an evolutionarily conserved developmental process that contributes to the formation of the body plan, histogenesis and organogenesis. In the late 19th century, mesenchymal and epithelial cells were recognized as having distinct phenotypes (Duval, 1879) and, although EMT was apparent to embryologists (Platt, 1894), it only became interesting to developmental biologists in the 1960s. Following pioneering work from Elizabeth Hay (Greenburg and Hay, 1982; Hay, 2005), we now know that epithelial cells lose apicobasal polarity and intercellular junctions during EMT. These changes in cell polarity and adhesion disrupt the epithelial basement membrane and allow cellular penetration into an extracellular matrix (ECM)-rich compartment: a process referred to as delamination (see Glossary, Box 1). These newly formed mesenchymal cells transiently express distinct mesenchymal markers, acquire a front-rear polarity and become invasive, favoring cell-ECM rather than cell-cell adhesions.Interestingly, EMT is not irreversible: cells frequently cycle between epithelial and mesenchymal states via EMT and the reverse process, mesenchymal-epithelial transition (MET). Importantly, EMT has been implicated in pathological conditions, such as organ fibrosis, and in cancer, where it contributes to tumor progression and metastasis (Kalluri and Weinberg, 2009;Thiery et al., 2009). As such, much effort has been devoted to understanding the molecular regulation of EMT during development as an insight into the role and regulation of EMT in pathology.EMT is context dependent, occurring within the framework of other signaling mechanisms, such as cell fate induction, commitment and differentiation. However, the precise events that drive EMT are not fully understood. Genetic studies in Drosophila originally identified the transcription factors Twist and Snail as potential drivers of EMT during gastrulation (Leptin and Grunewald, 1990). Soon after, a Snail ortholog, Slug (Snai2), was shown to be involved in EMT in chicken embryo gastrulation (Nieto et al., 1994). Since then, several genes encoding transcription factors, cell polarity proteins and effector proteins have been shown to govern EMT in normal and transformed epithelial cells (see Table 1), suggesting tha...

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Section: Primermentioning

confidence: 99%

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confidence: 99%

Epithelial-mesenchymal transitions: insights from development

2012

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“…In addition to CSC differentiation strategies, direct inhibition of the EMT program can potentially reduce migration, invasion, and survival of cancer cells (110). For example, induction of MET through SNAI2 inhibition might be a promising treatment strategy.…”

Section: Implications For Therapymentioning

confidence: 99%

Epithelial Plasticity, Cancer Stem Cells, and the Tumor-Supportive Stroma in Bladder Carcinoma

Horst

Bos

Pluijm

2012

Molecular Cancer Research

138

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High recurrence rates and poor survival rates of metastatic bladder cancer emphasize the need for a drug that can prevent and/or treat bladder cancer progression and metastasis formation. Accumulating evidence suggests that cancer stem/progenitor cells are involved in tumor relapse and therapy resistance in urothelial carcinoma. These cells seem less affected by the antiproliferative therapies, as they are largely quiescent, have an increased DNA damage response, reside in difficult-to-reach, protective cancer stem cell niches and express ABC transporters that can efflux drugs from the cells. Recent studies have shown that epithelial-to-mesenchymal transition (EMT), a process in which sessile, epithelial cells switch to a motile, mesenchymal phenotype may render cancer cells with cancer stem cells properties and/or stimulate the expansion of this malignant cellular subpopulation. As cancer cells undergo EMT, invasiveness, drug resistance, angiogenesis, and metastatic ability seem to increase in parallel, thus giving rise to a more aggressive tumor type. Furthermore, the tumor microenvironment (tumor-associated stromal cells, extracellular matrix) plays a key role in tumorigenesis, tumor progression, and metastasis formation. Taken together, the secret for more effective cancer therapies might lie in developing and combining therapeutic strategies that also target cancer stem/progenitor cells and create an inhospitable microenvironment for highly malignant bladder cancer cells. This review will focus on the current concepts about the role of cancer stem cells, epithelial plasticity, and the supportive stroma in bladder carcinoma. The potential implications for the development of novel bladder cancer therapy will be discussed. Mol Cancer Res; 10(8); 995-1009. Ó2012 AACR. Bladder CancerWorldwide, an estimated number of 386,300 new cases and 150,200 deaths from bladder cancer occurred in 2008, with the majority of cases (77%) occurring in men. Thereby, bladder cancer is the seventh most common cancer and the ninth most common cause of cancer-related death in men. Bladder cancer is most common in developed countries, where 63% of the cases occurred in 2002. In Europe and the United States, for example, bladder cancer is the fourth most common cancer in males. Overall, the 5-year survival rate of bladder cancer is approximately 80%, and it varies with the stage of the tumor, ranging from 97% for carcinoma in situ to 6% for metastatic disease.Urothelial carcinoma is a heterogeneous disease and multifocal tumors can develop in the same patient. Multifocality can be explained by the monoclonal theory, that is, multiple tumors arise from a single transformed cell or by the field cancerization theory (1). In the latter, exposure of the urothelium to important risk factors for bladder cancer, such as occupational carcinogens induces changes at different sites of the urothelium. As described by Cheng and colleagues (1), urothelial carcinoma in situ is a well-established precursor of invasive bladder cancer and may be...

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“…Metastatic cancer cells show upregulated motility [2], which enables cell migration and invasion through tumour stroma, followed by intravasation into and extravasation out of the blood vessels. Recently, tumour therapeutic targets have expanded into the non-cytotoxic domain with the objective of curbing cancer metastasis [3], in addition to the traditional chemotherapy and radiotherapy approaches. To screen for such non-cytotoxic drugs that can specifically inhibit pathological cell movement, it is necessary to develop a functional assay that can quantify the extent of cell migration and invasion through the tissue environment under the influence of these drugs [4,5].…”

Section: Introductionmentioning

confidence: 99%

Mechanistic adaptability of cancer cells strongly affects anti-migratory drug efficacy

Sun

Lim

Kurniawan

2014

J. R. Soc. Interface.

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Cancer metastasis involves the dissemination of cancer cells from the primary tumour site and is responsible for the majority of solid tumour-related mortality. Screening of anti-metastasis drugs often includes functional assays that examine cancer cell invasion inside a three-dimensional hydrogel that mimics the extracellular matrix (ECM). Here, we built a mechanically tuneable collagen hydrogel model to recapitulate cancer spreading into heterogeneous tumour stroma and monitored the three-dimensional invasion of highly malignant breast cancer cells, MDA-MB-231. Migration assays were carried out in the presence and the absence of drugs affecting four typical molecular mechanisms involved in cell migration, as well as under five ECMs with different biophysical properties. Strikingly, the effects of the drugs were observed to vary strongly with matrix mechanics and microarchitecture, despite the little dependence of the inherent cancer cell migration on the ECM condition. Specifically, cytoskeletal contractility-targeting drugs reduced migration speed in sparse gels, whereas migration in dense gels was retarded effectively by inhibiting proteolysis. The results corroborate the ability of cancer cells to switch their multiple invasion mechanisms depending on ECM condition, thus suggesting the importance of factoring in the biophysical properties of the ECM in anti-metastasis drug screenings.

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Target cell movement in tumor and cardiovascular diseases based on the epithelial–mesenchymal transition concept

Cited by 41 publications

References 111 publications

Epithelial-mesenchymal transitions: insights from development

Epithelial-mesenchymal transitions: insights from development

Epithelial Plasticity, Cancer Stem Cells, and the Tumor-Supportive Stroma in Bladder Carcinoma

Mechanistic adaptability of cancer cells strongly affects anti-migratory drug efficacy

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