A Transient, EMT-Linked Loss of Basement Membranes Indicates Metastasis and Poor Survival in Colorectal Cancer

Spaderna, Simone; Schmalhofer, Otto; Hlubek, Falk; Berx, Geert; Eger, Andreas; Merkel, Susanne; Jung, Andreas; Kirchner, Thomas; Brabletz, Thomas

doi:10.1053/j.gastro.2006.06.016

Cited by 436 publications

(393 citation statements)

References 29 publications

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“…Notably, ZEB1 was detected at invasive regions in breast and colorectal tumours and at the tumour-stroma interface, regions that display a strong reduction of LGL2 protein and no signs of polarity (Aigner et al, 2007;Spaderna et al, 2008). These recent observations are in line with previous studies indicating that EMT occurs at invasive regions of colorectal tumours (Brabletz et al, 2005) where ZEB1 may have an important function (Spaderna et al, 2006).…”

Section: Regulation Of Cell Polarity Genes During Emtsupporting

confidence: 87%

Transcriptional regulation of cell polarity in EMT and cancer

2008

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The epithelial-to-mesenchymal transition (EMT) is a crucial process in tumour progression providing tumour cells with the ability to escape from the primary tumour, to migrate to distant regions and to invade tissues. EMT requires a loss of cell-cell adhesion and apical-basal polarity, as well as the acquisition of a fibroblastoid motile phenotype. Several transcription factors have emerged in recent years that induce EMT, with important implications for tumour progression. However, their effects on cell polarity remain unclear. Here, we have re-examined the data available related to the effect of EMT related transcription factors on epithelial cell plasticity, focusing on their impact on cell polarity. Transcriptional and post-transcriptional regulatory mechanisms mediated by several inducers of EMT, in particular the ZEB and Snail factors, downregulate the expression and/or functional organization of core polarity complexes. We also summarize data on the expression of cell polarity genes in human tumours and analyse genetic interactions that highlight the existence of complex regulatory networks converging on the regulation of cell polarity by EMT inducers in human breast carcinomas. These recent observations provide new insights into the relationship between alterations in cell polarity components and EMT in cancer, opening new avenues for their potential use as therapeutic targets to prevent tumour progression.

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Section: Regulation Of Cell Polarity Genes During Emtsupporting

confidence: 87%

Transcriptional regulation of cell polarity in EMT and cancer

2008

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“…Several reports have shown a correlation between Zeb1 expression and the aggressiveness of tumors, including those of endometrial (Spoelstra et al, 2006;Singh et al, 2008), colon (Pena et al, 2005;Aigner et al, 2007b), breast (Aigner et al, 2007a), lung (Dohadwala et al, 2006), gallbladder (Adachi et al, 2009), ovarian (Bendoraite et al, 2010) and prostate origin (Graham et al, 2008). In colon cancer, Zeb1 expression is linked to loss of the basement membrane, which correlates with increased metastasis (Spaderna et al, 2006). More functional evidence of a critical role for Zeb1 in metastasis came from Spaderna et al (2008).…”

Section: Discussionmentioning

confidence: 99%

Zeb1 is required for TrkB-induced epithelial-mesenchymal transition, anoikis resistance and metastasis

Smit

Peeper

2011

Oncogene

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Anoikis (detachment-induced apoptosis) prevents the survival of cells at inappropriate sites of the body and can therefore act as a barrier to metastasis. In a functionbased genome-wide screen, we have previously identified the neurotrophic tyrosine kinase receptor TrkB as a potent suppressor of anoikis. Consistently, activated TrkB oncogenically transforms non-malignant epithelial cells and causes them to invade and produce metastatic tumors in vivo. Overexpression of activated TrkB also results in morphological transformation, resembling epithelial-mesenchymal transition (EMT). E-cadherin, an important EMT regulator, and two E-cadherin repressors, Twist and Snail, are critical for these TrkB functions. As Snail has been shown to induce Zeb1, another E-cadherin repressor, we hypothesized that Zeb1 could be a TrkB target, too. We show here that Zeb1 is required for TrkB-induced EMT in epithelial cells, as RNAi-mediated knockdown of Zeb1 reverted the morphological changes induced by TrkB. Furthermore, Zeb1 is involved in TrkB-induced anoikis resistance, migration and invasion. In vivo, knockdown of Zeb1 strongly reduced TrkB-induced metastasis. Finally, epistasis experiments showed that Zeb1 acts downstream of Twist and Snail. We conclude that Zeb1 is required for several TrkB-induced effects in vitro and in vivo, including metastasis.

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“…Actually, ZEB factors and miR200 reciprocally control their expression in a strict feedback loop [133]. Of note, ZEB1 is a key EMT regulator in many human cancers including prostate, colon, breast and pancreatic [132,[134][135][136], while miR200 family members are often down-regulated in cancer cells [131]. Actually, the regulation of EMT by miRNAs is a very general phenomenon not limited to TrkB signalling [137].…”

Section: Taddei Et Almentioning

confidence: 99%

Anoikis: an emerging hallmark in health and diseases

Taddei

Giannoni

Fiaschi

et al. 2011

The Journal of Pathology

507

404

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Anoikis is a programmed cell death occurring upon cell detachment from the correct extracellular matrix, thus disrupting integrin ligation. It is a critical mechanism in preventing dysplastic cell growth or attachment to an inappropriate matrix. Anoikis prevents detached epithelial cells from colonizing elsewhere and is thus essential for tissue homeostasis and development. As anchorage-independent growth and epithelial-mesenchymal transition, two features associated with anoikis resistance, are crucial steps during tumour progression and metastatic spreading of cancer cells, anoikis deregulation has now evoked particular attention from the scientific community. The aim of this review is to analyse the molecular mechanisms governing both anoikis and anoikis resistance, focusing on their regulation in physiological processes, as well as in several diseases, including metastatic cancers, cardiovascular diseases and diabetes.

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A Transient, EMT-Linked Loss of Basement Membranes Indicates Metastasis and Poor Survival in Colorectal Cancer

Cited by 436 publications

References 29 publications

Transcriptional regulation of cell polarity in EMT and cancer

Transcriptional regulation of cell polarity in EMT and cancer

Zeb1 is required for TrkB-induced epithelial-mesenchymal transition, anoikis resistance and metastasis

Anoikis: an emerging hallmark in health and diseases

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