EMT-activating transcription factors in cancer: beyond EMT and tumor invasiveness

Abstract

Cancer is a complex multistep process involving genetic and epigenetic changes that eventually result in the activation of oncogenic pathways and/or inactivation of tumor suppressor signals. During cancer progression, cancer cells acquire a number of hallmarks that promote tumor growth and invasion. A crucial mechanism by which carcinoma cells enhance their invasive capacity is the dissolution of intercellular adhesions and the acquisition of a more motile mesenchymal phenotype as part of an epithelial-to-mesenchymal transition (EMT). Although many transcription factors can trigger it, the full molecular reprogramming occurring during an EMT is mainly orchestrated by three major groups of transcription factors: the ZEB, Snail and Twist families. Upregulated expression of these EMT-activating transcription factors (EMT-ATFs) promotes tumor invasiveness in cell lines and xenograft mice models and has been associated with poor clinical prognosis in human cancers. Evidence accumulated in the last few years indicates that EMT-ATFs also regulate an expanding set of cancer cell capabilities beyond tumor invasion. Thus, EMT-ATFs have been shown to cooperate in oncogenic transformation, regulate cancer cell stemness, override safeguard programs against cancer like apoptosis and senescence, determine resistance to chemotherapy and promote tumor angiogenesis. This article reviews the expanding portfolio of functions played by EMT-ATFs in cancer progression.

Fig. 1

Domain structure human EMT-ATFs: human ZEB1 (GenBank reference sequence AAA20602.1), human ZEB2 (AAI27103), human Snail1 (NP_005976.2), human Snail2 (NP_003059.1), human Snail3 (NP_840101.1), human Twist1 (NP_000465.1), and human Twist2 (NP_476527.1)

Fig. 2

Regulatory networks between microRNAs and EMT-ATFs of the ZEB (a), Snail (b) and Twist (c) families. For simplification, some relationships have been consolidated or are not shown. Double color identification refers to miRs that have been described as having both pro- and anti-invasion/metastatic roles depending on the context and/or cell system analyzed. See text for discussion and references

Fig. 3

Cross-regulation among EMT-ATFs. Dashed lines indicate that different relationships have been reported depending on the cell system analyzed. See text for discussion and references

Fig. 4

ZEB1 and ZEB2 are expressed in stromal cells of normal colonic mucosa. Immunohistochemistry of colon samples from normal individuals stained by the 3,3′-diaminobenzidine (DAB) method with ZEB1 (H-102; Santa Cruz Biotechnology) and ZEB2 (H-260; Santa Cruz Biotechnology) as described in [69]. Scale bars 25 μm