Epithelial-Mesenchymal Plasticity in Cancer Progression and Metastasis

Abstract

Epithelial-to-mesenchymal transition (EMT) and its reversed process, mesenchymal-to-epithelial transition (MET), are fundamental processes in embryonic development and tissue repair but confer malignant properties to carcinoma cells, including invasive behavior, cancer stem cell activity, and greater resistance to chemotherapy and immunotherapy. Understanding the molecular and cellular basis of EMT provides fundamental insights into the etiology of cancer and may, in the long run, lead to new therapeutic strategies. Here, we discuss the regulatory mechanisms and pathological roles of epithelial-mesenchymal plasticity, with a focus on recent insights into the complexity and dynamics of this phenomenon in cancer.

Keywords: cellular plasticity; chemoresistance; epithelial-to-mesenchymal transition; immune evasion; metastasis; stemness.

Figure 1.. The diverse functions of EMT/MET in cancer progression and metastasis.

A) In primary tumor, cancer cells at the invasive front undergo EMT under the influence of EMT-inducing growth factors produced by tumor cells or stromal cells. Based on different degree of transition to the mesenchymal-like state, tumor cells invade through the basement membrane and surround tissues using a variety of movement modes, such as collective migration or individual cell invasion. During circulation, EMT can be induced by platelet-produced TGF-β and other signals (Labelle et al., 2011). Upon reaching the distant organs, tumor cells undergo MET under the influence of stromal cells, such as fibroblasts, endothelial cells and myeloid progenitor cells, and initiate outgrowth to form metastatic lesions. B) In addition to promoting metastasis, EMT also induces a variety of malignant features in cancer cells, such as cancer stemness, chemoresistance, immune evasion, altered metabolism (Dong et al., 2013) and blocked senescence (Ansieau et al., 2008).

Figure 2.. Multi-layer regulatory network of EMT.

A number of signaling pathways are known to induce EMT-related transcription factors, including the Snail, Twist and Zeb families and many other transcription factors, which in turn collaborate with a series of epigenetic regulators to induce a transcriptional program that mediate the downstream biological effects of EMT. These EMT-TFs are further regulated at the post-transcriptional and post-translational level by non-coding RNAs and protein stability/localization control mechanisms.

Figure 3.. The pathological impact of EMT is influenced by cellular context and transitional mechanisms and dynamics.

This schematic diagram illustrates some examples of the diversity of EMT and its biological consequences. A) Genetic deletion of EMT-TFs Snai1 and Twist1 does not reduce metastasis in KPC model of mouse pancreatic cancer. In contrast, Zeb1 deletion significantly reduces lung metastasis in the same pancreatic cancer model, and knockdown of Twist1 inhibits metastasis of allograft 4T1 mammary gland tumors. B) Classical EMT, which is often driven by EMT TFs and involves the down-regulation of typical epithelial markers and up-regulation of mesenchymal markers, promotes cancer metastasis. However, when cancer cell enter an extreme EMT state, the cells may become terminally differentiated or undergo cell death, leading to reduced metastasis. In some other instances, EMT is driven by non-canonical pathways, such as internalization of E-cadherin and other post-translational alteration of EMT-related effectors, but still lead to increased metastatic ability in cancer cells. C) EMT can occur through hysteresis or liner (non-hysteresis) dynamics, as reflected by bimodal or gradual reduction of E-cadherin expression. Such different dynamics may result in different metastatic ability of affected cancer cells, despite similar appearance of the mensenchymal state at the end point of the transition.