Epithelial-mesenchymal plasticity in carcinoma metastasis

Abstract

Tumor metastasis is a multistep process by which tumor cells disseminate from their primary site and form secondary tumors at a distant site. Metastasis occurs through a series of steps: local invasion, intravasation, transport, extravasation, and colonization. A developmental program termed epithelial-mesenchymal transition (EMT) has been shown to play a critical role in promoting metastasis in epithelium-derived carcinoma. Recent experimental and clinical studies have improved our knowledge of this dynamic program and implicated EMT and its reverse program, mesenchymal-epithelial transition (MET), in the metastatic process. Here, we review the functional requirement of EMT and/or MET during the individual steps of tumor metastasis and discuss the potential of targeting this program when treating metastatic diseases.

Keywords: carcinoma metastasis; epithelial–mesenchymal transition (EMT); extravasation; intravasation; invasion; mesenchymal–epithelial transition (MET); tumor dormancy.

Figure 1.

Model for reversible EMT over time. Epithelial cells undergo genetic transformation to become carcinoma in situ. Microenvironmental and genetic factors can promote the malignant conversion of these cells to activate the EMT program. During these early stages of tumor development, tumor cells that have undergone EMT can invade the local matrix (step I) and intravasate into the vasculature (step II). These epithelial–mesenchymal-transitioned cells are then transported in the circulation and survive via various prosurvival mechanisms (step III). At the distant tissue site, maintenance of the EMT program is required to help tumor cells extravasate into the parenchyma (step IV) to establish micrometastases. This initial seeding of tumor cells at distant sites can occur rapidly, after which cells may remain “dormant” for a long period of time. Subsequent colonization in distant organs requires the reversion of EMT and/or activation of the MET program to establish secondary tumors (step V).

Figure 2.

EMT in local invasion and intravasation. Activation of the EMT program is mostly characterized by the loss of E-cadherin expression. In order to invade through local basement membrane (surrounding the tumor or the tumor vasculature), these mesenchymal tumor cells up-regulate several secreted (MMPs) and membrane-tethered (MT-MMPs) proteases to break down ECM components. In addition, EMT factors can up-regulate specialized cellular structures such as invadopodia to promote local invasion. Expression of proteases can further induce EMT by breaking down cell–cell junctions, resulting in a positive feedback loop during malignant transformation of these cells.

Figure 3.

EMT in systemic transport and extravasation. Experimental and clinical samples have revealed an EMT signature in CTCs. This signature provides a possible biomarker to monitor tumor progression and/or therapeutic response. Experimental evidence suggests that platelets play a critical role in maintaining EMT activation in CTCs by providing the TGF-β signal. Furthermore, studies suggest that activation of EMT promotes microtentacle formation that allows tumor cell attachment to the endothelium and promotes cell survival. In order to extravasate at distant sites, tumor cells maintain an EMT phenotype and express cellular protrusions that allow extravasation, which is mediated by β1 integrin signaling.

Figure 4.

Mechanisms of EMT reversion. Colonization at distant sites requires the reversion of EMT to promote tumor cell proliferation. The interplay between EMT activators and inhibitors (i.e., MET activators) plays a critical role in metastatic outgrowth. The loss of EMT activators such as Twist1 or Prrx1 appears to be required to promote EMT reversion. However, signals from the microenvironment in distant sites may also shift the balance from EMT activators to EMT inhibitors or MET activators. It is unknown when or how these factors are regulated during tumor progression, which may impact treatment of metastatic disease.