A recent article published in the Journal of Translational Medicine by Songming Ding and colleagues from the Zhejiang University School of Medicine, China explores the molecular mechanisms of tumour metastasis. They focus on the epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET) – processes known to have key roles in the metastasis of epithelial cancers.
EMT is the process by which epithelial cells lose their cell polarity and cell-cell adhesion and gain migratory and invasive properties to become mesenchymal cells, whereas the reverse process, MET, involves the conversion of mesenchymal cells into epithelial cells. The tumour microenvironment – the cellular environment in which a tumour exists and which comprises blood vessels, immune cells, fibroblasts, signalling molecules, the extracellular matrix and numerous other cells – has recently been identified as one of the most important inducers of EMT and MET.
The relationship between tumours and their surroundings was described in the late nineteenth century by Stephen Paget’s ‘seed and soil’ theory, in which he suggests that a particular type of cancer (the ‘seed’) often metastasises to certain sites (the ‘soil’) based on the similarity of their environments. Tumour metastasis consists of a series of orderly and interrelated steps, influenced by the interaction between cancer cells and the local microenvironment. The ‘seed and soil’ theory states that EMT is crucial to the early stages of cancer metastasis, and MET is critical to the latter stages. It is therefore important to distinguish which component of the tumour microenvironment can induce EMT and which can induce MET, to better understand the metastatic process.
Bel-7402 hepatocellular carcinoma cells stained for actin (red). Image source: Ding et al, Journal of Translational Medicine, 2013, 11:164
Ding and colleagues determine how the various components of the tumour microenvironment induce EMT and MET in hepatocellular carcinoma (HCC) metastasis. They used the HCC cell line Bel-7402 co-cultured with either the normal liver cell line HL-7702 or with the retinal vascular endothelial cell line RF/6A to imitate the direct interaction between tumour cells and host cells. Bel-7402 was also cultured in conditioned media from the human lung fibroblast cell line MRC-5, HL-7702 or RF/6A, to imitate an indirect interaction.
The study found that Bel-7402 cells co-cultured with HL-7702 or RF/6A cells were induced to undergo MET. The expression of E-cadherin, α-catenin and β-catenin was up-regulated, accompanied with a strengthened E-cadherin/catenin complex on the membrane of co-cultured Bel-7402 cells, decreasing the invasion and migration ability of the cells. Conversely, Bel-7402 cells cultured in conditioned medium from MRC-5 cells underwent an EMT-like transformation as the cells became elongated with increased invasion and migration ability. The authors also found that HL-7702 cells could inhibit the tumourigenicity and viability of Bel-7402 cells.
Taken together, these findings show that by inducing the increased expression of adhesion molecules, including the E-cadherin/catenin complex, laminins and integrins, the tumour microenvironment is able to strongly influence tumour progression through EMT and MET.