Contribution of cells undergoing epithelial–mesenchymal transition to the tumour microenvironment

Human cancer mortality is predominantly determined by the spread of tumour cells from a primary to secondary anatomical location. The metastatic cascade follows tumour cell dissemination, passage through the blood and/or lymphatic system, and colonisation at a distant site. Increased cell motility of cancer cells at the leading tumour edge has been attributed to the epithelial–mesenchymal transition (EMT) which facilitates their release and invasiveness. Mechanisms behind cancer cell dissemination and homing of metastatic cells to a secondary site remain largely unknown. However, certain cancers have a propensity to metastasise to particular organs, and one possible explanation is the seed and soil hypothesis, which is predicated on circulating tumour cells settling in favourable conditions. Extracellular vesicles mediate communication in the tumour microenvironment, stimulate cell migration and invasion, and prepare the pre-metastatic niche. In addition, the tumour stroma can initiate EMT in cancer cells at the invasive front which, in turn, secrete a distinct suite of molecules into the tumour microenvironment. As a first step towards understanding precise regulatory mechanisms, it is important to identify secreted modulators residing within the metastatic niche. Determining the signals and stimuli required to initiate and propagate cancer cell spreading will potentially unearth candidates to limit metastasis.

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► Cancer mortality is primarily determined by metastasis.
► Cells at the leading tumour edge undergo epithelial–mesenchymal transition (EMT).
► EMT enhances tumour cell migration and invasion.
► Cancer cells undergoing EMT release factors that modify the tumour microenvironment and promote metastatic spread.