Tumour metastasis revisited
Metastasis – one of the hallmarks of cancer – is a highly complex sequence of events that commences with the transition of cancer cells to a migratory cell type. Cells invade the surrounding tissue, blood or lymphatic vessels and travel to distant sites where they form new tumours. Undoubtedly, cancer metastasis is a critical aspect for patient clinical management as treatments directed against metastatic cells hold great promise. Understanding the cellular and molecular biology of invasion and metastasis is at the forefront of research – a great challenge. Recent evidence indicating the existence of cancer stem cells (CSCs) and a permissive microenvironment for metastasis formation could radically change our view of the metastatic process. The EU-funded TUMIC (An integrated concept of tumour metastasis: implications for therapy) project investigated how CSCs contribute to metastasis and how metastasis-permissive niches form in different organs. Researchers studied squamous cell carcinoma to discover a stem cell marker functionally required for metastasis, while a particular gene expression signature specific to breast cancer CSCs proved to be a poor prognostic indicator. Several lines of evidence demonstrated the association between the epithelial-mesenchymal transition (EMT) process with CSC properties and metastasis as well as angiogenesis. Insight into the formation of metastatic niches underscored the role of the S100 family member S100A4 as a central regulator of the process. This molecule served to create a metastasis supportive inflammatory milieu and to suppress factors that counteract metastasis. Various other factors (VEGF-C, CCL2, c-Kit/KitL axis) and cells also emerged to positively regulate niche formation, indicating that the metastatic niche could be targeted therapeutically. Based on these findings, the TUMIC consortium developed inhibitory antibodies and designed novel compounds of potential therapeutic value. Among others, they discovered novel inhibitors of EMT as well as new ways of inhibiting metastatic niche formation. These drug discovery efforts alongside the fundamental knowledge on the process of metastasis will improve cancer prognosis and therapy.
Keywords
Tumour, metastasis, cancer stem cells, TUMIC, epithelial-mesenchymal transition, S100A4
