Pre-metastatic niches: organ-specific homes for metastases

Key Points Organs of future metastasis are selectively and actively modified by the primary tumour before metastatic spread has occurred. Tumours induce the formation of microenvironments in distant organs that are conducive to the survival and outgrowth of tumour cells before their arrival at these sites. These microenvironments are termed pre-metastatic niches (PMNs). PMN formation is a stepwise process resulting from the combined systemic effects of tumour-secreted factors and tumour-shed extracellular vesicles. PMN formation is initiated with local changes such as the induction of vascular leakiness, remodelling of stroma and extracellular matrix, followed by systemic effects on the immune system. The development of new technologies and approaches to identify PMNs in distant organ sites in patients could revolutionize cancer treatment and lead to pre-emptive treatments to hinder metastasis. The PMN is a new paradigm for the initiation of metastasis. Our ability to fight metastasis would benefit greatly from understanding the pathological processes occurring before the development of macrometastases. This Review summarizes the natural progression of pre-metastatic niche formation and evolution, highlighting recent advances and future hurdles. It is well established that organs of future metastasis are not passive receivers of circulating tumour cells, but are instead selectively and actively modified by the primary tumour before metastatic spread has even occurred. Sowing the 'seeds' of metastasis requires the action of tumour-secreted factors and tumour-shed extracellular vesicles that enable the 'soil' at distant metastatic sites to encourage the outgrowth of incoming cancer cells. In this Review, we summarize the main processes and new mechanisms involved in the formation of the pre-metastatic niche.