Fig. 1. The metastatic cascade.

Metastasis occurs in a number of steps starting with the invasion of tumour cells into the local stroma (1) and their intravasation (2) into the vascular or lymphatic system. In the case of haematogenous metastasis, they must survive the mechanical forces of the circulatory system and suppressive immune cells (3). Few circulating tumour cells (CTCs) survive the circulation but those that do then extravasate into the metastatic site (4). The systemic release of exosomes, inflammatory cytokines and growth factors by cancer and stromal cells in the primary tumour can ‘prime’ and remodel the microenvironment of distant organs to form a pre-metastatic niche that supports the outgrowth of DTCs before their arrival.¹⁴ Once in the metastatic site, disseminated tumour cells (DTCs) must overcome immune surveillance by resident immune cells, and can direct immune suppression by recruiting myeloid-derived suppressor cells. DTCs can also become dormant, induced by factors derived from metastatic niche stromal cells,^110–112 or supported by signalling from endothelial cells,¹¹³ and then subsequently ‘awakened’ by signals from surrounding stromal cells and the extracellular matrix (ECM).^15,114 Reawakening of dormant DTCs can also be induced by exosomes, either released by metastatic niche stromal cells or systemically released by cancer-associated fibroblasts (CAFs) in the primary site.^38,115 Proliferating DTCs form micrometastases and, finally, colonisation of the metastatic niche occurs and tumour cells form clinically relevant macrometastases, co-opting and recruiting local stromal cells to support metastatic cell growth (5). Created with BioRender.com.