Fig. 1. Schematic illustration of the detailed process of tumor metastasis showing that there are significant physical processes in the process of tumor metastasis and multiple types of microenvironmental cues are involved for promoting the successful metastasis of primary cancerous cells.

Reprinted with permission from Ref. [24]. Copyright 2019 Springer Nature. Tumor metastasis is a complex multistep process. Tumor cell production of angiogenetic factors and TGFβ can activate endothelial cells and fibroblasts to remodel tissues and promote tumor cell invasion of stromal-modified spaces. Intravasation of tumor cells is promoted by binding to macrophages that cause transient permeability in the vasculature. In the circulation, platelets can bind to the circulating tumor cells (CTCs) and protect CTCs from cytotoxic immune cell recognition, escorting tumor cells to the site of extravasation [33]. Preferred colonization sites, termed premetastatic niches, can be prepared in advance of the arrival of tumor cells through the actions of extracellular vesicles such as exosomes. When tumor cells arrive the new sites, only a small subset of tumor cells initiate cell division to form micrometastases, and only a small proportion of these micrometastases persist to become vascularized metastases [34].