Figure 1.

Extracellular matrix composition in the pre-metastatic niche. The remote conditioning of future organ sites of metastasis by the primary tumor is termed pre-metastatic niche formation. The lung pre-metastatic niche is depicted here, as it has been the most extensively characterized. Primary tumors secrete soluble factors, such as cytokines, chemokines, hormones, metabolites, and extracellular vesicles (EVs) that condition the future site of metastasis as well as the bone marrow. Bone marrow conditioning results in egress of VEGFR1⁺VLA-4⁺ bone marrow-derived progenitor cells, which are recruited to the pre-metastatic niche. Conditioning of the pre-metastatic niche induces vascular permeability, thrombosis, inflammation, and stromal cell activation, all of which cooperate in extracellular matrix remodeling. Pre-metastatic niche development generates a favorable milieu for circulating tumor cell (CTC) seeding and outgrowth, resulting in the formation of the metastatic niche.