Complex genetic changes are responsible for the selection of tumor subclones that are capable of metastasis.
All metastases can be understood as arising from a two-part process: invasion of local extracellular tissue and dissemination and colonization.
Invasion of extracellular tissue: loss of adhesion to the basement membrane → invasion through basement membrane → passage through extracellular tissue
Loss of E-cadherin expression is associated with tumor metastatic potential.
Overproduction of proteases such as collagenase and matrix metalloproteinases degrade the basement membrane and interstitial matrix. Neoplastic cells encounter various chemotactic and angiogenic factors in the newly exposed extracellular matrix.
Autocrine signaling via tumor-produced cytokines and paracrine signaling by cleaved matrix components and extracellular growth factors stimulate tumor cell locomotion towards vasculature or lymphatics.
Dissemination and colonization: encountering vascular or lymphatic routes → evasion of host defenses → implantation with distant tissue
Host defenses destroy the majority of circulating cancer cells. Mechanisms to avoid this include tumor cell aggregation, formation of platelet-tumor complexes, and binding of active coagulation factors to form malignant emboli.
Disruption of cellular adhesion molecules (laminins, cadherins) enables extravasation at distant tissues.
