Exosomes and pre-metastatic niche formation. Exosomes released from primary tumors into the circulatory system specifically home to distant target organs (step 1). Upon their arrival, tumor-derived exosomes actively prepare the pre-metastatic niche through myofibroblast activation, induction of angiogenesis, and ECM remodeling (step 2). Local invasion of the primary tumor by cancer cells is followed by their intravasation into the tumor vasculature. These cancer cells survive and travel within the circulatory system, and upon their arrest in capillaries at distant sites, they extravasate into the parenchyma of target organs to commence metastatic colonization (step 3).