Epistemology of the Origin of Cancer IV: Predisposing Conditions for Metastases

Causal therapy has achieved success in the treatment of epithelial tumors, which account for more than 80% of all cancers. Although frequently claimed as breakthroughs, cancer therapy has achieved limited increases in survival of only weeks to several months, and cancer incidence continues to increase while metastasis rates, which are primarily responsible for cancer mortality, remain constant. This reflects an incomplete understanding of carcinogenesis and metastatic progression. Over a 25-year timeframe, the series "Epistemology of the Origin of Cancer" has examined the biological basis of carcinogenesis and metastasis. Part I addressed carcinogenesis, Part II identified the first cancer cell, and Part III described the development of local pre-metastatic niches and traveling cancer satellites. In this fourth part, the conditions required for distant metastasis are discussed, including the sequential development of metastatic niches (MN-1, MN-2, and MN-3), transendothelial migration, dormancy, immune modulation, extracellular matrix remodeling, and metastatic niche maturation. The review proposes that metastatic progression depends on the formation of metastatic cancer satellites consisting of metastatic cancer cells, metastasis-associated fibroblasts (MAFs), stromal components, chemokine coatings, platelets, and neutrophil extracellular traps (NETs), each contributing to immune evasion and dissemination. This sequential distant metastatic niche model provides a biological framework explaining clinical observations including metastatic dormancy, relapse after surgery or anticancer therapy, tumor heterogeneity, and the limited long-term success of current therapeutic approaches.