Epistemology of the Origin of Cancer III: Fundamentals of How Metastasis Arises

Metastasis, like carcinogenesis, involves the disruption of homeostasis such that cancer cells travel from the primary tumor to distant parts of the body. Almost all cancer deaths are due to metastatic spread. The prevailing theory of metastasis is an incomplete doctrine and far from sufficient as only 0.2% of free cancer cells result in the spread of cancer. To develop reasonable and effective cancer therapies and to prevent (or reverse) carcinogenesis and metastasis, a comprehensive understanding of how both carcinogenesis and metastasis arise is necessary. Fundamental questions in cancer biology have been asked and answered over decades of research: How do most cancers develop (Epistemology of the Origin of Cancer I, 2014-2022)? Which is the first cancer cell (II, 2023)? The third basic question in cancer biology remaining to be addressed is: What are the fundamentals of how metastasis develops? The pre-cancerous niche (PCN) that forms during carcinogenesis is altered by ongoing complex signaling into a premetastatic niche 1 (PMN-1): p130(cas)/crk/DOCK180 formation is necessary for lamellipodia formation, thereby enabling cell mobility. Cancer-associated fibroblasts (CAFs) begin to release fibronectin CXCL12 and Keratin 19. PMN-1 is transformed into PMN-2 during ongoing crosstalk and transformation of anti- into pro-tumorigenic platelets, macrophages, and neutrophils. Finally, persistent signaling and immune evasion result in the conversion of PMN-2 to PMN-3 with heterogeneous cancer satellites - the term "satellite" is used herein in accordance with its original meaning (a cell or particle escorting another). PMN-3 serves as a prerequisite for intravasation, traveling, and dissemination of cancer cells away from the primary tumor. Eight heterogeneous cancer satellites, including Trojan horses (immune evasion), travel alone or in combination: (1) cancer cells and (2) CAFs migrate along the CXCL12 and fibronectin gradient; (3) cancer cells surrounded by CAFs are shielded from the immune system and travel away from the primary cancer; (4) CXCL12 and Keratin 19 coat cancer cells; (5) platelets surround cancer cells and (6) CAFs, thereby facilitating cancer spread; and (7) neutrophil extracellular traps shield cancer cells and (8) CAFs. Metastasis in epithelial cancer occurs in parallel with carcinogenesis after the pre-cancerous niche is transformed into pre-metastatic niches (PMNs), which are indispensable to the origin of metastasis. Eight heterogeneous cancer satellites, including Trojan horses responsible for immune evasion, alongside reciprocally affecting sequences, wander alone or in conjunction with other cancer cells. This elucidates why the current practice of multimodal anti-cancer cell therapy should now be seen in a new light in which the benefits depend not on direct cancer cell effects, but on indirect cytopenic effects, which have previously been regarded merely as adverse effects.