{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,2]],"date-time":"2026-05-02T00:18:54Z","timestamp":1777681134953,"version":"3.51.4"},"reference-count":0,"publisher":"Cell Physiol Biochem Press GmbH and Co KG","issue":"6","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cell Physiol Biochem"],"abstract":"<jats:p>Metastasis, like carcinogenesis, involves the disruption of homeostasis such that cancer cells\ntravel from the primary tumor to distant parts of the body. Almost all cancer deaths are due\nto metastatic spread. The prevailing theory of metastasis is an incomplete doctrine and far\nfrom sufficient as only 0.2% of free cancer cells result in the spread of cancer. To develop\nreasonable and effective cancer therapies and to prevent (or reverse) carcinogenesis and\nmetastasis, a comprehensive understanding of how both carcinogenesis and metastasis\narise is necessary. Fundamental questions in cancer biology have been asked and answered\nover decades of research: How do most cancers develop (Epistemology of the Origin of\nCancer I, 2014\u20132022)? Which is the first cancer cell (II, 2023)? The third basic question in\ncancer biology remaining to be addressed is: What are the fundamentals of how metastasis\ndevelops? The pre-cancerous niche (PCN) that forms during carcinogenesis is altered by\nongoing complex signaling into a premetastatic niche 1 (PMN-1): p130(cas)\/crk\/DOCK180\nformation is necessary for lamellipodia formation, thereby enabling cell mobility. Cancerassociated fibroblasts (CAFs) begin to release fibronectin CXCL12 and Keratin 19. PMN-1\nis transformed into PMN-2 during ongoing crosstalk and transformation of anti-into protumorigenic platelets, macrophages, and neutrophils. Finally, persistent signaling and\nimmune evasion result in the conversion of PMN-2 to PMN-3 with heterogeneous cancer\nsatellites \u2013 the term \u201csatellite\u201d is used herein in accordance with its original meaning (a cell\nor particle escorting another). PMN-3 serves as a prerequisite for intravasation, traveling,\nand dissemination of cancer cells away from the primary tumor. Eight heterogeneous cancer\nsatellites, including Trojan horses (immune evasion), travel alone or in combination: (1)\ncancer cells and (2) CAFs migrate along the CXCL12 and fibronectin gradient; (3) cancer\ncells 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\nshield cancer cells and (8) CAFs. Metastasis in epithelial cancer occurs in parallel with\ncarcinogenesis after the pre-cancerous niche is transformed into pre-metastatic niches\n(PMNs), which are indispensable to the origin of metastasis. Eight heterogeneous cancer\nsatellites, including Trojan horses responsible for immune evasion, alongside reciprocally\naffecting sequences, wander alone or in conjunction with other cancer cells. This elucidates\nwhy the current practice of multimodal anti-cancer cell therapy should now be seen in a new\nlight in which the benefits depend not on direct cancer cell effects, but on indirect cytopenic\neffects, which have previously been regarded merely as adverse effects.<\/jats:p>","DOI":"10.33594\/000000826","type":"journal-article","created":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T20:49:01Z","timestamp":1761770941000},"page":"753-799","source":"Crossref","is-referenced-by-count":1,"title":["Epistemology of the Origin of Cancer III: Fundamentals of How Metastasis Arises"],"prefix":"10.33594","volume":"59","author":[{"name":"Department of Surgery, Medical University Lausitz \u2013 Carl-Thiem, Cottbus, Germany","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bj\u00f6rn L. D. M.","family":"Br\u00fccher","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ijaz S.","family":"Jamall","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"19235","published-online":{"date-parts":[[2025,11,2]]},"container-title":["Cellular Physiology and Biochemistry"],"original-title":[],"deposited":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T20:49:01Z","timestamp":1761770941000},"score":1,"resource":{"primary":{"URL":"https:\/\/cellphysiolbiochem.com\/Articles\/000826\/PDF\/000826.pdf"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,2]]},"references-count":0,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2025,11,2]]}},"URL":"https:\/\/doi.org\/10.33594\/000000826","relation":{},"ISSN":["1015-8987","1421-9778"],"issn-type":[{"value":"1015-8987","type":"print"},{"value":"1421-9778","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,2]]}}}