{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T08:47:25Z","timestamp":1782722845305,"version":"3.54.5"},"reference-count":0,"publisher":"Cell Physiol Biochem Press GmbH and Co KG","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cell Physiol Biochem"],"abstract":"<jats:p>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 and metastasis rates, which are primarily responsible for cancer mortality, remain constant. This broadly reflect an incomplete understanding of the genesis and progression of cancers and metastases. Over a 25-year timeframe, the fundamentals of the origin of carcinogenesis and metastasis, titled Epistemology of the Origin of Cancer were addressed in Part I, 2014\u20132022, how carcinogenesis develops; Part II, 2023, which is the first cancer cell; Part III, 2025, how metastasis arise with the formation of local pre-metastatic niches (PMN-1, PMN-2, PMN-3) and traveling cancer satellites. Herein, Part IV discusses the conditions required for metastasis: the development of distant metastatic niches (MN-1, MN-2, MN-3) after traveling, extravasation and nidation at the endothelium of the capillary bed. First, MN-1 develops by transendothelial migration of cancer satellites to the subendothelial matrix, followed by de-coating into constituent parts, induction of cell plasticity, recruitment of immuno-competent cells, and dormancy. MN-1 then transforms into MN-2 triggered by ongoing chronic inflammation, and remodeling (lysyl oxidase): pro-tumor-associated cells, extravesicular vesicles, and CXCL2 induce immune suppression, granulin, periostin, fibronectin, CXCL12, and K19 followed by migration of non-dormant cancer associated fibroblasts (CAFs) and cancer cells. Finally, MN-3 develops where high cell plasticity leads to more aggressive active elongated cancer cells and newly developed metastasis-associated fibroblasts (MAFs), which re-trigger dormancy. Anticancer therapy, surgery, trauma, and ongoing inflammation exacerbate immune suppression, which induce awakening from dormancy. Gelsolin and atypical EMT induce conversion into spherical, inactive cancer cells (enabling immune evasion), followed by another spell of dormancy. When overwhelmed, this can lead to the essential predisposing conditions for metastases by formation of metastatic cancer satellites: (1) metastatic cancer cells and (2) MAFs; (3) metastatic cancer cells surrounded by MAFs; (4) CXCL12 and K19 coated metastatic cancer cells; (5) platelets surrounding metastatic cancer cells and (6) MAFs; (7) NETs shielded metastatic cancer cells and (8) MAFs. The sequential distant metastatic niche model can serve as a coherent framework to better understand metastatic progression: metastatic cancer satellites, each with its distinct biology, are shielded from the immune system, and consequently migrate to distant sites, which fulfills the predisposing conditions for metastases. Analogously it provides biological meaning to long observed phenomena so far not satisfactorily explained: metastasis occurs concurrently with carcinogenesis; vast molecular and clinical heterogeneity; most disseminated cancer cells remain dormant for years; surgery or anticancer therapy can paradoxically trigger relapse; oncology therapies, despite direct anti-cancer cellular effects, have so far failed to substantially alter the natural history of most epithelial cancers.<\/jats:p>","DOI":"10.33594\/000000872","type":"journal-article","created":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T08:23:34Z","timestamp":1782721414000},"page":"291-335","source":"Crossref","is-referenced-by-count":0,"title":["Epistemology of the Origin of Cancer IV: Predisposing Conditions for Metastases"],"prefix":"10.33594","volume":"60","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3930-6416","authenticated-orcid":false,"given":"Bj\u00f6rn L. D. M.","family":"Br\u00fccher","sequence":"first","affiliation":[{"name":"Department of Surgery, Medical University Lausitz \u2013 Carl-Thiem, Cottbus, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1437-2281","authenticated-orcid":false,"given":"Ijaz S.","family":"Jamall","sequence":"additional","affiliation":[{"name":"Cancer Metastases Research Fund, Sacramento, California, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"19235","published-online":{"date-parts":[[2026,6,29]]},"container-title":["Cellular Physiology and Biochemistry"],"original-title":[],"deposited":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T08:23:35Z","timestamp":1782721415000},"score":1,"resource":{"primary":{"URL":"https:\/\/cellphysiolbiochem.com\/Articles\/000872\/index.html"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,29]]},"references-count":0,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,6,29]]}},"URL":"https:\/\/doi.org\/10.33594\/000000872","relation":{},"ISSN":["1015-8987"],"issn-type":[{"value":"1015-8987","type":"print"}],"subject":[],"published":{"date-parts":[[2026,6,29]]}}}