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It integrates endosymbiotic cell evolution with systems biology principles in eukaryotic cells, linking malignant transformation to breakdown of an “endosymbiotic contract” between nuclear-cytoplasmic and mitochondrial systems. This decoupling produces uncoordinated functions resembling unicellular organisms and activates embryonic-like traits, enabling survival in hypoxic, nutrient-poor tumor microenvironments through metabolic reprogramming.",{"@graph":69,"@context":123},[70,84,106],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/the-systemic-evolutionary-theory-of-the-origin-of-cancer-setoc-an-update/372063/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/the-systemic-evolutionary-theory-of-the-origin-of-cancer-setoc-an-update/372063.png","ImageObject",300,407,{"name":92,"@type":93},"Himbo","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-31","2026-09-23",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",15,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"What core mechanism does SETOC propose for cancer origin?","Question",{"text":113,"@type":114},"SETOC proposes malignant transformation occurs through continuous cellular adaptation to long-term injuries, driven by breakdown of an endosymbiotic contract between nuclear-cytoplasmic and mitochondrial subsystems.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"How does SETOC connect cancer to endosymbiosis and cell evolution?",{"text":118,"@type":114},"SETOC integrates Lynn Margulis’ cooperative/endosymbiotic evolution and systems-biology concepts, arguing that endosymbiotic decoupling yields new, tumor-permitting phenotypes.",{"name":120,"@type":111,"acceptedAnswer":121},"What metabolic changes does the theory link to transformed cells?",{"text":122,"@type":114},"It describes metabolic reprogramming of glycolysis, the TCA cycle, and oxidative phosphorylation, promoting increased lactate fermentation (Warburg effect), respiratory dysfunction, and TCA cycle reversal.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},372063,1790480808,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":140,"language":141,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":142,"faqs":143,"seo_title":144,"seo_description":67,"update_tm":145,"read_time":146},687197100911,"https://ap-avatar.wpscdn.com/avatar/a000239b6f1da00475?x-image-process=image/resize,m_fixed,w_180,h_180&k=1785132997149421697","Mazzocca et al. Molecular Medicine (2025) 31:12 [https://doi.org/10.1186/s10020-025-01069-w](https://doi.org/10.1186/s10020-025-01069-w)  \nMolecular Medicine  \n HYPOTHESIS Open Access  \nThe systemic evolutionary theory  \nof the origin of cancer (SETOC): an update  \nAntonio Mazzocca1,2*, Giovanni Ferraro2 and Giovanni Misciagna2  \nAbstract  \nThe Systemic Evolutionary Theory of the Origin of Cancer (SETOC) is a recently proposed theory founded on two primary principles: the cooperative and endosymbiotic process of cell evolution as described by Lynn Margulis, and the integration of complex systems operating in eukaryotic cells, which is a core concept in systems biology. The SETOC proposes that malignant transformation occurs when cells undergo a continuous adaptation process in response to long-term injuries, leading to tissue remodeling, chronic inflammation, fibrosis, and ultimately cancer. This process involves a maladaptive response, wherein the ’endosymbiotic contract’ between the nuclear-cytoplasmic system (derived from the primordial archaeal cell) and the mitochondrial system (derived from the primordial α-proteobacterium) gradually breaks down. This ultimately leads to uncoordinated behaviors and functions in transformed cells. The decoupling of the two cellular subsystems causes transformed cells to acquire phenotypic characteristics analogous to those of unicellular organisms, as well as certain biological features of embryonic development that are normally suppressed. These adaptive changes enable cancer cells to survive in the harsh tumor microenvironment characterized by low oxygen concentrations, inadequate nutrients, increased catabolic waste, and increased acidity. De-endosymbiosis reprograms the sequential metabolic functions of glycolysis, theTCA cycle, and oxidative phosphorylation (OxPhos) . This leads to increased lactate fermentation (Warburg effect), respiratory chain dysfunction, and TCA cycle reversal. Here, we present an updated version of the SETOC that incorporates the fundamental principles outlined by this theory and integrates the epistemological approach used to develop it.  \nKeywords Cancer theories, Endosymbiosis, Archaea, Evolution, Systems biology, Mitochondria, Warburg effect  \nIntroduction  \nCancer is described as a disease caused by genetic mutations in somatic cells due to the mutagenic orgenotoxic action of carcinogens. This represents the basis of the somatic mutation theory (SMT), which is the dominant paradigm for carcinogenesis, a paradigm that is seen as a fact rather than a theory. The SMT has recently faced opposition from alternative ideas of the disease. One such theory is the Tissue Organization  \n*Correspondence:  \nAntonio Mazzocca [antonio. mazzocca@uniba.it](antonio. mazzocca@uniba.it)  \n1 Interdisciplinary Department of Medicine, University of Bari School of Medicine, Piazza G. Cesare, 11, 70124 Bari, Italy  \n2 Association for Systems Science, Via S. Stefano, 42, I-75100 Matera, Italy  \nField Theory of Cancer (TOFT), proposed by Sonnenschein and Soto (Sonnenschein and Soto 2005), which views cancer as a disease of tissue communication. The metabolic theory is a different theory proposing that cancer originates from mitochondrial dysfunction, which was first introduced by Otto Warburg and later expanded upon by Thomas Seyfried (Seyfried et al. 2015) . These divergent perspectives, like many scientific theories, have sparked significant controversy, but they have not received the attention they deserve, probably because they challenge the SMT. Questioning the current paradigm could potentially undermine the effectiveness and adequacy of many existing pharmacological treatments for cancer that are based on SMT. Our previously proposed Systemic Evolutionary Theory of Cancer (SETOC) provides a conceptual  \n© The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distributio","cbCaidTb1CN83sKI","https://ap.wps.com/l/cbCaidTb1CN83sKI","pdf",1259996,11,"English","# Abstract\n# Introduction\n# Evidence against the somatic mutation theory (SMT)","[{\"question\":\"What core mechanism does SETOC propose for cancer origin?\",\"answer\":\"SETOC proposes malignant transformation occurs through continuous cellular adaptation to long-term injuries, driven by breakdown of an endosymbiotic contract between nuclear-cytoplasmic and mitochondrial subsystems.\"},{\"question\":\"How does SETOC connect cancer to endosymbiosis and cell evolution?\",\"answer\":\"SETOC integrates Lynn Margulis’ cooperative/endosymbiotic evolution and systems-biology concepts, arguing that endosymbiotic decoupling yields new, tumor-permitting phenotypes.\"},{\"question\":\"What metabolic changes does the theory link to transformed cells?\",\"answer\":\"It describes metabolic reprogramming of glycolysis, the TCA cycle, and oxidative phosphorylation, promoting increased lactate fermentation (Warburg effect), respiratory dysfunction, and TCA cycle reversal.\"}]","The Systemic Evolutionary Theory of the Origin of Cancer (SETOC) - an update | PDF",1790193623,28]