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Rethinking Carcinogenesis Models - A New Epistemological Tool","","A growing body of studies indicates that cancer cells can undergo phenotypic transformation from malignant to benign, a process termed “tumor reversion”. However, current cancer models treat gene mutations as the primary and irreversible cause, creating a conceptual tension: if mutations are causative and irreversible, how can reversibility be sustained? Evidence suggests intrinsic cancer-cell plasticity may be exploited therapeutically to enable phenotypic reprogramming in vitro and in vivo.",{"@graph":69,"@context":122},[70,84,105],{"@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/is-cancer-reversible-rethinking-carcinogenesis-models-a-new-epistemological-tool/376833/",{"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/is-cancer-reversible-rethinking-carcinogenesis-models-a-new-epistemological-tool/376833.png","ImageObject",300,407,{"name":92,"@type":93},"River Wang","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-29","2026-09-24",true,{"@type":102,"interactionType":103,"userInteractionCount":52},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What is “tumor reversion” in cancer research?","Question",{"text":112,"@type":113},"“Tumor reversion” refers to the phenotypic transformation of cancer cells from malignant to benign states when exposed to specific conditions, especially aspects of the cellular microenvironment.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"Why does the concept of reversibility challenge common cancer models?",{"text":117,"@type":113},"Many current models regard gene mutations as the primary cause of cancer and as irreversible. If causative mutations cannot change, the idea of a reversal process raises a conceptual problem.",{"name":119,"@type":110,"acceptedAnswer":120},"What role do microenvironment and systems approaches play in tumor reversion models?",{"text":121,"@type":113},"Experiments highlight that embryonic and cellular microenvironments can control cancer-cell proliferation and outcomes. The article also argues that modeling reversion requires systemic, epistemological tools rather than purely reductionist frameworks.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},376833,1790313748,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":52,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145},1099514067438,"https://ap-avatar.wpscdn.com/avatar/100002539ee87300030?x-image-process=image/resize,m_fixed,w_180,h_180&k=1780474512215547542","biomolecules  \nReview  \nIs Cancer Reversible? Rethinking Carcinogenesis Models—ANew Epistemological Tool  \nAndrea Pensotti 1,2, *, Marta Bertolaso 1 and Mariano Bizzarri 2  \nCitation: Pensotti, A.; Bertolaso, M.; Bizzarri, M. Is Cancer Reversible? Rethinking Carcinogenesis Models—A New Epistemological Tool. Biomolecules 2023, 13, 733 . [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)biom13050733  \nAcademic Editor: Jeffrey Brender  \nReceived: 24 February 2023  \nRevised: 17 April 2023  \nAccepted: 19 April 2023  \nPublished: 24 April 2023  \nCopyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) .  \n1 Research Unit of Philosophy of Science and Human Development, University Campus Bio-Medico of Rome, 00128 Rome, Italy  \n2 Systems Biology Group Lab, Department of Experimental Medicine, Sapienza University, 00185 Rome, Italy  \n* Correspondence: [a.pensotti@unicampus.it](a.pensotti@unicampus.it)  \nAbstract: A growing number of studies shows that it is possible to induce a phenotypic transformation of cancer cells from malignant to benign. This process is currently known as “tumor reversion”. However, the concept of reversibility hardly fits the current cancer models, according to which gene mutations are considered the primary cause of cancer. Indeed, if gene mutations are causative carcinogenic factors, and if gene mutations are irreversible, how long should cancer be considered asan irreversible process? In fact, there is some evidence that intrinsic plasticity of cancerous cells maybe therapeutically exploited to promote a phenotypic reprogramming, both in vitro and in vivo. Not only are studies on tumor reversion highlighting a new, exciting research approach, but they are also pushing science to look for new epistemological tools capable of better modeling cancer.  \nKeywords: tumor reversion; microenvironment; embryo development; systems biology; morphogenesis; biological network  \n1. Introduction  \nThe first clinical evidence of spontaneous cancer regression came from teratocarcinoma. In 1907, the Swiss pathologist, Max Askanazy, observed the spontaneous reversion of an ovarian teratocarcinoma [1] . A more thorough study of these processes was possible in 1954 after Stevens and Little's work on the 129/SvJ mouse had led to a model ofteratocarcinoma [2] .  \nIn 1959, Pierce made his first observations on the spontaneous differentiation of embryonal cancer cells deriving from testicular teratocarcinoma in the 129/SvJ mouse [3] . Pierce highlighted the pivotal role of the cell microenvironment and introduced the hypothesis of“the development of methods that would direct the differentiation of embryonal carcinoma cells to benign forms as a logical means of controlling this type of cancer” [4] . These results were instrumental in introducing the concept of “cancer reversion”, indicating the recovery of a normal phenotype by cancerous cells when exposed to a specific microenvironment.  \nIn 1974, Brinster confirmed Pierce's hypothesis. He injected testicular teratocarcinoma cells from the 129/SvJ black agouti into murine blastocysts, and then implanted these blastocysts into albino female mice. This resulted in a healthy black-white hybrid offspring, suggesting that “the embryo environment can bring under control the autonomous proliferation of the teratocarcinoma cells” [5] . Similar results were obtained by Mintz and Illmensee. They had injected embryonal cancer cells into 280 different blastocysts that were further implanted into as many adoptive mothers. Both analyses on the fetus and the offspring showed no signs of cancer cells. Even more interesting were the results of the analyses on the composition of hair","cbCaiq0iBtm7q5ib","https://ap.wps.com/l/cbCaiq0iBtm7q5ib","pdf",1299169,27,"English","# Introduction\n## Historical evidence for spontaneous cancer regression and tumor reversion","[{\"question\":\"What is “tumor reversion” in cancer research?\",\"answer\":\"“Tumor reversion” refers to the phenotypic transformation of cancer cells from malignant to benign states when exposed to specific conditions, especially aspects of the cellular microenvironment.\"},{\"question\":\"Why does the concept of reversibility challenge common cancer models?\",\"answer\":\"Many current models regard gene mutations as the primary cause of cancer and as irreversible. If causative mutations cannot change, the idea of a reversal process raises a conceptual problem.\"},{\"question\":\"What role do microenvironment and systems approaches play in tumor reversion models?\",\"answer\":\"Experiments highlight that embryonic and cellular microenvironments can control cancer-cell proliferation and outcomes. The article also argues that modeling reversion requires systemic, epistemological tools rather than purely reductionist frameworks.\"}]","Is Cancer Reversible? Rethinking Carcinogenesis Models - A New Epistemological Tool | PDF",1790221550,68]