{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T08:06:28Z","timestamp":1753862788555,"version":"3.41.2"},"reference-count":62,"publisher":"Wiley","issue":"18","license":[{"start":{"date-parts":[[2024,9,24]],"date-time":"2024-09-24T00:00:00Z","timestamp":1727136000000},"content-version":"vor","delay-in-days":23,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Medicine"],"published-print":{"date-parts":[[2024,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Cancer initiation has long been \u201cunknowable\u201d in biology and medicine. In 1987, however, Moore and our research group observed single hepatocytes and minifoci that were strongly positive for glutathione S\u2010transferase P\u2010form (GST\u2010P) in the rat liver as early as 2 to 3 days after initiation by diethylnitrosamine prior to the induction of GST\u2010P<jats:sup>+<\/jats:sup> foci and nodules. The induction of GST\u2010P<jats:sup>+<\/jats:sup> single hepatocytes, precursors of GST\u2010P<jats:sup>+<\/jats:sup> foci and nodules, was considered genetic. But, the details of the induction mechanism have remained unclear despite various examinations over a long period.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Male Sprague\u2010Dawley rats (aged 6 weeks) were fed a basal diet containing either benzyl isothiocyanate (BITC, 0.5% by wt) or 2\u2010acetylaminofluorene (AAF, 0.04%) <jats:italic>ad<\/jats:italic> <jats:italic>libitum<\/jats:italic> for appropriate time intervals. All animals were anesthetized and euthanized. The livers obtained were excised, cut into 3\u2010 to 4\u2010mm\u2010thick slices and fixed in cold acetone at 4 \u00b0C. The liver specimens were then sliced into 25\u2010\u00b5m\u2010thick sections in PBS using an automated microtome (Vibratome 1500 Sectioning System, Vibratome Products, NY, USA). Immunocytochemical staining was performed in free solution, and the results were examined via digital light microscopy (Coolscope, Nikon, Tokyo).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>3D analysis using a vibratome showed that GST\u2010P is rapidly excreted into the bile of the liver of animals in response to strong carcinogenic stress caused by promoters or initiators. \u201cRapid biliary excretion of GST\u2010P\u201d was widely and commonly observed in all hepatocytes, GST\u2010P<jats:sup>+<\/jats:sup> single hepatocytes, minifoci, foci and nodules under appropriate conditions. Surprisingly, on the basis of these key findings, a new mechanism of cancer initiation involving the transformation of hepatocytes into GST\u2010P<jats:sup>+<\/jats:sup> single hepatocytes and minifoci in animal livers was identified. In addition, the initiation process was determined to be nongenetic because mutation is an invisible rare event.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This short review describes several details about breakthrough findings on cancer initiation in rat livers, the application of 3D analysis to other cancers and the importance in the genetic analysis in malignant diseases.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cam4.70165","type":"journal-article","created":{"date-parts":[[2024,9,25]],"date-time":"2024-09-25T04:30:13Z","timestamp":1727238613000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A new mechanism of cancer initiation that involves the transformation of hepatocytes into preneoplastic single hepatocytes and minifoci positive for glutathione S\u2010transferase P\u2010form (<scp>GST<\/scp>\u2010P) in rat livers: <scp>3D<\/scp> analysis using a 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