Direct experimental proof that a mutatant cKit causes GIST is provided by inserting the mutant gene into the mouse genome. Amazingly, the same gene identified in the human GIST causes the same disease when expressed in the same tissues in the mouse. This is the modern version of Koch’s Postulates. The mouse model is a geneocopy and phenocopy of the human disease.
Several mouse models of GIST tumors have been developed. The example shown here is a “knock in” of a mutant of c-Kit bearing a specific mutation (Kit K641E). This mutation results in Intermediate Cell of Cajal (ICC) hyperplasia suggesting the cell of origin and GIST tumors that are immunohistochemically positive for cKit. Note: the same gene creates cancer in the same cell with the same histopathology in mouse and man.
Top: Image of H&E stained tumor mass below the GI mucosa. Note the spindle cell mass which is heavily stained using an anti-cKit antibody (lower image). (Images and slides courtesy of Dr. Brian P. Rubin, M.D., Ph.D. Cleveland Clinic, Cleveland Ohio.)
For more information, please go to the following references:
Rubin BP, Antonescu CR, Scott-Browne JP, Comstock ML, Gu Y, Tanas MR, Ware CB, Woodell J. 2005. A knock-in mouse model of gastrointestinal stromal tumor harboring Kit K641E. Cancer Res 65:6631-6639. PMID:16061643
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