Fig. 3.

New approaches to reproduce the hierarchical structure of human cancer in the mouse. (A) Based on the reprogramming nature of oncogenes, it has been proven that restricting the expression of the oncogenic alterations to the stem cell compartment is all that is needed to recapitulate all the tumoral heterogeneity. Using a stem cell-restricted transgenic expression system, the expression of the oncogene in the reprogramming-prone stem cells and progenitors allows the development of all the cells that compose the tumor mass by a ‘hands-off’ mechanism. The modified gene is present in all the mouse cells but expression of the oncogene is limited to the stem/progenitor compartment. (B) Conditional activation of an oncogenic alteration from the stem cell onwards: by using a conventional transgene that can be activated by recombinase, with the regulatory sequences of a constitutive or tissue-restricted gene (B1); by modifying the locus of an oncogene by introducing a recombinase-inducible activating mutation (B2) or, by modifying the locus of a tumor suppressor to achieve a recombinase-mediated deletion (B3). In these three cases, in combination with a stem/progenitor-restricted recombinase, the oncogenic anomaly is initiated in stem cells and maintained in all their descendants in a manner that is very similar to how it happens in humans.