Genetic events and the role of TGF beta in epithelial tumour progression

The mouse skin model of chemical carcinogenesis has been very well characte rized with respect to epigenetic changes, which occur during tumour cell in itiation, promotion and progression. The use of transgenic and gene knock-o ut mice has contributed greatly to knowledge in this area. The H-ras geneti c locus has been shown to undergo multiple genetic changes, including mutag enic activation, amplification of the mutant gene, and loss of the normal a llele, These different genetic events lead to thresholds of ras activity wh ich contribute to different stages along the pathway to neoplasia. The gene tic and epigenetic events which lead to tumour invasion and metastasis hale been less well characterized than studies on tumour initiation and promoti on, despite the fact that it is metastases which ultimately kill the animal /patient. In the mouse skin model, loss of p53 contributes to malignant con version. Gene deletion of the INK4 locus is associated with transformation to a highly invasive spindle cell tumor phenotype, This spindle cell transf ormation can also be induced in vitro or in vivo by TGF beta 1, possible by synergizing with mutant H-ras. TGF beta can have both positive and negativ e effects on tumourigenesis, acting early as a tumour suppresser, but later as a stimulator of tumour invasion. It is this latter effect which may be clinically more significant, since many human tumours overexpress TGF beta, yet the majority still retain the intracellular signaling systems necessar y for the cell to respond to this growth factor. Copyright (C) 1999 John Wi ley & Sons, Ltd.