WHEN THE CONTROL IS LACKING - THE ROLE OF TUMOR-SUPPRESSOR GENES IN CANCER DEVELOPMENT

The potential to genetically dissect tumorigenesis provides the major reason to study this process in the fruit fly Drosaphila. Over the las t 30 years genetic analysis has identified some 55 genes in which rece ssive mutations cause the appearance of specific tumours during develo pment in tissues such as the imaginal discs, the brain hemispheres, th e hematopoietic organs or the gonads. Since the normal allele acts dom inantly over the mutated allele, these genes are designated as tumour suppressor genes. The estimate of the number of genes that can be muta ted to tumour formation may be, however, much higher ranging between 1 00 to 200. The challenge before this field is how best to identify the se genes and elucidate their function. Current molecular procedures, s uch as mutagenesis mediated by P-element transposon, provide new ways for tagging any gene of interest in Drosophila and thus for cloning it rapidly. Function of the gene product can be inferred by comparing it s amino acid sequence with sequences of proteins with known function o r can be determined by histochemical and biochemical investigations. P rogress in the understanding of tumour suppression in Drosophila is mo st advanced in the case of genes regulating cell growth in imaginal di scs. The imaginal discs are small groups of cells displaying a strong apical-basal polarity and form folded sacs of epithelia which grow thr oughout the larval life and give rise to the adult tegument during met amorphosis. Tumour suppressor genes regulating cell growth of imaginal discs, such as the lethal(2)giant larvae (l(2)gl), lethal(1)discs lar ge-1 and expanded genes, were found to encode proteins localized in do mains of cell to cell contact on the plasma membrane and were thus tho ught to maintain cell adhesion. However, recent studies of l(2)gl have revealed that the l(2)gl protein is a component of the normal cytoske leton which can participates to the cytoskeletal matrix underlaying th e plasma membrane. These findings indicate that the changes in cell sh ape and the loss of apical-basal polarity in imaginal disc cells resul t primarily from alterations in the cytoskeleton structure. Furthermor e the neoplastic growth of the mutated cells may be caused by the diso rganization of an intracellular communication system that ultimately c ontrols cell proliferation and/or cell differentiation.