THE INTESTINAL EPITHELIUM AND ITS NEOPLASMS - GENETIC, CELLULAR AND TISSUE INTERACTIONS

The Min (multiple intestinal neoplasia) strain of the laboratory mouse and its derivatives permit the fundamental study of factors that regu late the transition between normal and neoplastic growth. A gene of ce ntral importance in mediating these alternative patterns of growth is Ape, the mouse homologue of the human adenomatous polyposis coli (APC) gene. When adenomas form in the Min mouse, both copies of the Apc gen e must be inactivated. One copy is mutated by the nonsense Apc allele carried in heterozygous form in this strain. The other copy can be sil enced by any of several mechanisms. These range from loss of the homol ogue bearing the wild-type Apc allele; to interstitial deletions surro unding the wild-type allele; to intragenic mutation, including nonsens e alleles; and finally to a reduction in expression of the locus, perh aps owing to mutation in a regulatory locus. Each of these proposed me chanisms may constitute a two-hit genetic process as initially posited by Knudson; however, apparently the two hits could involve either a s ingle locus or two loci. The :kinetic order for the transition to aden oma may be still higher than two, if polyclonal adenomas require stron ger interactions than passive fusion. The severity of the intestinal n eoplastic phenotype of the Min mouse is strongly dependent upon loci o ther than Ape. One of these, Mom1, has now been rigorously identified at the molecular level as encoding an active resistance conferred by a secretory phospholipase. Mom1 acts locally within a crypt lineage, no t systemically. Within the crypt lineage, however, its action seems to be non-autonomous: when rumours arise in il Mom1 heterozygotes, the a ctive resistance allele is maintained in the tumou (MOH or maintenance of heterozygosity). Indeed, the secretory phospholipase is synthesize d by post-mitotic Paneth cells, not by the proliferative cells that pr esumably generate the tumour. An analysis of autonomy of modifier gene action in chimeric mice deserves detailed attention both to the numbe r of genetic factors for which an animal is chimeric and to the clonal structure of the tissue in question. Beyond Mom1, other loci can stro ngly modify the severity of the Min phenotype. An emergent challenge i s to find ways to identify the full set of genes that interact with th e intestinal cancer predisposition of the Min mouse strain. With such a set, one can then work, using contemporary mouse genetics, to identi fy the molecular, cellular and organismal strategies that integrate th eir functions. Finally, with appropriately phenotyped human families, one can investigate by a candidate approach which modifying factors in fluence the epidemiology of human colon cancer. Even if a candidate mo difier does not explain any of the genetic epidemiology of colon cance r in human populations, modifier activities discovered by mouse geneti cs provide candidates for chemopreventive and/or therapeutic modalitie s in the human.