The intestinal epithelium and its neoplasms: genetic, cellular and tissue interactions

Abstract

The Min (multiple intestinal neoplasia) strain of the laboratory mouse and its derivatives permit the fundamental study of factors that regulate the transition between normal and neoplastic growth. A gene of central importance in mediating these alternative patterns of growth is Apc, the mouse homologue of the human adenomatous polyposis coli (APC) gene. When adenomas form in the Min mouse, both copies of the Apc gene must be inactivated. One copy is mutated by the nonsense Apc allele carried in heterozygous form in this strain. The other copy can be silenced by any of several mechanisms. These range from loss of the homologue bearing the wild-type Apc allele; to interstitial deletions surrounding the wild-type allele; to intragenic mutation, including nonsense alleles; and ¢nally, to a reduction in expression of the locus, perhaps owing to mutation in a regulatory locus. Each of these proposed mechanisms may constitute a two-hit genetic process as initially posited by Knudson; however, apparently the two hits could involve either a single locus or two loci. The kinetic order for the transition to adenoma may be still higher than two, if polyclonal adenomas require stronger interactions than passive fusion.The severity of the intestinal neoplastic phenotype of the Min mouse is strongly dependent upon loci other than Apc. One of these, Mom1, has now been rigorously identi¢ed at the molecular level as encoding an active resistance conferred by a secretory phospholipase. Mom1 acts locally within a crypt lineage, not systemically. Within the crypt lineage, however, its action seems to be non-autonomous: when tumours arise in Mom1 heterozygotes, the active resistance allele is maintained in the tumour (MOH or maintenance of heterozygosity). Indeed, the secretory phospholipase is synthesized by post-mitotic Paneth cells, not by the proliferative cells that presumably generate the tumour. An analysis of autonomy of modi¢er gene action in chimeric mice deserves detailed attention both to the number of genetic factors for which an animal is chimeric and to the clonal structure of the tissue in question.Beyond Mom1, other loci can strongly modify the severity of the Min phenotype. An emergent challenge is to ¢nd ways to identify the full set of genes that interact with the intestinal cancer predisposition of the Min mouse strain. With such a set, one can then work, using contemporary mouse genetics, to identify the molecular, cellular and organismal strategies that integrate their functions. Finally, with appropriately phenotyped human families, one can investigate by a candidate approach which modifying factors in£uence the epidemiology of human colon cancer. Even if a candidate modi¢er does not explain any of the genetic epidemiology of colon cancer in human populations, modi¢er activities discovered by mouse genetics provide candidates for chemopreventive and/or therapeutic modalities in the human.

Polyclonality of familial murine adenomas: Analyses of mouse chimeras with low tumor multiplicity suggest short-range interactions

“…A modification of the random collision hypothesis considers that the intestinal tract is regionally heterogeneous in tumor susceptibility (21). Again, our findings weigh against this regionally restricted collision hypothesis: heterotypic tumors were observed more frequently in the proximal region of the small intestine, where tumor multiplicity is lower than in the distal region (9).…”

A resistant genetic background leading to incomplete penetrance of intestinal neoplasia and reduced loss of heterozygosity in Apc Min /+ mice

“…2). We can only speculate at this stage as to how the Apc ϩ allele becomes silent in the apparent absence of LOH or somatic mutation (32). This result demonstrates that lack of Apc tumor suppressor function is critical for tumor formation in both strains.…”

Intracellular Role for Sphingosine Kinase 1 in Intestinal Adenoma Cell Proliferation

“…We investigated the expression of sphingolipid metabolic enzymes and S1P receptors in the intestinal tissues of the Apc Min/ϩ mouse, a widely used model system in which intestinal adenomas develop spontaneously (6). S1P receptors (S1PR1, S1PR2, and S1PR3) were expressed in normal intestinal mucosa; however, S1PR1 and S1PR2 transcripts were induced in the adenomas.…”