Inactivation of the Muc2 gene and colorectal cancer

DESCRIPTION (provided by applicant): This proposal capitalizes on our development of a mouse model in which we have targeted the Muc2 gene which encodes the major colonic mucin, forinactivation. The Muc2-/- mice, which are viable and fertile, do not develop recognizable goblet cells, and the histopathology of the intestinal mucosa is distorted. By six months of age the Muc2-/-animals develop dysplasia and carcinoma in the gastrointestinal tract, including the rectum, a site at which tumors do not form in mice with Apc mutations. This is of particular importance since there exists no other rodent model of human rectal cancer, a major site of cancer that is clinically and biologically distinct from colon cancer. The development of the Muc2-/- mouse is the next step of our extensive work on the structural and functional analysis of the human and mouse MUC2 genes and on the observation that there is loss of mucin production in human, and chemically induced rodent aberrant crypt foci (ACF), early morphological lesions in the development of colon tumors, which are characterized by under-representation of goblet cells. Most important, the development of ACF precedes tumor formation in the Apc 1638 mouse, which carries a genetically inactivated Apc allele. Thus, tumor development in the Muc2-/- mouse strongly supports the hypothesis that loss of mucin production and the goblet cell phenotype is a sufficient, and perhaps a necessary early step for intestinal tumor formation and may specifically lead to rectal cancer. In this application, we will: 1) characterize the molecular biology and phenotype of the Muc2-/- mouse by determining the mechanisms contributing to the disruption of intestinal cell maturation in the Muc2-/- mouse, and whether compensatory mechanisms take place regarding levels and location of the expression of other mucin genes and intestinal trefoil factor (ITF), specifically expressed in goblet cells. 2) determine whether and how the genetic lesion in the Muc2 gene is related to the Apc pathway of tumor formation by investigating whether mutations in Apc, or alterations of the Apc pathway, are obligatory in tumor development, or whether mutations in alternative pathways (i.e. cdx2) are involved in tumor formation in the Muc2-/- mouse. 3) by utilizing mouse models already available (Apcl 638 and ITF-/- animals), we will directly test whether there is interaction between loss of Muc2 and mutation in Apc, and the role that absence of the major products of goblet cells (Muc2 and ITF) has in tumor development.