In a pedigree derived from a mouse treated with the mutagen ethylnitrosourea, a mutation has been identified that predisposes to spontaneous intestinal cancer. The mutant gene was found to be dominantly expressed and fully penetrant. Affected mice developed multiple adenomas throughout the entire intestinal tract at an early age.
Germ-line mutations of the APC gene are responsible for familial adenomatous polyposis (FAP), an autosomal dominantly inherited disease in humans. Patients with FAP develop multiple benign colorectal tumors. Recently, a mouse lineage that exhibits an autosomal dominantly inherited predisposition to multiple intestinal neoplasia (Min) was described. Linkage analysis showed that the murine homolog of the APC gene (mApc) was tightly linked to the Min locus. Sequence comparison of mApc between normal and Min-affected mice identified a nonsense mutation, which cosegregated with the Min phenotype. This mutation is analogous to those found in FAP kindreds and in sporadic colorectal cancers.
. Min is a fully penetrant dominant mutation that leads to the development of multiple intestinal adenomas throughout the duodenal-to-colonic axis.Minl+ C57BL6/J mice have an average life-span of 120 d. Mufti-label immunocytochemical studies of these lesions demonstrate patches of differentiated enterocytes, and scattered enteroendocrine, goblet and Paneth cells . Expression of endogenous marker genes within these differentiated cells can be directly correlated with the position occupied by the adenoma along the duodenal-to-colonic axis and mirrors the regional differentiation of the normal gut epithelium . The presence of multiple lineages in adenomas together with their retention of spatial information suggests that tumorigenesis in Minl+ mice may be initiated in a multipotent stem cell normally located at the base of intestinal crypts . To study the time-dependent properties of these tumors, genetic conditions were T HE mouse intestinal epithelium undergoes perpetual renewal of its four principal terminally differentiated cell types: the polarized absorptive enterocyte, the mucus-producing goblet cell, a complex population of enteroendocrine cells, and the defensin/lysozyme containing Paneth cell which is thought to function as part ofthe biological barrier to bacterial translocation across the gut (reviewed in Gordon, 1989) . Renewal and differentiation are rapid, extraordinarily well organized in several spatial dimensions, and dependent upon multipotent stem cells that are functionally anchored at the base of intestinal crypts (Cheng and Leblond, 1974). In the adult small intestine, 6-10 crypts, each composed of -250 cells, surround each villus. ['H]Thymidine labeling studies indicate that 150 cells, located in the middle portion of each crypt, pass through the cell cycle every 12 h resulting in the generation of 300 new cells/ crypt/d (reviewed in Potten and Loefer, 1990). These cells undergo a bipolar migration . -12 cells emerge from each crypt per hour and are translocated in coherent vertical bands up the adjacent villus (Cheng and Leblond, 1974; Potten and Loefer, 1990;Schmidt et al., 1985b). Differentiation ofenterocytes, goblet and enteroendocrine cells occurs during this upward migration which is completed in 3 d when the sooner. These studies indicate that the Minl+ mouse is a powerful model system for analyzing the mechanisms that establish and maintain a balance between proliferation and differentiation in the continuously renewing gut epithelium and for an assessment of the multi-step hypothesis of intestinal neoplasia . cells are exfoliated into the gut lumen at the apical extrusion zone of the villus . Each villus contains a steady state level of -3,500 surface epithelial cells and sheds -1,400 cells/
ApcMLU (Min, multiple intestinal neoplasia) is a point mutation in the murine homolog of the APC gene. Min/+ mice develop multiple intestnal adenomas, as do humans carrying germ-line mutations in APC. Female mice carying Min are also prone to develop mammary tumors. Min/+ mammary glands are more sensitive to chemical carcinogenesis than are +/+ mammary glands. Transplantation of mmary celsfromMin/+ or +/+ donors into +/+ hosts demonstrates that the propensity to develop mammary tumors is intrinsic to the Miun/+ mammary cells. Long-term grfts of Min/+ mammar glands also gave rise to focal alveolar hyperplslas, indicating that the presence of the Min mutation also has a role in the development of these lesions.Mutations in the human APC gene have been shown to be involved in both sporadic and familial colon cancer. Individuals carrying germ-line mutations in the APC gene are at risk for the development of adenomatous colon polyps that can progress to cancer (1, 2). In some families there is also an increased risk for desmoid tumors, small intestine tumors, mandibular osteomas, or retinal dysplasias (3).The APC gene is expressed in most tissues that have been surveyed (4, 5), in contrast to the narrow spectrum of tissues overtly predisposed to neoplasia by mutations in this gene. A limited spectrum of neoplastic transformation is also observed for other broadly expressed genes in which mutations can predispose to cancer, such as RB (6), P53 (7), and NF (8 10). The mammary glands from donors ofeach genotype, +/+ orMin/+, were pooled on ice, enzymatically treated, and processed to produce a monodispersed epithelial cell suspension as described (13). Recipient females were injected with 2.5 x 104 mammary cells in each oftwo sites in the white intrascapular fat pad. Any one animal received either Min/+ or +/+ cells.At 5 weeks after transplantation, animals from the set that received the Min/+ cells and from the set that received the +/+ cells were each randomly assigned to one of three treatment groups: 7,12-dimethylbenz[a]anthracene (DMBA), ENU, or control. DMBA at 1 mg (Eastman Kodak) in 0.2 ml of sesame oil was delivered by intubation weekly for 6 weeks. ENU was delivered by a single i.p. injection at a dose of 200 mg/kg (body weight). Untreated animals were followed as controls.The untreated and ENU-treated mice received a graft of a whole pituitary gland from a B6 female under the left kidney capsule 8-9 weeks after cell transplantation (3-4 weeks after ENU treatment). DMBA-treated mice received pituitary grafts 3 weeks after the final DMBA treatment.At 1-to 2-week intervals for 52 weeks, all mice were palpated for the presence oftumors at both the transplant site and the 10 intact in situ mammary glands of the host animals. Whenever possible, tumors were resected and the animals were kept for further observation. Moribund animals were sacrificed, and complete necropsies were performed. Any tumors or growths were recorded and fied in buffered 10%o formalin, embedded, sectioned, and stained for histologic...
Wnt and Hedgehog signaling pathways play central roles in embryogenesis, stem cell maintenance, and tumorigenesis. However, the mechanisms by which these two pathways interact are not well understood. Here, we identified a novel mechanism by which Wnt signaling pathway stimulates the transcriptional output of Hedgehog signaling. Wnt/β-catenin signaling induces expression of an RNA-binding protein, CRD-BP, which in turn binds and stabilizes GLI1 mRNA, causing an elevation of GLI1 expression and transcriptional activity. The newly described mode of regulation of GLI1 seems to be important to several functions of Wnt, including survival and proliferation of colorectal cancer cells. [Cancer Res 2009;69(22):8572-8]
The Min mouse provides a genetically defined model for inherited and sporadic forms of human colorectal tumorigenesis. To test the suitability of this model for the evaluation and optimization of chemopreventive agents, we examined the effects of sulindac on tumorigenesis in Min mice as this compound can inhibit colorectal tumorigenesis in human familial adenomatous polyposis patients. Treatment of Min mice with sulindac in their drinking water (84 mg/l) or diet (167 and 334 p.p.m.) resulted in a significantly decreased average tumor load. The conservation of sulindac activity in the Min mouse provides an opportunity to explore the mechanism of sulindac suppression as well as to test other potential chemopreventive agents.
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