The structural and functional organization of the adult mouse small intestinal epithelium lends itself to studying both the regulation and integration of cellular proliferation, differentiation, and death programs. The epithelium contains four principal cell types: absorptive enterocytes (comprising Ͼ80% of the total population), enteroendocrine cells, mucus-producing goblet cells, and Paneth cells. All four lineages are derived from a multipotent stem cell that is functionally anchored near the base of each of the small intestine's 1.1 million crypts of Lieberkü hn (1-4). Cell division is confined to these crypts (5). Enterocytes, enteroendocrine, and goblet cells migrate out of the crypt and up an adjacent villus. Migration is highly ordered and associated with terminal differentiation. Cell death occurs near the villus tip where cells are exfoliated into the lumen (6, 7). Proliferation, differentiation, and death take place in a spatially well-organized continuum that extends from the crypt to the apex of a villus. This sequence is completed rapidly (2-5 days in the case of enterocytes, enteroendocrine, and goblet cells; Refs. 1 and 8 -10) and is recapitulated throughout the lifespan of the mouse.The Paneth cell lineage differs from the others in a number of notable ways. It is the only lineage that executes its terminal differentiation program during a downward migration from the stem cell zone to the crypt base (11). It is the longest lived lineage, and the only one that exists entirely within the proliferative compartment. Each crypt contains 30 -50 mature Paneth cells that survive for 18 -23 days before degenerating and undergoing phagocytosis by their neighbors (11-13). Paneth cell age correlates with position in the crypt; the most mature cells are located at or near the crypt base (2). The size of the Paneth cell's apical secretory granules also correlates with age; larger granules are produced by older cells (2, 11).The function of the Paneth cell has not yet been clearly defined. Residency at the crypt base places this lineage in a position to release products from its apical granules that could affect establishment and/or maintenance of the stem cell's niche or influence the properties of the stem cell's descendants. A number of factors exported by Paneth cells could regulate epithelial proliferation and differentiation programs. They include tumor necrosis factor-␣ (14), guanylin (15), and epidermal growth factor (16). Two Paneth cell products have been implicated as modifiers of adenoma formation in mice heterozygous for a mutation in the adenomatous polyposis coli gene, Apc Min (17). Production of matrilysin, a matrix metalloprotein-

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Neoadjuvant therapy for adenocarcinoma of the rectum is well tolerated and can produce substantial down-staging and a high curative resection rate. Chemoradiation can achieve high complete pathologic response rates, although toxicity during neoadjuvant therapy is greater than for radiation alone. Short-course radiation can achieve down-staging of both T stage and N stage.

Homeostasis in the self-renewing mouse intestinal epithelium appears to be regulated in large part by cell nonautonomous mechanisms. The society of nonpathogenic bacteria that resides in the intestine is an important source of instructions that modify epithelial differentiation programs. The stability of this society is remarkable given its numerical, compositional, and spatial complexity, the openness of the ecosystem, and the fact that the epithelium is replaced so rapidly. The ability of components of this society to influence epithelial differentiation may represent a critical step in allowing specific groups of organisms to be assembled in specific regions of the gut. Simplified model systems have been created to define and dissect the conversations between microbe and host. These systems use inbred strains of mice that are raised under germ-free conditions and then monocontaminated with a single component of the microflora. The results suggest that a trialogue involving communications between the microflora, the epithelium, and the diffuse gut-associated lymphoid tissue (GALT) may play a key role in establishing and maintaining the spatial diversity of this remarkable ecosystem.

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