Growth control mechanisms in normal and transformed intestinal cells

Abstract

The cells populating the intestinal crypts are part of a dynamic tissue system which involves the self-renewal of stem cells, a commitment to proliferation, lineage-specific differentiation, movement and cell death. Our knowledge of these processes is limited, but even now there are important clues to the nature of the regulatory systems, and these clues are leading to a better understanding of intestinal cancers. Few intestinal-specific markers have been described; however, homeobox genes such as cdx-2 appear to be important for morphogenic events in the intestine. There are several intestinal cell surface proteins such as the A33 antigen which have been used as targets for immunotherapy. Many regulatory cytokines (lymphokines or growth factors) influence intestinal development: enteroglucagon, IL-2, FGF, EGF family members. In conjunction with cell-cell contact and/or ECM, these cytokines lead to specific differentiation signals. Although the tissue distribution of mitogens such as EGF, TGF alpha, amphiregulin, betacellulin, HB-EGF and cripto have been studied in detail, the physiological roles of these proteins have been difficult to determine. Clearly, these mitogens and the corresponding receptors are involved in the maintenance and progression of the tumorigenic state. The interactions between mitogenic, tumour suppressor and oncogenic systems are complex, but the tumorigenic effects of multiple lesions in intestinal carcinomas involve synergistic actions from lesions in these different systems. Together, the truncation of apc and activation of the ras oncogene are sufficient to induce colon tumorigenesis. If we are to improve cancer therapy, it is imperative that we discover the biological significance of these interactions, in particular the effects on cell division, movement and survival.

Vasopressin-mediated mitogenic signaling in intestinal epithelial cells

“…The proliferation of epithelial cells of the intestinal mucosa is a tightly regulated process that is modulated by a broad spectrum of regulatory peptides (8,36,70). Nontransformed IEC-6 and IEC-18 cells, derived from rat small intestinal crypt (56), have provided an in vitro model to examine intestinal epithelial cell migration, differentiation, and proliferation (16,27,58,70).…”

“…Furthermore, AVP acts as a potent growth factor for IEC-18 cells, inducing DNA synthesis and cell proliferation through ERK-, Ca 2ϩ -, PKC-, EGFR tyrosine kinase-, and Src-dependent pathways. arginine vasopressin; protein kinase D; protein kinase C; Src; proline-rich tyrosine kinase 2; intestinal epithelial proliferation THE SEQUENTIAL PROLIFERATION, lineage-specific differentiation, migration, and cell death of epithelial cells of the intestinal mucosa is a tightly regulated process that is modulated by a broad spectrum of regulatory peptides (8,36,70). The nontransformed IEC-6 and IEC-18 cells, derived from rat small intestinal crypt (56), have provided an in vitro model to examine intestinal epithelial cell migration, differentiation, and proliferation (16,27,58,70).…”

α5β1 Integrin Protects Intestinal Epithelial Cells from Apoptosis through a Phosphatidylinositol 3-Kinase and Protein Kinase B–dependent Pathway

“…Both in the small intestine and in the colon, epithelial renewal is accompanied by directed migration of differentiating cells away from the stem cell-rich crypts and ultimately results in apoptosis and shedding of terminally differentiated cells into the lumen of the gut (Stappenbeck et al, 1998;Karam, 1999). A variety of factors, including soluble hormones and cytokines, interactions with mesenchymal cells, and interactions with extracellular matrix, have been implicated in growth control mechanisms in the gastrointestinal tract (Burgess, 1998;Kedinger et al, 1998). Integrins are clearly involved in the regulation of intestinal cell function and differentiation (Pignatelli, 1993;Beaulieu, 1999); however, their role in this tissue is not as well understood as it is in mammary or epidermal epithelia.…”

ANG II stimulates PKC-dependent ERK activation, DNA synthesis, and cell division in intestinal epithelial cells

“…The proliferation of epithelial cells of the intestinal mucosa is a highly precise process that is modulated by a broad spectrum of peptides (3,15,27), but the signal transduction pathways involved in intestinal cell proliferation remain poorly characterized. Nontransformed IEC-18 cells, derived from rat ileal crypts, have served as an in vitro model for studying intestinal epithelial cell migration, differentiation, and proliferation (8,12,23,27).…”

“…THE SEQUENTIAL proliferation, lineage-specific differentiation, migration, and cell death of epithelial cells of the intestinal mucosa is a tightly regulated process that is modulated by a broad spectrum of regulatory peptides (3,15,27). The nontransformed IEC-6 and IEC-18 cells, derived from rat small intestinal crypt (22), have provided an in vitro model to examine intestinal epithelial cell migration, differentiation, and proliferation (8,12,23,27).…”