Cell-cell contact and specific cytokines inhibit apoptosis of colonic epithelial cells: growth factors protect against c-myc-independent apoptosis

Abstract

Summary In this study we sought factors that determine the survival of human colonic epithelial cells. Normal colonic epithelial cells are dependent on cell-cell contacts and survival factors for the inhibition of apoptosis whereas, during colorectal tumorigenesis, cells develop mechanisms to evade these controls. The ability to survive loss of cell-cell contacts and/or growth factor deprivation is a marker of tumour progression. Many adenoma (premaligant) cultures survive only if cell-cell contacts are maintained in vitro and die by apoptosis if trypsinized to single cells. This also occurs in adenomas derived from familial adenomatous polyposis (FAP) patients, therefore APC mutations do not confer resistance to cell death in response to loss of cell-cell contacts. We show here that if cell-cell contacts are maintained such cells are capable of survival in suspension. Adenoma cells also undergo apoptosis in response to removal of serum and growth factors from the medium. After removal of serum and growth factors c-myc is down-regulated within 2 h. Therefore, the induction of apoptosis is not an inappropriate response of the cells due to a deregulated c-myc gene. The apoptotic response is also p53 independent. Such cultures have been used to determine specific survival factors for colonic epithelial cells. Insulin, the insulin-like growth factors I and 11, hydrocortisone and epidermal growth factor (EGF) protect cells from the induction of apoptosis in the absence of serum over a short-term period of 24 h. This approach may give insight into the factors governing growth and survival of colonic epithelial cells in vivo. This is the first report of specific growth factors protecting against apoptosis in human colonic epithelial cells.

Apoptosis-prone phenotype of human colon carcinoma cells with a high level amplification of the c-myc gene

“…Altogether these observations lead us to consider that the response of colon cancer cells to growthrestrictive conditions might involve a c-myc-dependent, but p53-independent pathway. This would be at variance with the situation described in colon adenoma (premalignant) cells in which the apoptotic response to serum starvation is apparently both c-myc-and p53-independent (Hague et al, 1997).…”

Expression and transcriptional regulation of caspase-14 in simple and complex epithelia

“…It is remarkable that two Of note, caspase-14 overexpression in forced suspension culture was not due to enhanced cell-cell contact as described previously in spheroid cultures. 31,32 This conclusion is based on the fact that in these assays we used a culture medium, which contained only 0.06 mM Ca 2+ . At this Ca 2+ concentration cadherin-based cell-cell interactions cannot be established or maintained.…”

Inhibition of Apoptosis by Amphiregulin via an Insulin-like Growth Factor-1 Receptor-dependent Pathway in Non-small Cell Lung Cancer Cell Lines

“…Several lines of evidence suggest that AR is an autocrine growth factor in human carcinoma cells (44 -51) and tumorigenicity of a human breast epithelial cell line is abolished by treatment with AR antisense (49). A protective role of the EGF-like growth factors against apoptosis has been demonstrated in several non-transformed and tumor cell types (52)(53)(54)(55)(56). Accordingly, anti-apoptotic activity of AR has been suggested by a study in human breast carcinoma cells (48).…”