CELL-CELL CONTACT AND SPECIFIC CYTOKINES INHIBIT APOPTOSIS OF COLONICEPITHELIAL-CELLS - GROWTH-FACTORS PROTECT AGAINST C-MYC-INDEPENDENT APOPTOSIS

In this study we sought factors that determine the survival of human c olonic epithelial cells. Normal colonic epithelial cells are dependent on cell-cell contacts and survival factors for the inhibition of apop tosis whereas, during colorectal tumorigenesis, cells develop mechanis ms to evade these controls. The ability to survive loss of cell-cell c ontacts and/or growth factor deprivation is a marker of tumour progres sion. Many adenoma (premaligant) cultures survive only if cell-cell co ntacts are maintained in vitro and die by apoptosis if trypsinized to single cells. This also occurs in adenomas derived from familial adeno matous polyposis (FAP) patients, therefore APC mutations do not confer resistance to cell death in response to loss of cell-cell contacts. W e show here that if cell-cell contacts are maintained such cells are c apable of survival in suspension. Adenoma cells also undergo apoptosis in response to removal of serum and growth factors from the medium. A fter removal of serum and growth factors c-myc is down-regulated withi n 2 h. Therefore, the induction of apoptosis is not an inappropriate r esponse of the cells due to a deregulated c-myc gene. The apoptotic re sponse is also p53 independent. Such cultures have been used to determ ine specific survival factors for colonic epithelial cells. Insulin, t he insulin-like growth factors I and II, hydrocortisone and epidermal growth factor (EGF) protect cells from the induction of apoptosis in t he absence of serum over a short-term period of 24 h. This approach ma y give insight into the factors governing growth and survival of colon ic epithelial cells in vivo. This is the first report of specific grow th factors protecting against apoptosis in human colonic epithelial ce lls.