COLON GOBLET CELLS LOSE PROLIFERATIVE RESPONSE TO TGF-ALPHA AS THEY DIFFERENTIATE

Two cell line models for colon goblet cells expressed 6- to 14-fold el evated levels of the EGF receptor, 3- to 5-fold levels of TCF alpha an d 11- to 15-fold levels of amphiregulin compared with 2 cell lines whi ch model colon enterocytic differentiation, suggesting a role for the EGF receptor and its ligands in goblet cell growth control. Two HT29 c olon carcinoma sublines were used to model normal goblet cells at diff erent stages of maturation. TGF alpha induced a 2-fold increase in gro wth of the HD8 subline but inhibited the growth of the more differenti ated HD6 subline by 40%. EGF receptors were activated in each line by ligand, but signal transduction varied sharply. Both MAP kinase isofor ms, p44 and p42, were markedly activated in HD8 cells for at least 20 min, while only a marginal activation was seen in HD6 cells. In contra st, the more differentiated HD6 cells showed an increase in 105 kDa MB P kinase activity with EGF treatment, while HD8 cells displayed consti tutively elevated levels of this kinase. Thus, activated EGF receptors initiated different signalling pathways in model cell lines for colon goblet cells at different stages of maturation. TGF alpha protein lev els have been shown by other investigators to be restricted to the top of the cylinder-like colonic crypt, where cells terminally differenti ate and cease division, an unexpected location for an epithelial cell mitogen. Our data with model cell lines imply that normal colon goblet cells lose proliferative response to TGF alpha as they differentiate and the elevated levels of TGF alpha at the top of the colonic crypt i n vivo serve to inhibit goblet cell growth. (C) 1995 Wiley-Liss, Inc.