THE EFFECT OF EXTRACELLULAR CALCIUM ON COLONOCYTES - EVIDENCE FOR DIFFERENTIAL RESPONSIVENESS BASED UPON DEGREE OF CELL-DIFFERENTIATION

Calcium supplementation decreases the incidence of colon cancer in ani mal models and may prevent colon cancer in man. Potential mechanisms i nclude binding of mitogens and direct effects of calcium on colonic ep ithelial cells. In this study, the effects of extracellular calcium on epithelial cell growth and differentiation were studied in three colo n carcinoma and two colonic adenoma cell lines. The characteristics st udied included morphology, cell cycle kinetics, [Ca2+](IC) (intracellu lar calcium concentration), proliferation, and expression of different iation markers such as carcinoembryonic antigen (CEA) and alkaline pho sphatase (AP), Sodium butyrate (NaB) and 1,25-dihydroxyvitamin D-3 wer e used as controls in the latter three assays as these two agents are known differentiating agents, Alteration of [Ca+2](EC) (extracellular calcium concentration) did not affect carcinoembryonic antigen (CEA) o r alkaline phosphatase (AP) expression. NaB enhanced the expression of AP three-fold and CEA five-fold. This effect was augmented by increas ing [Ca2+](EC). The exposure of cells to 1,25-(OH)(2)-Vitamin D-3 incr eased CEA but not AP. [Ca2+](IC) increased in response to 1,25-(OH),vi tamin D-3 and NaB but not with variation in [Ca2+](EC). Increased [Ca2 +](EC) inhibited proliferation of well-differentiated cells, but had n o effect on poorly-differentiated cells. Morphological studies showed that extracellular calcium was necessary for normal cell-cell interact ions. These studies have demonstrated direct effects of calcium on col onic epithelial cells which may contribute to the protective effects o f dietary calcium against colon cancer. Loss of responsiveness to the antiproliferative effects of [Ca2+](EC) with de-differentiation sugges ts that calcium supplementation may be most beneficial prior to the de velopment of neoplastic changes in colonic epithelium.