THE CHEMOPREVENTION OF CANCER BY DIETARY CAROTENOIDS - STUDIES IN MOUSE AND HUMAN-CELLS

Dietary carotenoids, particularly beta-carotene, have in many epidemiologic studies been associated with a decreased risk of cancer. Experimental studies have been inhibited by difficulties in delivering these molecules to target cells. A novel delivery system has been developed in the mouse 10T1/2 cell line. With these cells several carotenoids of dietary and commercial interest have been shown capable of inhibiting carcinogen-induced neoplastic transformation. Their action appears qualitatively similar to the previously documented action of retinoids (vitamin A derivatives) in this cell system, in that inhibition occurs in the post-initiation phase of carcinogenesis, but higher concentrations (10-1000 fold) are required. Both types of compound were found to strongly upregulate gap junctional intercellular communication (GJC) and these activities were statistically correlated. Up-regulation of gap junctional intercellular communication was caused by the increased expression of connexin 43 (Cx43) at the message and protein level. Cx43 is one member of a family of gap junctional structural proteins. While protection from carcinogen-induced neoplastic transformation cannot be directly studied in human cells, we have shown that Cx43 expression is also up-regulated in human fibroblasts, suggesting that carotenoids have chemopreventive action in humans. We have proposed that increased junctional communication is mechanistically linked to inhibition of transformation in 10T1/2 cells. In this model, the gap junction serves as a conduit for growth regulatory signals from normal to carcinogen-initiated cells, thereby suppressing their transformation.