The glycosphingolipid globotriaosylceramide in the metastatic transformation of colon cancer

The most devastating aspect of cancer is the emergence of metastases. Thus, identification of potentially metastatic cells among a tumor cell population and the underlying molecular changes that switch cells to a metastatic state are among the most important issues in cancer biology. Here we show that, although normal human colonic epithelial cells lack the glycosphingolipid globotriaosylceramide Gb(3) this molecule is highly expressed in metastatic colon cancer. In addition, a subpopulation of cells that are greatly enriched in Gb(3) and have an invasive phenotype was identified in human colon cancer cell lines. In epithelial cells in culture, Gb(3) was necessary and sufficient for cell invasiveness. Transfection of Gb(3) synthase, resulting in Gb(3) expression in noncancerous polarized epithelial cells lacking endogenous Gb(3), induced cell invasiveness. Furthermore, Gb(3) knockdown by small inhibitory RNA in colon cancer epithelial cells inhibited cell invasiveness. Gb(3) is the plasma membrane receptor for Shiga toxin 1. The noncatalytic B subunit of Shiga toxin 1 causes apoptosis of human colon cancer cells expressing Gb(3). Injections of the B subunit of Shiga toxin 1 into HT29 human colon cancer cells engrafted into the flanks of nude mice inhibited tumor growth. These data demonstrate the appearance of a subpopulation of Gb(3) containing epithelial cells in the metastatic stage of human colon cancer and suggest their possible role in colon cancer invasiveness.