CD44 Is a Metastasis Suppressor Gene for Prostatic Cancer Located on Human Chromosome 11p13

Abstract

We have used microcell fusion-mediated chromosomal transfer to introduce normal human chromosomes into highly metastatic rodent prostatic cancer cells to map the location of a metastasis suppressor gene(s). Using this approach, several chromosomal regions have been identified that harbor such metastatic suppressor genes, including human chromosome 11 between p11.2–13 (T. Ichikawa et al., Cancer Res., 52: 3486–3490, 1992, 54: 2299–2302, 1994; N. Nihei et al., Genes Chromosomes & Cancer, 14: 112–119, 1995; C. W. Rinker-Schaeffer et al., Cancer Res., 54: 6249–6256, 1994). Using positional cloning, a metastatic suppressor gene, termed KAI1, was identified, which is located at human chromosome 11p11.2 (5). Overexpression of KAI1 results in metastasis suppression in certain highly metastatic Dunning R-3327 rat prostatic cancer sublines, such as AT6.1, without metastasis suppression in other highly metastatic sublines, such as A%3.1. This suggests that an additional metastasis suppressor gene is located within the human chromosome 11p11.2–13 region. The CD44 gene is located on human chromosome 11p13 and encodes an integral membrane glycoprotein that participates in specific cell-cell and cell-extracellular matrix interactions. Down-regulation of CD44 expression both at the mRNA and protein levels correlates with metastatic potential within the Dunning system of rat prostatic cancer sublines. Transfection-induced enhanced expression of the M_r 85,000 standard form of CD44 in the highly metastatic AT3.1 rat prostatic cells greatly suppresses their metastatic ability to the lungs without suppression of their in vivo growth rate or tumorigenicity. These results suggest that CD44 is a metastasis suppressor for prostatic cancer and that decreased expression of the standard form of CD44 is involved in the progression of prostatic cancer to a metastatic state.