Perturbation of hyaluronan interactions by soluble CD44 inhibits growth ofmurine mammary carcinoma cells in ascites

Hyaluronan accumulates in ascites during intraperitoneal proliferation of T A3/St murine mammary carcinoma cells and at sites of their invasion of the peritoneal wall. To determine whether hyaluronan is functionally involved i n these events, ascites tumor formation was compared in mice injected intra peritoneally with stable transfectants of TA3/St cells that overexpress sol uble CD44, a hyaluronan-binding protein, versus in mice injected with trans fectants expressing mutated soluble CD44 that does not bind hyaluronan, The soluble CD44 transfectants temporarily grew at a reduced rate within the p eritoneal cavity, then went into G(1) arrest and were subsequently cleared from the peritoneum, However, transfectants overexpressing mutant soluble C D44 that does not bind hyaluronan exhibited similar ascites accumulation, g rowth rates, and cell-cycle profiles in vivo to wild-type and vector-transf ected TA3/St cells, all of which continued to grow until the tumors became fatal. The soluble CD44-transfected TA3/St cells also failed to attach to a nd form tumors in the peritoneal wall. When grown in vitro in soft agar, th e soluble CD44 transfectants exhibited a dramatic reduction in colony forma tion compared to wild-type, vector-transfected, and mutant soluble CD44-tra nsfected TA3/St cells. Thus, perturbation of hyaluronan interactions by sol uble CD44 has a direct effect on the growth characteristics of these tumor cells, leading to inhibition of anchorage-independent growth in vitro and a scites growth in vivo.