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© The Rockefeller University Press, 0022-1007/1997/12/1985/ $5.00
The Journal of Experimental Medicine, Volume 186, Number 12, December 15, 1997 1985-1996

Article

Induction of Apoptosis of Metastatic Mammary Carcinoma Cells In Vivo by Disruption of Tumor Cell Surface CD44 Function

Qin Yu*, Bryan P. Toole{ddagger}, and Ivan Stamenkovic*

From the * Molecular Pathology Unit and MGH Cancer Center, Massachusetts General Hospital, Charlestown Navy Yard, Boston, Massachusetts 02129; and Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115; and {ddagger} Department of Anatomy and Cellular Biology, Tufts University School of Medicine, Boston, Massachusetts 02111

To understand how the hyaluronan receptor CD44 regulates tumor metastasis, the murine mammary carcinoma TA3/St, which constitutively expresses cell surface CD44, was transfected with cDNAs encoding soluble isoforms of CD44 and the transfectants (TA3sCD44) were compared with parental cells (transfected with expression vector only) for growth in vivo and in vitro. Local release of soluble CD44 by the transfectants inhibited the ability of endogenous cell surface CD44 to bind and internalize hyaluronan and to mediate TA3 cell invasion of hyaluronan-producing cell monolayers. Mice intravenously injected with parental TA3/St cells developed massive pulmonary metastases within 21–28 d, whereas animals injected with TA3sCD44 cells developed few or no tumors. Tracing of labeled parental and transfectant tumor cells revealed that both cell types initially adhered to pulmonary endothelium and penetrated the interstitial stroma. However, although parental cells were dividing and forming clusters within lung tissue 48 h following injection, >80% of TA3sCD44 cells underwent apoptosis. Although sCD44 transfectants displayed a marked reduction in their ability to internalize and degrade hyaluronan, they elicited abundant local hyaluronan production within invaded lung tissue, comparable to that induced by parental cells. These observations provide direct evidence that cell surface CD44 function promotes tumor cell survival in invaded tissue and that its suppression can induce apoptosis of the invading tumor cells, possibly as a result of impairing their ability to penetrate the host tissue hyaluronan barrier.

Address correspondence to Ivan Stamenkovic, Molecular Pathology Unit and MGH Cancer Center, Massachusetts General Hospital, 149 13th Street, Charlestown Navy Yard, Boston, MA 02129. Phone: 617-726-5634; FAX: 617-726-5684.

1 Abbreviations used in this paper: bPG, biotinylated proteoglycan; CMFDA, 5-chloromethyl-fluorescein diacetate; ECM, extracellular matrix; FBS, fetal bovine serum; FL-HA, fluorescein-labeled hyaluronan; HA, hyaluronan; ICAM, intracellular adhesion molecule; RT, reverse transcriptase; TUNEL, Tdt-mediated dUTP-biotin nick end labeling.


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