We have shown recently that the hyaluronan receptor, CD44, and matrix metalloproteinase 9 (MMP-9) form a complex on the surface of TA/St mouse mammary carcinoma cells that activates latent transforming growth factor-beta (TGF-beta) and is required for tumor invasion. Disruption of the CD44/MMP-9 complex by expression of soluble CD44 results in the loss of tumor invasiveness and abrogates tumor cell survival in host lung parenchyma following intravenous injection into syngeneic mice. To explore the molecular nature of the survival signals derived from the CD44/MMP-9 complex during the development of tumor metastasis, we investigated the possibility that activation of latent TGF-beta by the CD44/MMP-9 complex is responsible for tumor cell survival in host lung parenchyma. TA3 cells overexpressing dominant negative soluble CD44 (TA3sCD44), which compromises native CD44 function and the ability of TA3 cells to develop metastases, were transfected with constitutively active or latent TGF-beta2 and tested for their ability to form tumors in syngeneic mice. Our results demonstrate that expression of the constitutively active, but not the latent, form of TGF-beta2 rescues TA3sCD44 cells from apoptosis during lung colonization. These observations provide evidence that activation of latent TGF-beta constitutes an event downstream of CD44-dependent signals that is required for tumor cell survival and metastatic colony formation. The functional axis composed of CD44, MMP-9 and TGF-beta may therefore play an important role in the metastatic proclivity of selected tumor types.