Dysregulation of the Fas pathway has been implicated in tumor progression; however, how alterations in Fas expression influence metastatic behavior remains unresolved. In this study, we investigated the link between Fas expression and metastatic capacity in two mouse tumor models: one was a sarcoma, which was used to analyze the consequences of loss of Fas function in experimental pulmonary metastases, and the other was a mammary carcinoma, where Fas expression was examined in matched pairs of primary and metastatic cell lines as well as by immunohistochemistry of tissues taken from primary and metastatic sites of spontaneous tumor development. In the sarcoma model, a Fas-resistant/refractory subline was produced in vitro from the parental line by biologic selection against Fas-responsive cells, and it was then compared with the poorly metastatic parental line and to an in vivo-derived subline that was highly metastatic for growth in the lungs. In both tumor models, an inverse correlation was demonstrated between Fas expression and metastatic phenotype. Subsequent studies in the sarcoma model revealed that although the Fas-resistant/refractory subline displayed significant metastatic ability, the parental line from which it was derived exhibited little to no additional metastatic activity if experimentally rendered Fas-resistant by molecular-based strategies or transplanted into a Fas ligand-deficient host. Therefore, these findings suggested that down-regulation of Fas was associated with the metastatic phenotype, but alterations in Fas expression alone were insufficient for acquisition of full metastatic potential. Rather, the ability of such Fas-resistant neoplastic subpopulations to achieve metastatic competence apparently required co-possession of additional malignant characteristics.
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