TRANSFORMING GROWTH-FACTOR-BETA-1 STIMULATES CONTRASTING RESPONSES INMETASTATIC VERSUS PRIMARY MOUSE PROSTATE CANCER-DERIVED CELL-LINES IN-VITRO

Tumor progression to the stage of metastasis may result in part from t he selection of certain primary tumor cell clones which are phenotypic ally competent for survival, invasion, and growth at secondary sites. Selection for traits such as loss of growth inhibitory responses, acqu isition of increased adhesiveness, increased local immunosuppression, and enhanced motility and collagenase activities likely contribute to cancer progression and may be regulated through the action of growth f actors. The transforming growth factor beta (TGF-beta) family of growt h factors has often been associated with these traits and tumor progre ssion; therefore, elimination or subversion of TGF-beta-responsive pat hways should be considered as a mechanistic framework for metastatic e vents. In this report, we have compared growth and extracellular matri x responses to TGF-beta in six metastatic and six primary tumor-derive d cell lines in a mouse model of prostate cancer. We have found that t umor cell lines derived from focal pulmonary metastasis secreted relat ively greater quantities of total TGF-beta s, lost most or all TGF-bet a 1 growth inhibition, but responded to TGF-beta 1 through induction o f the type IV collagenase matrix metalloproteinase-9, whereas cell lin es derived from tumors which proliferated at the primary site retained the growth inhibition but lacked collagenase activity, Synthesis of a nother extracellular matrix protein, plasminogen activator inhibitor 1 , was stimulated by TGF-beta 1 in both primary as well as metastatic t umors, These results suggest that acquisition of differential response s to the TGF-beta family could result in phenotypic traits which facil itate tumor metastasis from certain primary site clones.