v-fps protein-tyrosine kinase coordinately enhances the malignancy and growth factor responsiveness of pre-neoplastic lung fibroblasts.
The v-fps oncoprotein was expressed in a pre-neoplastic, growth factor-dependent Chinese hamster lung fibroblast line (CCL39) to study its effect on growth controls and on the induction of malignancy. Two transfectants were characterized which expressed low (39FPS-8) or high (51FPS-6) levels of P130gag-f ps protein-tyrosine kinase activity. 39FPS-8 cells still arrested in quiescence when deprived of growth factors, but developed an increased sensitivity to the mitogenic actions of epidermal growth factor (20-fold) and alpha-thrombin (50-fold), although not to insulin. In contrast, 51FPS-6 cells completely escaped growth controls, divided in serum-free medium, and were insensitive to further growth factor stimulation. Both transfectants produced rapidly growing tumors in nude mice that formed pulmonary metastases from a subcutaneous site, unlike the parental cells which are non-metastatic. 51FPS-6 cells were comparatively more efficient than 39FPS-8 cells in colonizing the lungs after intravenous inoculation. The v-fps tyrosine kinase therefore induces a partial to complete relaxation of growth factor-mediated controls on the CCL39 cell cycle, with the extent of factor independence reflecting the amount of P130gag-f ps synthesized. This reduction in growth factor requirements correlates with the capacity of v-fps to confer the attributes of metastatic tumors upon preneoplastic CCL39 fibroblasts. We speculate that increased sensitivity to growth factor stimulation represents a common mechanism by which tumor cells acquire metastatic properties.
Sadowski
I
I
Division of Molecular and Developmental Biology, Mount Sinai Hospital Research Institute, Toronto, Ontario, Canada.
Pawson
T
T
Lagarde
A
A
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D006224:Cricetinae; D004815:Epidermal Growth Factor / Q000494:pharmacology; D006133:Growth Substances / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D007399:Interphase; D008168:Lung / Q000166:cytology*; D008175:Lung Neoplasms / Q000473:pathology*; D009362:Neoplasm Metastasis; D009856:Oncogene Proteins, Viral / Q000502:physiology*; D011230:Precancerous Conditions / Q000473:pathology*; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D013917:Thrombin / Q000494:pharmacology
D006133:Growth Substances; D007328:Insulin; D009856:Oncogene Proteins, Viral; D004815:Epidermal Growth Factor; D011505:Protein-Tyrosine Kinases; D013917:Thrombin