Granulocyte-macrophage colony-stimulating factor stimulates the metastatic properties of lewis lung carcinoma cells through a protein kinase a signal-transduction pathway

✍ Scribed by M. Rita I. Young; Yvonne Lozano; Andelka Djordjevic; Sandeep Devata; John Matthews; Melvin E. Young; Mark A. Wright

• Publisher: John Wiley and Sons
• Year: 1993
• Tongue: French
• Weight: 767 KB
• Volume: 53
• Category: Article
• ISSN: 0020-7136
• DOI: 10.1002/ijc.2910530424

✦ Synopsis

Expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) by metastatic Lewis lung carcinoma cells (LLC-LN7) was previously shown to contribute to the maintenance of phenotypic characteristics associated with an increased capacity t o metastasize. In the present study, pre-incubation of LLC-LN7 cells with neutralizing anti-GM-CSF antibodies diminished the capacity of the tumor cells to form experimental metastases after i.v. inoculation, while pre-incubation with recombinant GM-CSF (rGM-CSF) increased formation of metastases. In the presence of rGM-CSF, the LLC-LN7 cells exhibited an increased capacity to migrate, invade through a reconstituted basement membrane, and adhere to lung tissue. Studies to identify the signal transduction pathway through which GM-CSF enhanced the in vitro metastatic properties of the LLC-LN7 tumor cells implicated protein kinase A (PKA). Signaling through PKA was suggested by the demonstration that the stimulation of tumor-cell motility by GM-CSF was blocked in the presence of the adenylate cyclase inhibitor nicotinic acid, or the PKA inhibitors A3 or KT5720. In addition, the role of PKA as a signaling mechanism for GM-CSF was assessed by using REV-LN7 cells, which are LLC-LN7 cells that have been stably tranrfected with an expression vector encoding a mutant PKA R,. subunit and which, in turn, express a CAMP-resistant PKA. Adherence and invasion by the PKA-defective REV-LN7 cells were not stimulated by rGM-CSF, contrasting with the stimulation observed for wild-type LLC-LN7 cells. These data suggest that rGM-CSF can further enhance the in vitro metastatic characteristics of LLC-LN7 tumor cells and that this is dependent on signal transduction through PKA.