PROTEIN-KINASE-A REGULATES LEWIS LUNG-CARCINOMA ADHERENCE TO EXTRACELLULAR-MATRIX COMPONENTS AND SPONTANEOUS METASTASIS

Tumor cell adhesion to and migration through the extracellular matrix (ECM) can influence their capacity to disseminate, Since prior studies with Lewis lung carcinoma (LLC) tumors had shown metastatic clones to have more protein kinase A (PKA) activity than nonmetastatic clones, the present study assessed if PKA regulates the interaction between tu mor and the ECM, and how this may be associated with the metastatic ca pacity of the tumor cells, This was accomplished with the use of metas tatic (LLC-LN7) and nonmetastatic (LLC-C8) variants that had been stab ly transfected to overexpress the PKA C-alpha subunit or to have block ed PKA activity, Cells with increased PKA activity were less adherent to vitronectin, laminin, and collagen I, and could more readily migrat e through these ECM components than could transfectants with reduced P KA activity, PKA did not regulate adhesion to or migration through fib ronectin, and did not appear to be associated with changes in expressi on of surface integrins, In addition to modulating tumor adhesion and migration in vitro, PKA activation caused an increased formation of me tastases from s.c. tumors, but did not regulate formation of experimen tal metastases by i.v. injected tumor cells, These results suggest tha t PKA signaling is important for modulating the tumor-ECM interaction and can facilitate tumor transit from the primary tumor site.