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 tumor and the ECM, and how this may be associated with the metastatic capacity of the tumor cells. This was accomplished with the use of metastatic (LLC-LN7) and nonmetastatic (LLC-C8) variants that had been stably transfected to overexpress the PKA Calpha subunit or to have blocked PKA activity. Cells with increased PKA activity were less adherent to vitronectin, laminin, and collagen I, and could more readily migrate through these ECM components than could transfectants with reduced PKA activity. PKA did not regulate adhesion to or migration through fibronectin, and did not appear to be associated with changes in expression of surface integrins. In addition to modulating tumor adhesion and migration in vitro, PKA activation caused an increased formation of metastases from s.c. tumors, but did not regulate formation of experimental metastases by i.v. injected tumor cells. These results suggest that PKA signaling is important for modulating the tumor-ECM interaction and can facilitate tumor transit from the primary tumor site.
Maier
G D
GD
Department of Pathology, Loyola University Stritch School of Medicine, Maywood, IL, USA.
Vellody
K
K
Meisinger
J
J
Djordjevic
A
A
Lozano
Y
Y
Young
M R
MR
D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000378:metabolism* / Q000473:pathology; D003094:Collagen / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism*; D006801:Humans; D016023:Integrins / Q000096:biosynthesis; D007797:Laminin / Q000378:metabolism; D051379:Mice; D009361:Neoplasm Invasiveness; D014162:Transfection; D014407:Tumor Cells, Cultured; D014746:Vimentin / Q000378:metabolism
D016023:Integrins; D007797:Laminin; D014746:Vimentin; D003094:Collagen; D017868:Cyclic AMP-Dependent Protein Kinases