The mitogen activated protein kinase pathway is required for proliferation but not invasion of human squamous cell carcinoma lines

Growth factor receptors of the tyrosine kinase family regulate proliferation and migration of a variety of cell types. Binding of cognate ligands to these receptors induces multiple cellular responses, including cell cycle progression and motility in culture model systems. In stratified squamous epithelial cells, these receptors include epidermal growth factor receptor (EGFR) that binds both EGF and transforming growth factor alpha (TGF alpha), and c-met whose ligand is hepatocyte growth factor/scatter factor (HGF/SF). Intracellular signaling via these receptors occurs by several mechanisms, including activation of ras, phosphatidylinositol 3-kinase (PI3K), and the mitogen activated protein kinase (MAPK) pathways. Growth factor independence is a characteristic feature of transformation in cancer cells. Previous studies have shown that human squamous cell carcinoma (SCC) lines do not require EGF or TGF alpha for proliferation. We show that while these cell lines expressed EGFR and c-met, stimulation with their respective ligands did not induce proliferation but markedly increased invasion of reconstituted basement membranes. However, EGFR kinase activity was required for proliferation and EGF induced invasion by these cells. Signaling via I as, PI3K, and MAPK was required for proliferation of SCC lines. However, inhibition of, ns and MAPK did not significantly reduce invasion by these cells nor completely block stimulation of this activity by EGF and HGF. We concluded that MAPK signaling was required for proliferation but not invasion of human SCC lines.