KIT receptor activation by autocrine and paracrine stem cell factor stimulates growth of merkel cell carcinoma in vitro.

The co-expression of KIT receptor and its ligand stem cell factor (SCF) has been reported in biopsy specimens of Merkel cell carcinoma (MCC). However, the functional role of SCF/KIT in the pathogenesis of this aggressive tumor has not been elucidated. The present study reports expression and effects of SCF and KIT in the Merkel cell carcinoma cell line MCC-1 in vitro. SCF and KIT were endogenously co-expressed in MCC-1 cells. Exogenous soluble SCF modulated KIT receptor mRNA and protein expression, stimulated growth of MCC-1 cells, upregulated endogenous activation of KIT, AKT, and of extracellular signal-regulated kinase (ERK) 1/2 signaling pathway. On the contrary, an inhibitory antibody that neutralized the KIT ligand binding site, reduced growth of MCC-1 cells, as did high doses of the KIT kinase inhibitors imatinib and nilotinib. Also, inhibitors of KIT downstream effectors, U0126 that blocks MEK1/2 as well as wortmannin and LY294002 that inhibit phosphatidylinositol 3-kinase-dependent AKT phosphorylation, inhibited the proliferation of MCC-1 cells. These data support the hypothesis that KIT is activatable by paracrine or autocrine tumor cell-derived SCF and stimulates growth of Merkel cell carcinoma in vitro. Blockade of KIT and the downstream signaling cascade at various levels results in inhibition of Merkel cell carcinoma growth in vitro, suggesting targets for therapy of this cancer.