ctivation of EGFR promotes ACC cell proliferation by inducing VEGF autocrine secretion

Adrenocortical cancer (ACC) is a rare and aggressive malignancy. Currently the main therapeutic option is surgery, but due to difficult and delayed diagnosis and to the onset of metastases, medical therapy is often tried. ACC treatment is mainly represented by Mitotane alone or in association with chemotherapy, with variable results. Understanding the molecular mechanisms that regulate ACC proliferation could be useful to identify new therapeutic options. Aim of our study is to identify growth factors that may regulate ACC proliferation, using two human ACC cell lines, the SW13 and the NCI-H295 cells. Our data show that epidermal growth factor (EGF) and transforming growth factor (TGF)-α enhance SW13 cell proliferation and reduced apoptosis, while had modest effects on NCI-H295 cells. Sunitinib, an EGF receptor (EGFR) inhibitor, and NVP-BEZ235, a PI3K/mTOR inhibitor, reduced cell viability in both cell lines, being counteracted by both EGF and TGF-α in SW13 cells. Since in other settings EGF regulates cell proliferation by inducing VEGF, we investigated VEGF secretion by the two cells lines. EGF and TGF-α enhanced VEGF secretion only in SW13 cells while had no effects on NCI-H295. In addition, a VEGF receptor blocking antibody significantly reduced EGF and TGF-α induced cell proliferation. We investigated in both cell lines the expression of EGFR, which is higher and ubiquitous in SW13 cells, while it is weaker and sparse in NCI-H295 cells, where it is present only on the membrane. These data demonstrate that EGF and TGF-α are important in regulating Sw13 cell proliferation, also by modulating VEGF secretion. In conclusion our data suggest that EGF pathway could represent a new molecular target in drug design for treatment of ACC that display enhanced EGFR expression