In non-small cell lung cancer (NSCLC), vasoactive intestinal peptide (VIP)/PACAP and transforming growth factor alpha (TGFalpha)/EGF are autocrine growth factors. TGFalpha binds with high affinity to epidermal growth factor (EGF) receptors causing tyrosine kinase activity, whereas VIP and pituitary adenylate cyclase activating peptide (PACAP) bind to G-protein coupled receptors, stimulating adenylate cyclase. In the present period, PACAP receptors were characterized in NSCLC cells. 125-I-PACAP bound with high affinity to NCI-H838 cells. Specific 125-I-PACAP binding was inhibited with high affinity by PACAP, moderate affinity by PACAP(6-38) and low affinity by VIP. PACAP elevated cAMP and increased cytosolic Ca2+ whereas PACAP(6-38) was an antagonist and inhibited the increase caused by PACAP. PACAP stimulated NSCLC growth, whereas PACAP(6-38) inhibited NSCLC growth in vitro and in vivo. These data suggest that PACAP(6-38) may be a therapeutic agent for NSCLC. Sigma opiates receptors were detected in high density in NSCLC and breast cancer cells. 125-I-PAB binding was inhibited with high affinity by PAB, moderate affinity by pentazocine and ditolyguanidine and low affinity by haloperidol. Using nude mice bearing NSCLC xenografts, 125-I-PAB localized to tumors as opposed to normal organs. These data suggest that sigma receptors may be used for early detection of epithelial cancers. VIP may be an autocrine growth factor for breast cancer. Breast cancer cells make and secrete VIP. VIP binds with high affinity to breast cancer cells. Using MCF-7 cells, 125-I-VIP binding is inhibited with high affinity by VIP or PACAP and moderate affinity by VIP hybrid. VIP elevates the cAMP and the increase in cAMP caused by VIP is inhibited by VIP hybrid. Also, VIP hybrid inhibits breast cancer growth in vitro and in vivo. These data indicate that VIP hybrid is an antagonist for breast cancer VIP receptors. In the upcoming year, animal models of epithelial cell carcinogenesis will be established using transgenic mice overexpressing TGFalpha.