Abstract C45: Somatostatin receptor activation by agonist-like antibodies can reverse neuroendocrine tumor BON cell dedifferentiation and increase cell death

Abstract

Abstract The somatostatin receptors (SSTR) are effective therapeutic targets for treating neuroendocrine tumors, primarily achieved through the inhibition of both cellular proliferation and hormone secretion. SSTR are comprised of five major subtypes, namely subtypes 1, 2 (A and B), 3, 4 and 5. The somatostatin signaling also works as a determinant in the TGF-β dependent neuroendocrine-mesenchymal transition (NMT) process. NMT is similar to the epithelial-mesenchymal transition (EMT), but has the opposite cellular differentiation response to TGF-β. For instance, TGF-β promotes cell dedifferentiation in EMT but promotes cell differentiation in NMT. The process of EMT is a critical morphogenic event during the progression of epithelial tumors. Recently, in epithelial tumors, the micro RNA 200c (miR-200c) has been found to negatively regulate E-cadherin's transcriptional repressor ZEB1 and capable of keeping the EMT invasiveness in check. In our study, the miR-200c repressor (Oligoengine Inc. designed by Todd Hauser) has been successful in up-regulating ZEB1 and ultimately driving the neuroendocrine tumor BON cells into the dedifferentiated mesenchymal state. The miR-200c repressor induces changes in the tumor metastasis markers, such as the ZEB1 increase, E-cadherin decrease, and ultimately with both Vimentin and Twist increases. Our anti-SSTR antibodies raised against receptor's ectodomain region (anti-SSTR ECL2 antibodies) were able to reverse the BON cell from its mesenchymal state back to the differentiated neuroendocrine state. Our results suggest that similar to EMT, both miR-200c and ZEB1 are also involved in the NMT dedifferentiation programming. In summary, we conclude that miR-200c/ZEB1 signaling can be regulated by the SSTR activation. This is evident because anti-SSTR agonist-like SSTR2, 3 and 5 antibodies are capable of overcoming neuroendocrine tumor's miR-200c commitment to metastasis. Furthermore, we also found that these anti-SSTR antibodies can sensitize tumor cells to death. Citation Information: Cancer Res 2009;69(23 Suppl):C45.