Functional role of neural cell adhesion molecule in tumorigenesis and beta-cell function

Abstract

Cancer metastasis is the main lethal cause for cancer patients today. It has been demonstrated that angiogenesis is crucial for growth of both primary tumors and metastasis. In Rip1Tag2 (RT) mice expression of SV40 large T antigen under the control of the rat insulin 1 promoter results in beta-cell specific tumors in the pancreatic islets of Langerhans. RT tumor progression involves hyperplasia, angiogenesis, adenoma and carcinoma formation, but no metastasis. The angiogenic switch, which occurs between 7-9 weeks of age, is instrumental in the transition from hyperplasia to tumors. The neural cell adhesion molecule (N-CAM) is a member of the immunoglobulin superfamily that mediates Ca2+-independent homophilic and heterophilic cell adhesion. By studying tumor progression in N-CAM-deficient (loss-of-function) Rip1Tag2 (RTNC/KO) mice, we recently showed that 50% of the animals developed metastases mainly to local lymph nodes but also to distant organs. Strikingly, re-expression of N-CAM 120 in beta tumor cells totally prevented metastases, indicating that N-CAM within beta tumor cells limits tumor cell dissemination. Here, we have addressed the underlying mechanism for N-CAM s role in tumor cell metastasis. We showed that RTNC/KO islets/tumors prematurely develop disturbed micro-vessel phenotypes, such as impaired pericyte--endothelial cell interaction, and that this phenotype correlated with increased blood vessel leakiness. Moreover, the continuity between blood filled cavities containing isolated cell clusters and the circulation in RTNC/KO provides a potential metastatic route for tumor cells. To further test the role of N-CAM in regulating the integration of perivascular cells into the vessel wall, we showed that ectopic expression of N-CAM (gain-of-function) in a skin fibrosarcoma (T241) tumor model resulted in improved pericyte recruitment and coverage in a tumor cell-autonomous manner. To test if pericyte dysfunction is causally involved in tumor cell dissemination, we intercrossed RT with a genetic mouse model for defective pericyte recruitment and investment into the micro-vessel wall (pdgf-bret/ret mice). Remarkably, RTpdgf-bret/ret mice developed metastasis into local lymph node and distant organ, providing the first evidence for a causal role of pericyte dysfunction in both haematogenous and lymphatic tumor cell dissemination. We also provide data which suggests that the way N-CAM influences pericyte-endothelial cell interactions is by regulating the perivascular distribution/composition of extracellular matrix components.Insulin is exclusively secreted by beta-cell in islets of Langerhans, loss of N-CAM function in islets led to impaired systemic glucose tolerance and insulin secretion. Our studies showed that exocytosis was significantly reduced in N-CAM-/- mice, and that this observation was associated with an unusually compact submembrane actin network. These results indicate that N-CAM plays a crucial role in insulin secretion by affecting the status of the submembrane actin network.