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The migration of tumor cells is a prerequiste for invasion and metastasis development. The most prominent inducers of tumor cell migration are the ligands to seven-helices receptors, namely the chemokines and the neurotransmitters, whereas the chemokines are much better investigated than the neurotransmitters. We have thus focussed on the role of neurotransmitters in metastasis development. We have shown that cancer cells derived from different origins (breast, colon, prostate) are susceptible for the initiation of migration and chemotaxis by several neurotransmitters in vitro. This neurotransmitter-induced migratory behaviour can be blocked effectively by established pharmacological receptor antagonists. We have therefore proven in BALB/c nude mice that the neurotransmitter norepinephrine enhances the metastasis development of PC-3 prostate carcinoma cells, which can also be inhibited by the application of beta-blockers. It is hypothesized that the neurotransmitters can be released by nerve cells which reside directly in the tumors. We have shown the presence of nerve cell markers in prostate, colon and breast carcinoma by tissue microarrays, and the release of neurotrophins by cell lines originated from accordant tumors. In clinical settings the presence of such nerve cell markers is correlated to a poorer outcome for the patients. Moreover, tumor cells are able to release neurotrophins, which differentiate nervous precursor cells or provoke the ingrowth of axons from nerve cells into the tumor, a process we have termed neoneurogenesis according to neoangiogenesis. These nerve cells then release neurotransmitters which initiate tumor cell migration. We herewith provide a line of evidence for this interplay of the neuro-endocrine system with the tumor-enviroment and show a possible way of interfering this kind of metastatic cascade. This work was supported by grants from the German Cancer Aid (Deutsche Krebshilfe, Bonn, Germany) and the Fritz Bender-Foundation (Munich, Germany). References: Palm D, Lang K, Niggemann B, Drell TL, Masur K, Zaenker KS, Entschladen F. 2006. The norepinephrine-driven metastasis development of PC-3 prostate carcinoma cells in BALB/C nude mice is inhibited by beta-blockers. Int J Cancer, accepted. Entschladen F, Drell TL, Lang K, Joseph J, Zaenker KS. 2004. Tumour cell migration, invasion and metastasis: navigation by neurotransmitters. Lancet Oncol, 5: 254.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]