The development of metastases is a decisive step in the course of a cancer disease. The detection of metastases in cancer patients is correlated with a poor prognosis, and over 90% of all deaths from cancer are not due to the primary tumor, which often can be successfully treated, but are due to the metastases. Tumor cell migration, a prerequisite for metastasis development, is not merely genetically determined, but is distinctly regulated by signal substances of the environment including chemokines and neurotransmitters. We have shown previously that the migration of breast, prostate, and colon carcinoma cells is enhanced by the stress-related neurotransmitter norepinephrine in vitro, and that this effect can be inhibited by the b-blocker propranolol. We now provide for the first time evidence for the in vivo relevance of this neurotransmitter-driven regulation using PC-3 prostate carcinoma cells. The development of lumbar lymph node metastases in athymic BALB/c nude mice increased with the application of norepinephrine via microosmotic pumps, while propranolol inhibited this effect. However, the growth of the primary tumor was not affected by either treatment. Additionally, experiments using human tissue microarrays showed that 70-90 percent of breast, colon, and prostate carcinoma tissues express the relevant b2-adrenoceptor. Thus, our work contributes to the understanding of the basic cellular mechanisms of metastasis development, and furthermore delivers a rationale for the chemopreventive use of clinically established b-blockers for the inhibition of metastases. 1 Their theory is supported by the finding that certain mutations, e.g. mutations of the tumor-suppressor gene MADH4, occur more frequently in metastatic tumors.2 On the other hand, the comparative gene expression profiling of primary breast tumors and distant metastases showed striking similarity, suggesting that the metastatic capability in breast cancer is an inherent feature and is not based on clonal selection.3 Recent research has shown that ligands to serpentine receptors play an important role in the regulation of tumor cell migration. These ligands predominantly consist of 2 groups, the chemokines and the neurotransmitters. 4 Among the chemokines, the stromal cell-derived factor-1 (SDF-1) is best investigated for its role in metastasis development, 5 and in the localization of metastases as shown in mice.6 Within the group of neurotransmitters, norepinephrine is one of the most potent known stimulators for the migration of tumor cells. We have shown previously in this journal and elsewhere that norepinephrine induces migration in breast, colon and prostate carcinoma cells, and that this induction can be inhibited by b2-adrenoceptor blocking drugs in vitro. [7][8][9] In this present study, we address the question whether the previously observed increase of tumor cell migration in response to norepinephrine in vitro corresponds to an in vivo increase of metastasis development in mice, and whether this effect can be inhibited by the chemoprev...
