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 beta-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 beta2-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 beta-blockers for the inhibition of
metastases.