The active migration of
tumor cells, a crucial requirement for
metastasis development and
cancer progression, is regulated by signal substances including
neurotransmitters. We investigated the migration of
tumor cells within a three-dimensional
collagen matrix using time-lapse videomicroscopy and computer-assisted analysis of the migration path.
Tumor cell migration is induced by
norepinephrine,
dopamine and
substance P. We show that this induced migration, using MDA-MB-468 breast and PC-3 prostate
carcinoma cells, can be inhibited by using specific, clinically established receptor antagonists to the beta2-adrenoceptor, the D2 receptor, or the
neurokinin-1 receptor, respectively. All of the investigated
neurotransmitters significantly activated the cyclic
adenosine-monophosphate response element
binding protein (CREB). Furthermore, microarray analysis revealed changes of gene expression toward a highly motile
tumor cell type, including an upregulation of the
alpha2 integrin, which is an essential
adhesion receptor for
collagen in migration. The gene for the
tumor suppressor
gelsolin was downregulated. These 2 critical alterations were confirmed on the
protein level by flow-cytometry and immunoblotting, respectively.
Neurotransmitters thus induce a metastatogenic
tumor cell type by directly regulating gene expression and increased migratory activity, which can be prevented by established
neurotransmitter antagonists.