Induction of a metastatogenic tumor cell type by neurotransmitters and its pharmacological inhibition by established drugs

Abstract

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 threedimensional 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 ␤2-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 ␣2 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. © 2004 Wiley-Liss, Inc. Key words: metastasis formation; tumor cell migration; neurotransmitters; signal transduction; gene expressionMost patients suffering from cancer do not die due to the primary tumor, but from distant metastases descending from it. The development of these metastases is a multi-step process for which the metastasizing tumor cells need to acquire the ability of active migration. This migratory activity is not solely an intrinsic property of tumor cells, but a cell function which is regulated by signal substances similar to the regulation of migratory activity in leukocytes. 1 Chemokines are the key regulatory signal substances of the immune system, whereas neurotransmitters are also known to regulate the adhesion, migration, and homing of leukocytes. 2 In addition to their function in the immune system, chemokines have been shown to induce the migration of tumor cells, 2,3 and direct the tumor cells to specific organs. 4 The involvement of psychosocial factors in the incidence and progression of cancer has also been discussed for decades and has been reviewed recently by Heffner et al. 5 In further support of this psycho neuro-oncological link we identified neurotransmitters, which induce the migration of MDA-MB-468 breast carcinoma cells. 6 Norepinephrine was the most potent inducer of migration. This induction of migration is not based on a recruitment of formerly non-migrating cells, but is a very subtle composition of changes of migratory parameters such as of the velocity as well as of the frequency and duration of pauses during migratory activity; morphological changes, e.g., with...

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