Induction of a metastatogenic tumor cell type by neurotransmitters and its pharmacological inhibition by established drugs.
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.
Lang
Kerstin
K
Institute of Immunology, Witten/Herdecke University, Witten, Germany.
Drell
Theodore L
TL
Lindecke
Antje
A
Niggemann
Bernd
B
Kaltschmidt
Christian
C
Zaenker
Kurt S
KS
Entschladen
Frank
F
D001943:Breast Neoplasms / Q000473:pathology*; D002277:Carcinoma / Q000473:pathology*; D002465:Cell Movement; D003094:Collagen; D017362:Cyclic AMP Response Element-Binding Protein / Q000096:biosynthesis* / Q000494:pharmacology; D004298:Dopamine / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008297:Male; D018715:Microscopy, Video; D009362:Neoplasm Metastasis / Q000503:physiopathology*; D009638:Norepinephrine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis; D011471:Prostatic Neoplasms / Q000473:pathology*; D015398:Signal Transduction; D013373:Substance P / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D015854:Up-Regulation
D017362:Cyclic AMP Response Element-Binding Protein; D018492:Dopamine Antagonists; D013373:Substance P; D003094:Collagen; D004298:Dopamine; D009638:Norepinephrine