Effects of Neurotransmitters on the Chemokinesis and Chemotaxis of MDA-MB-468 Human Breast Carcinoma Cells

Abstract

Most patients suffering from breast carcinoma do not die due to the primary tumor but from the development of metastases. Active migration of cancer cells is a prerequisite for development of these metastases. We used time-lapse videomicroscopy and computer-assisted cell tracking of MDA-MB-468 human breast carcinoma cells, which were incorporated into a three-dimensional collagen matrix, in order to analyze the migratory activity of these cells in response to different neurotransmitters. Our results show that met-enkephalin, substance P, bombesin, dopamine, and norepinephrine have a stimulatory effect on the migration of the breast cancer cells; moreover, these cells show positive chemotaxis towards norepinephrine as was analyzed by the directionality and persistence on a single-cell basis. Gamma-aminobutyric acid (GABA) however has an inhibitory effect. Endorphin and leu-enkephalin, as well as histamin and acetylcholine, had no influence on the migratory activity of the cells. In summary, we provide evidence for a strong regulatory involvement of neurotransmitters in the regulation of breast cancer cell migration, which might provide the basis for the use of the pharmacological agonists and antagonists for the chemopreventive inhibition of metastasis development.

Does Beta-blocker Therapy Improve the Survival of Patients with Metastatic Non-small Cell Lung Cancer?

“…Another explanation for the association of beta-adrenergic signaling with cancer growth may be related to the immune system (Ben-Eliyahu et al, 2000). Norepinephrine and beta-AR signaling have strong stimulating effects on a number of cancer types, including cancers of the colon (Masur et al, 2001;, prostate (Palm et al, 2006), ovary (Sood et al, 2006;Thaker et al, 2006), breast (Drell et al, 2003) and pancreas .…”

“…According to recent studies, beta-adrenergic signaling stimulates cancer growth Cole and Sood, 2012). Preclinical studies have demonstrated that beta-adrenergic receptor (AR) signaling has strong stimulating effects in cancers of the colon (Masur et al, 2001;, prostate (Palm et al, 2006), ovary (Sood et al, 2006;Thaker et al, 2006), breast (Drell et al, 2003) and pancreas . Regarding the impact of beta-blockers (BBs) on cancer survival, a recent study showed that BBs reduce the development of metastasis and recurrence in non-metastatic breast cancer and improve cancer-specific survival (Powe et al, 2010).…”

Neuroendocrine influences on cancer biology

“…There is growing evidence that stress hormones affect tumor cell motility and invasion. Drell and associates showed that multiple neurotransmitters such as substance P, dopamine, and norepinephrine had a stimulatory effect on the migration of breast cancer cells, but only norepinephrine had a chemotactic effect on breast cancer cells [41]. Similarly, other groups have demonstrated that norepinephrine was a potent inducer of colon cancer and prostate cancer cell migration, which could be inhibited by beta-blockers [30,42].…”

“…Substance P is a peptide in the neurokinin family, is located in both the central and peripheral nervous systems, and plays a role in stress reactions, anxiety, and depression [93,94]. Substance P promotes the migration of colon and breast carcinoma cell lines and is a chemoattractant for squamous cell lung cancer [40,41,95].…”

A selective alpha1D-adrenoreceptor antagonist inhibits human prostate cancer cell proliferation and motility “in vitro”

“…Given that active migration and the ability to adhere to host tissues are critical determinants for metastasis development and that norepinephrine is a potent inducer of cancer cell migration [47],…”