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Dopamine regulates endothelial progenitor cell mobilization from mouse bone marrow in tumor vascularization
Debanjan Chakroborty, … , Partha Sarathi Dasgupta, Sujit Basu
Debanjan Chakroborty, … , Partha Sarathi Dasgupta, Sujit Basu
Published March 13, 2008
Citation Information: J Clin Invest. 2008;118(4):1380-1389. https://doi.org/10.1172/JCI33125.
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Research Article Oncology

Dopamine regulates endothelial progenitor cell mobilization from mouse bone marrow in tumor vascularization

Abstract

Mobilization of endothelial progenitor cells (EPCs) from the bone marrow and their subsequent participation in neovessel formation are implicated in tumor growth and neovascularization. As the neurotransmitter dopamine (DA) modulates adult endothelial cell function, we hypothesized that DA might have a regulatory role in mobilization of EPCs from the bone marrow niche. We show that there was a significant decrease in bone marrow DA content and an increase in EPC mobilization in tumor-bearing mice associated with tumor neovascularization. DA treatment of tumor-bearing mice inhibited EPC mobilization and tumor growth through its D2 receptors, as DA treatment failed to inhibit EPC mobilization in tumor-bearing mice treated with a specific DA D2 receptor antagonist and in tumor-bearing mice lacking the D2 receptor. In addition, we found that DA, through D2 receptors, exerted its inhibitory effect on EPC mobilization through suppression of VEGFA-induced ERK1/ERK2 phosphorylation and MMP-9 synthesis. These findings reveal a new link between DA and EPC mobilization and suggest a novel use for DA and D2 agents in the treatment of cancer and other diseases involving neovessel formation.

Authors

Debanjan Chakroborty, Uttio Roy Chowdhury, Chandrani Sarkar, Rathindranath Baral, Partha Sarathi Dasgupta, Sujit Basu

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Response to Chakroborty et. al.

Submitter: Rivka Inzelberg | inzelber@post.tau.ac.il

The Sagol Neuroscience Center, Sheba Medical Center

Published May 14, 2008

We have read with interest the article by Chakroborty et al (1), entitled "Dopamine regulates endothelial progenitor cell mobilization from mouse bone marrow in tumor vascularization". The authors found a significant decrease in bone marrow dopamine in tumor-bearing mice and increased mobilization of endothelial progenitor cells (EPC) associated with tumor neo-vascularization. Dopamine treatment, by activating D2 receptors, inhibited EPC mobilization and tumor growth by the suppressing the vascular endothelial growth factor (VEGFA) induced ERK1/ERK2 phosphorylation.

The link between VEGF and dopamine may be potentially important in the development of dopaminergic agents for the treatment of cancer.

The link between dopamine and its potential anti-cancer effect is not fully understood but some insights may be derived from the observation that Parkinson disease (PD) patients show low rates of certain cancers (2, 3). This inverse relationship between PD and some cancers may be possibly related to common PD-related genes, such as parkin and PINK-1 (PTEN-induced kinase 1) that are also tumor suppressor genes(2). A second possible mechanism is autophagy-lysosomal pathway abnormalities which are involved in both diseases(4). A third mechanism could be the inhibitory effect of dopamine on tumor growth as noted by Chakroborty et al.(1). Is it is possible that dopamine and/or dopamine agonists induce VEGF suppression and thus reduce tumor growth rates or consequently lower the risk of cancer in patients with PD? This latter mechanism is supported by the recent observation that dopamine increases the efficacy of anticancer drugs in breast and colon cancer in mice models(5). It is likely that different mechanisms play a role in the relationship between PD and cancer since not all cancers are less frequent in PD patients. Besides melanomas (2, 6), other cancers may occur at higher frequency in certain populations of patients with PD.

Strongosky et al(7) followed a large family with PARK8 parkinsonism (LRRK2, R1441C) and found that four of the 18 members known LRRK2 mutation had colon cancer.

There are at least two pathways involved in cell survival that involve products of genes associated with PD(2): 1. the mitogen-activated protein kinases (MAPK) (Erk1/2) signaling pathway and 2. the PI3K/Akt dependent pathway. The LRRK2 gene encodes a MAPKKK protein(8, 9), but its potential influence in tumor growth remains to be elucidated. Better understanding of the relationship between PD and cancers may provide insights into the treatment of both diseases.

Rivka Inzelberg, MD 1,2 and Joseph Jankovic, MD 3

1 The Sagol Neuroscience Center, Department of Neurology, Sheba Medical Center, Tel Hashomer and 2 Rappaport Faculty of Medicine, Technion, Haifa, Israel 3 Baylor College of Medicine, Department of Neurology, Houston Texas, USA

The authors have no conflict of interest.

Address for correspondence: Rivka Inzelberg, MD, The Sagol Neuroscience Center, Department of Neurology, Sheba Medical Center, Tel Hashomer, 52621, Tel/Fax: +972-3-5304718, e-mail: inzelber@post.tau.ac.il cc to rivka.inzelberg@gmail.com

References

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