Dopamine regulates endothelial progenitor cell mobilization from mouse bone marrow in tumor vascularization
Debanjan Chakroborty, Uttio Roy Chowdhury, Chandrani Sarkar, Rathindranath Baral, Partha Sarathi Dasgupta, Sujit Basu
Debanjan Chakroborty, Uttio Roy Chowdhury, Chandrani Sarkar, Rathindranath Baral, Partha Sarathi Dasgupta, Sujit Basu
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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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Figure 2

DA, by acting through its D2 receptors on EPCs, inhibits tumor-induced mobilization of CEPCs and thereby incorporation into the tumor neovasculature.

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DA, by acting through its D2 receptors on EPCs, inhibits tumor-induced m...
(A and B) Respective isotype controls. (C–I) Flow cytometric analysis of CEPCs in tumor-bearing, tumor-bearing plus DA-treated, and tumor-bearing plus eticlopride (Eti) plus DA-treated mice. CEPCs were detectable in tumor-bearing mice, but were undetectable in the blood of tumor-bearing DA-treated animals. DA had no effect on EPC frequency in tumor-bearing animals treated with the D2 receptor antagonist eticlopride prior to DA administration, indicating that this inhibition was D2 receptor mediated. Figures represent EPC frequency on posttransplantation day 6 in both tumor-bearing and DA-treated, tumor-bearing animals after completion of DA treatment schedule. (I) Absolute number of EPCs. (J and K) Late outgrowth colonies from PBMCs of tumor-bearing normal mice. The endothelial nature of the late outgrowth colony-forming cells was confirmed by the uptake of Dil–Ac-LDL. (L and M) Absent late outgrowth colonies from PBMCs of DA-treated, tumor-bearing normal mice. PBMCs isolated from circulation were plated onto fibronectin-coated dishes, and thereafter, late outgrowth colonies were scored. (N–T) Flow cytometric analysis of circulating EPCs in tumor-bearing D2(–/–) mice showed significantly higher CEPCs when compared with tumor-bearing wild-type mice (P < 0.05). (T) Absolute number of EPCs. DA treatment caused no change in EPC frequency in peripheral blood of tumor-bearing D2(–/–) mice. Scale bars: 50 μm. D2(–/–), D2 receptor–knockout mice. Figures are representative of 4 separate experiments in each group. N, wild type.