Dopamine stabilizes tumor blood vessels by up-regulating angiopoietin 1 expression in pericytes and Kruppel-like factor-2 expression in tumor endothelial cells.

Abstract

Impaired blood flow in the tumor vascular bed caused by structurally and functionally abnormal blood vessels not only hinders the delivery of chemotherapeutic agents but also aggravates tumor hypoxia, making the tumor cells further resistant to antineoplastic drugs. Therefore, normalization of tumor blood vessels may be an important approach to increase therapeutic efficacy in the treatment of cancer patients. As blood vessels are supplied by sympathetic nerves containing dopamine (DA), and DA regulates functions of normal blood vessels through its receptors present in these vessels, we investigated the effect of DA on tumor vasculature. Here we report loss of sympathetic innervation and endogenous DA in abnormal and immature tumor blood vessels in malignant colon and prostate tumor tissues. In contrast, exogenous administration of DA normalizes the morphology and improves the functions of these vessels by acting on pericytes and endothelial cells, the two major cellular components of blood vessels. DA acts through its D(2) receptors present in these cells to up-regulate directly the expression of angiopoietin 1 (Ang1) in pericytes and the expression of the zinc finger transcriptional factor, Krüppel-like factor-2 (KLF2) in tumor endothelial cells. Importantly, this vessel stabilization by DA also significantly increases the concentration of anticancer drug in tumor tissues. These results show a relationship between vascular stabilization and a neurotransmitter and indicate that DA or its D(2) receptor-specific agonists can be an option for the treatment of cancer and disorders in which normalization of blood vessels may have therapeutic benefits.

• Authors: Debanjan Chakroborty, Chandrani Sarkar, Hongmei Yu, Jiang Wang, Zhongfa Liu, Partha Sarathi Dasgupta, Sujit Basu
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 108 Issue 51 Pg. 20730-5 (Dec 20 2011) ISSN: 1091-6490 [Electronic] United States
• PMID: 22143796 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Angiopoietin-1
• Antineoplastic Agents
• KLF2 protein, human
• Klf2 protein, mouse
• Kruppel-Like Transcription Factors
• Dopamine

Topics

• Angiopoietin-1 (biosynthesis)
• Animals
• Antineoplastic Agents (therapeutic use)
• Blood Vessels (metabolism)
• Cell Line, Tumor
• Dopamine (metabolism)
• Endothelial Cells (cytology)
• Gene Expression Regulation, Neoplastic
• Humans
• Hypoxia (metabolism)
• Kruppel-Like Transcription Factors (biosynthesis)
• Mice
• Microscopy, Confocal (methods)
• Neovascularization, Pathologic
• Pericytes (metabolism)
• Up-Regulation