The role of CXC chemokine ligand (CXCL)12-CXC chemokine receptor (CXCR)4 signalling in the migration of neural stem cells towards a brain tumour

• Published in: Neuropathology and applied neurobiology Vol. 35; no. 6; pp. 579 - 591
• Main Authors: Van Der Meulen, A. A. E., Biber, K., Lukovac, S., Balasubramaniyan, V., Den Dunnen, W. F. A., Boddeke, H. W. G. M., Mooij, J. J. A.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.11.2009; Blackwell
• Subjects: Adult Stem Cells - physiology; Alcoholism and acute alcohol poisoning; Animals; Biological and medical sciences; Brain Neoplasms - physiopathology; brain tumours; Calcium - metabolism; Cell Line, Tumor; Cell Movement - physiology; Chemokine CXCL12 - metabolism; Chemotaxis - physiology; CXCL12; CXCR4; Medical sciences; melanoma; Melanoma - physiopathology; Mice; Mice, Inbred C57BL; migration; Neoplasms, Experimental - physiopathology; neural stem cells; Neurology; Neurons - cytology; Neurons - physiology; Receptors, CXCR - metabolism; Receptors, CXCR4 - metabolism; RNA, Messenger - metabolism; SDF-1a; Signal Transduction; Stem Cell Niche - physiopathology; Toxicology; Nervous system diseases; Ligand; neural stem cells; Stem cell; Migration; SDF-1a; CXCR4; melanoma; Chemokine receptor; Malignant tumor; Intracranial tumor; Cerebral disorder; brain tumours; Cell motility; CXCL12; Central nervous system disease; Malignant melanoma; Brain stem tumor; CXC chemokine; Cancer
• ISSN: 0305-1846; 1365-2990
• DOI: 10.1111/j.1365-2990.2009.01036.x

Aims: It has been shown that neural stem cells (NSCs) migrate towards areas of brain injury or brain tumours and that NSCs have the capacity to track infiltrating tumour cells. The possible mechanism behind the migratory behaviour of NSCs is not yet completely understood. As chemokines are involved in the migration of immune cells in the injured brain, they may also be involved in chemoattraction of NSCs towards a brain tumour. Methods: The expression profile of various chemokine receptors in NSCs, harvested from the subventricular zone of adult mice, was investigated by reverse transcriptase‐ polymerase chain reaction analysis. Furthermore, the functionality of the chemokine receptors was assessed in in vitro chemotaxis assays and calcium signalling experiments. To test the in vivo migration of NSCs, a syngeneic mouse model was developed, whereby a B16F10 melanoma cell line was grafted into one hemisphere and later NSCs were grafted in the contralateral hemisphere. Furthermore, the expression of chemokines in this melanoma cell line was investigated. Results and conclusions: Adult mouse NSCs functionally express various chemokine receptors of which CXC chemokine receptor (CXCR)4 shows the highest mRNA levels and most pronounced functional responses in vitro. CXC chemokine ligand (CXCL)12, the ligand for CXCR4, is expressed by the melanoma cell line. In this mouse model for metastatic brain tumours, it is shown that NSCs express CXCR4 at their cell membranes while they migrate towards the tumour, which produces CXCL12. It is therefore suggested that the CXCR4/CXCL12 pathway plays a role in the mechanism underlying tumour‐mediated attraction of NSCs.