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Highlights on the molecular signalizations which regulate the specific migration of glioblastoma-initiating cells to the subventricular zones

Nicolas Goffart1*, Emmanuel Di Valentin2, Jérôme Kroonen3, 4, Jessica Nassen1, Alexandre Denne1 and Bernard Rogister1, 5, 6
  • 1 Laboratory of Developmental Neurobiology, GIGA-Neurosciences Research Center, University of Liège, Belgium
  • 2 GIGA-Viral Vector Plateform, University of Liège, Belgium
  • 3 Human Genetics, CHU and University of Liège, Belgium
  • 4 Department of Neurosurgery, Stratenum UMC, Netherlands
  • 5 Department of Neurology, CHU and University of Liège, Belgium
  • 6 GIGA – Development, Stem Cells and Regenerative Medicine, University of Liège, Belgium

Primary brain tumors are considered amongst the most refractory malignancies and their most aggressive form, glioblastoma multiform (GBM, WHO grade IV), is also the most common and lethal subtype (1). Although multimodal therapies including surgery, radiation, and chemotherapy have been developed, the median survival for patients with GBM hardly reaches 12 to 15 months from the time of diagnosis (2). This catastrophic survival rate is mainly the consequence of systematic relapses which unfortunately occur despite classical therapeutic strategies.
In this context, the description by Singh et al. of the existence of glioblastoma-stem cells or initiating cells (GIC), which were shown to be specifically involved in experimental tumorigenesis and could therefore be a possible cause of tumor recurrence, raised great hopes (3). Our lab recently demonstrated that these GIC exhibit a specific tropism to the subventricular zones (SVZ) once grafted into the brain of mice tolerating xenografts (4). As the SVZ is a mitotically active cell layer which retains the ability to produce neurons and glia throughout life, functioning as a source of stem cells in adults (5), we hypothesized that this GIC specific localization could play a role in GBM relapses. The SVZ notably acts as a vascular niche which releases soluble factors essential to promote self-renewal and to inhibit neural stem cells differentiation (6). It has recently been suggested that GIC also need to rely on interactions with a vascular niche to maintain their stem-like properties and their ability to drive tumor growth (7, 8). Moreover, recent findings in our lab have shown that GIC located in the SVZ micro-environment are more resistant to radiotherapy. All together, those data strongly suggest a close relationship between the GIC population and the SVZ which, in this case, could behave as a reservoir of GIC and therefore account for tumor recurrence.
This study is dedicated to bring to light the molecular mechanisms which underline the orientated migration of GIC to the SVZ and, more precisely, questioned the possible role of the CXCL12/CXCR4 pathway in this migratory phenotype. Indeed, a better understanding of these mechanisms could promote the use of new therapies to prevent relapses and therefore increase patients’ survival.
We showed, on one hand, that CXCR4 was expressed on different glioblastoma cells types and, on the other hand, that CXCL12 was secreted by the endothelial cells overlaying the lateral wall of the ventricle (SVZ). Later, in vitro migration bio-assays using recombinant CXCL12 and SVZ conditioned medium (SVZ-CM) showed that two distinct populations of glioblastoma cell lines didn’t behave the same. The U87 cell line migrates dose dependently in response to both stimulations whereas the U373 cell line does not although both cell types express CXCR4. Those results were also observed in vivo. Indeed, after grafting both types of cells in the striatum of immunodeficient mice, only the U87 cells were shown to be able to migrate to the SVZ. Inhibition of the CXCR4 signalization by an antagonist molecule (AMD3100) then revealed a significant decrease but not a complete inhibition of the U87 cells’ migration in response to the SVZ CM. This particular observation showed that CXCL12 and CXCR4 play an important role in the orientated migration of GIC to the SVZ but they might not be the only candidates. Screening for chemokines in the SVZ-CM thereafter revealed the presence of CXCL1, CXCL2, CXCL5, CXCL10, CCL2, CCL5 and CCL9. Time lapse analysis finally displayed that chemokine CCL5 is also able to attract the U87 cell population in vitro. All together these data demonstrate the important role of the CXCL12/CXCR4 signalling pathway and the possible role of chemokine CCL5 in the specific migration of the GIC population to the subventricular zones.

Acknowledgements

This study was supported by grants from the National Fund for Scientific Research (F.N.R.S/F.R.I.A) (Belgium).
The authors are grateful to Mrs. Arlice Marquet for valuable technical support.

References

1. D. N. Louis et al., The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114, 97 (Aug, 2007).
2. F. B. Furnari et al., Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes Dev 21, 2683 (Nov 1, 2007).
3. S. K. Singh et al., Identification of a cancer stem cell in human brain tumors. Cancer Res 63, 5821 (Sep 15, 2003).
4. J. Kroonen et al., Human glioblastoma-initiating cells invade specifically the subventricular zones and olfactory bulbs of mice after striatal injection. Int J Cancer 129, 574 (Aug 1, 2011).
5. C. Lois, A. Alvarez-Buylla, Long-distance neuronal migration in the adult mammalian brain. Science 264, 1145 (May 20, 1994).
6. Q. Shen et al., Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells. Science 304, 1338 (May 28, 2004).
7. C. Calabrese et al., A perivascular niche for brain tumor stem cells. Cancer Cell 11, 69 (Jan, 2007).
8. C. Folkins et al., Anticancer therapies combining antiangiogenic and tumor cell cytotoxic effects reduce the tumor stem-like cell fraction in glioma xenograft tumors. Cancer Res 67, 3560 (Apr 15, 2007).

Keywords: Glioblastoma Multiforme, Cancer-Initiating Cells, Migration, Subventricular zone, Chemokines

Conference: Belgian Brain Council, Liège, Belgium, 27 Oct - 27 Oct, 2012.

Presentation Type: Poster Presentation

Topic: Other basic/clinical neurosciences topic

Citation: Goffart N, Di Valentin E, Kroonen J, Nassen J, Denne A and Rogister B (2012). Highlights on the molecular signalizations which regulate the specific migration of glioblastoma-initiating cells to the subventricular zones. Conference Abstract: Belgian Brain Council. doi: 10.3389/conf.fnhum.2012.210.00116

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Received: 14 Aug 2012; Published Online: 12 Sep 2012.

* Correspondence: Mr. Nicolas Goffart, Laboratory of Developmental Neurobiology, GIGA-Neurosciences Research Center, University of Liège, Liège, Belgium, ngoffart@student.ulg.ac.be