Patients diagnosed with malignant glioma tumours have median survivals of 1.6 yrs and 5 months, respectively, highlighting the deadly nature of this disease. Despite aggressive multimodal treatment, patients with malignant glioma often present with secondary brain tumours at sites distal to the primary tumour mass. These secondary tumours are a consequence of renegade neoplastic cells that infiltrate the surrounding normal brain, a hallmark feature of malignant glioma. Brain fatty acid-binding protein (FABP7), which binds omega-3 docosahexaenoic acid (DHA) and omega-6 arachidonic acid (AA), is overexpressed and associated with a poor prognosis in patients with malignant glioma compared with normal brain. These data suggest that FABP7 plays an important role in gliomagenesis; however, the mechanism(s) underlying a role for FABP7 in malignant glioma has, until now, been unexplored.
Here, we demonstrate that expression of FABP7 in malignant glioma cells is accompanied by increased cell migration. Consistent with our in vitro results, we show that expression of FABP7 in astrocytoma tumours is associated with sites of tumour infiltration and tumour recurrence. Furthermore, we demonstrate that the fatty-acid ligands of FABP7 affect cell migration in an FABP7-dependent manner. More specifically, DHA inhibits migration, whereas AA stimulates cell migration. Finally, we reveal that uptake and incorporation of DHA and AA in the phospholipids of malignant glioma cells is enhanced by FABP7 expression, suggesting a mechanism by which DHA and AA may affect cell migration by altering signal transduction at the cell membrane.
We propose that the inherent ability of malignant glioma cells to express the radial glial marker FABP7 underlies their infiltrative capacity, allowing tumour cells to migrate long distances from the main tumour mass. We propose a model whereby FABP7 expression and relative levels of DHA and AA determine tumour infiltrative potential. Our findings provide insight into the role of FABP7 and its fatty acid ligands in controlling the migration of malignant glioma cells and point to the potential use of DHA as a natural anti-infiltrative agent in the treatment of malignant glioma. We believe that targeting FABP7-expressing cells may make a significant impact on the treatment of high grade astrocytomas. / Experimental Oncology
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:AEU.10048/1336 |
| Date | 11 1900 |
| Creators | Mita, Raja |
| Contributors | Godbout, Roseline (Oncology), Field, Catherine (Agriculture Food and Nutrition Sciences), Turner, Joan (Oncology), Shaw, Andrew (Oncology), Baracos, Vickie (Oncology), Spener, Friedrich (Molecular Biology and Biochemistry) |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | 3845145 bytes, application/pdf |
| Relation | Mita, Raja (2007). http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1993858/pdf/neo0909_0734.pdf |
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