Brain fatty acid-binding protein and omega-3/omega-6 fatty acids: mechanistic insight into malignant glioma cell migration.

Malignant gliomas (MG) are highly infiltrative tumors that consistently recur despite aggressive treatment. Brain fatty acid-binding protein (FABP7), which binds docosahexaenoic acid (DHA) and arachidonic acid (AA), localizes to sites of tumor infiltration and is associated with a poor prognosis in MG. Manipulation of FABP7 expression in MG cell lines affects cell migration, suggesting a role for FABP7 in tumor infiltration and recurrence. Here, we show that DHA inhibits and AA stimulates migration in an FABP7-dependent manner in U87 MG cells. We demonstrate that DHA binds to and sequesters FABP7 to the nucleus, resulting in decreased cell migration. This anti-migratory effect is partially dependent on peroxisome proliferator-activated receptor γ, a DHA-activated transcription factor. Conversely, AA-bound FABP7 stimulates cell migration by activating cyclooxygenase-2 and reducing peroxisome proliferator-activated receptor γ levels. Our data provide mechanistic insight as to why FABP7 is associated with a poor prognosis in MG and suggest that relative levels of DHA and AA in the tumor environment can make a profound impact on tumor growth properties. We propose that FABP7 and its fatty acid ligands may be key therapeutic targets for controlling the dissemination of MG cells within the brain.

Fatty acid binding proteins in brain development and disease.

Long chain polyunsaturated fatty acids (PUFAs) are critical structural components of the brain and essential for normal brain development. The cellular transportation and physiological actions of PUFAs are mediated by fatty acid binding proteins (FABPs) which are encoded by the intracellular lipid-binding protein gene family. Three of the ten mammalian FABPs identified to date (FABP3, FABP5, FABP7) are expressed in the brain. These three FABPs, along with their fatty acid ligands, have distinct and dynamic spatio-temporal expression profiles that correlate with specific developmental stages and processes in the brain. Functional studies have revealed a variety of roles for FABPs in brain development including the generation of neuronal and/or glial cells, differentiation, neuronal cell migration and axis patterning. A number of transcription factors have been shown to be involved in the developmental regulation of FABP gene expression in the brain. Furthermore, FABPs appear to be major downstream effectors of signaling pathways such as Reelin-Dab1/Notch which mediate neuron-glia crosstalk during brain development. As PUFAs and FABPs play critical roles in brain development, considerable effort has been placed in elucidating their function in the pathogenesis and progression of brain cancers and neuropsychiatric disorders.

Expression of AP-2delta in the developing chick retina.

AP-2 is a family of transcription factors that play important roles during embryonic development. Two AP-2 genes, AP-2alpha and AP-2beta, have previously been characterized in chick retina. Here, we demonstrate that a third member of the chicken AP-2 family, AP-2delta, is primarily expressed in the retina and brain, with highest levels at embryonic days 7 to 11. By in situ hybridization and immunohistochemical analysis, we show that AP-2delta RNA and protein are found in a subset of ganglion cells in embryonic chick retina. Co-immunostaining with anti-Brn3a and anti-AP-2delta antibodies indicates that approximately one-third of Brn3a-positive ganglion cells express AP-2delta. AP-2delta RNA but not AP-2delta protein is also found in cells located in the outer half of the inner nuclear layer. The spatial and temporal distribution of AP-2delta protein in the retina suggests a transient role in a subset of late-born ganglion cells likely involving axonal trafficking or pathfinding.

B-FABP-expressing radial glial cells: the malignant glioma cell of origin?

Brain fatty acid-binding protein (B-FABP) is normally expressed in radial glial cells, where it plays a role in the establishment of the radial glial fiber network required for neuronal migration. B-FABP is also expressed in astrocytoma tumors and in some malignant glioma cell lines. To address the role of B-FABP in malignant glioma, we have studied the growth properties of clonal populations of malignant glioma cells modified for B-FABP expression. Here, we demonstrate that expression of B-FABP in B-FABP-negative malignant glioma cells is accompanied by the appearance of radial glial-like properties, such as increased migration and extended bipolar cell processes, as well as reduced transformation. Conversely, B-FABP depletion in B-FABP-positive malignant glioma cells results in decreased migration, reduction in cell processes, and a more transformed phenotype. Moreover, expression of B-FABP in astrocytomas is associated with regions of tumor infiltration and recurrence. Rather than being a direct manifestation of the tumorigenic process, we propose that the ability of high-grade astrocytoma cells to migrate long distances from the primary tumor reflects properties associated with their cell of origin. Thus, targeting B-FABP-expressing cells may make a significant impact on the treatment of these tumors.