Intermediate filament (IF)
proteins are cytoplasmic and nuclear
cytoskeletal proteins. Of the ~70 IF
proteins, nearly 12 are found in the nervous system, where their expression is largely cell-type specific. Astrocytes express
glial fibrillary acidic protein (GFAP), whereas different neuron types contain
neurofilament proteins, α-internexin, or
peripherin. These
proteins are often downregulated in
brain cancer. In addition,
brain cancer cells may also contain
vimentin,
nestin, and
synemin, which are the IF
proteins found in neural progenitor cells. In different
brain tumor types, the expression of
nestin,
vimentin, and α-internexin appears to correlate with the clinical outcome. Experimental investigations have also demonstrated that IF
proteins have distinct roles in specific
brain tumor cell behaviors:
nestin, for instance, is important for the proliferation of
glioma cells, whereas
synemin also affect their mobility. The mechanisms responsible for these effects involve the interaction of IF
proteins with specific signaling pathways.
Synemin, for instance, positively regulates
glioma cell proliferation by antagonizing
protein phosphatase 2A. Further evidence for the potential of IF
proteins as therapeutic targets derives from animal models showing the influence of IF
proteins on
tumor growth.
Nestin downregulation, for instance, dramatically reduced intracerebral
glioma growth. Selective targeted
therapies of IFs to date primarily include gene therapy approaches using
nestin or GFAP gene promoters to drive transgene expression into
glioma cells. Although attempts to identify small molecules specifically antagonizing IF
proteins have been unsuccessful to date, it is anticipated that the identification of such compounds will be instrumental in expanding therapeutic approaches for
brain tumors.