Identification of proteins involved in neural progenitor cell targeting of gliomas.
BACKGROUND
Glioblastoma are highly aggressive tumors with an average survival time of 12 months with currently available treatment. We have previously shown that specific embryonic neural progenitor cells (NPC) have the potential to target glioma growth in the CNS of rats. The neural progenitor cell treatment can cure approximately 40% of the animals with malignant gliomas with no trace of a tumor burden 6 months after finishing the experiment. Furthermore, the NPCs have been shown to respond to signals from the tumor environment resulting in specific migration towards the tumor. Based on these results we wanted to investigate what factors could influence the growth and progression of gliomas in our rodent model.


METHODS
Using microarrays we screened for candidate genes involved in the functional mechanism of tumor inhibition by comparing glioma cell lines to neural progenitor cells with or without anti-tumor activity. The expression of candidate genes was confirmed at RNA level by quantitative RT-PCR and at the protein level by Western blots and immunocytochemistry. Moreover, we have developed in vitro assays to mimic the antitumor effect seen in vivo.


RESULTS
We identified several targets involved in glioma growth and migration, specifically CXCL1, CD81, TPT1, Gas6 and AXL proteins. We further showed that follistatin secretion from the NPC has the potential to decrease tumor proliferation. In vitro co-cultures of NPC and tumor cells resulted in the inhibition of tumor growth. The addition of antibodies against proteins selected by gene and protein expression analysis either increased or decreased the proliferation rate of the glioma cell lines in vitro.


CONCLUSIONS
These results suggest that these identified factors might be useful starting points for performing future experiments directed towards a potential therapy against malignant gliomas.
Staflin
Karin
K
CNS Gene Therapy Unit, Dept Experimental Medical Science, Lund University, Lund, Sweden. kstaflin@scripps.edu
Zuchner
Thole
T
Honeth
Gabriella
G
Darabi
Anna
A
Lundberg
Cecilia
C
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000378:metabolism* / Q000628:therapy*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D018450:Disease Progression; D005910:Glioma / Q000378:metabolism* / Q000628:therapy*; D007150:Immunohistochemistry / Q000379:methods; D009474:Neurons / Q000166:cytology*; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000166:cytology*; D013997:Time Factors; D016896:Treatment Outcome; D000090324:Tumor Protein, Translationally-Controlled 1
D000970:Antineoplastic Agents; C000715649:Tpt1 protein, rat; D000090324:Tumor Protein, Translationally-Controlled 1