Abstract
BackgroundHigh-grade gliomas, including glioblastomas (GBMs), are recalcitrant to local therapy in part because of their ability to invade the normal brain parenchyma surrounding these tumors. Animal models capable of recapitulating glioblastoma invasion may help identify mediators of this aggressive phenotype.MethodsPatient-derived glioblastoma lines have been propagated in our laboratories and orthotopically xenografted into the brains of immunocompromized mice. Invasive cells at the tumor periphery were isolated using laser capture microdissection. The mRNA expression profile of these cells was compared to expression at the tumor core, using normal mouse brain to control for host contamination. Galectin-1, a target identified by screening the resulting data, was stably over-expressed in the U87MG cell line. Sub-clones were assayed for attachment, proliferation, migration, invasion, and in vivo tumor phenotype.ResultsExpression microarray data identified galectin-1 as the most potent marker (p-value 4.0 x 10-8) to identify GBM cells between tumor-brain interface as compared to the tumor core. Over-expression of galectin-1 enhanced migration and invasion in vitro. In vivo, tumors expressing high galectin-1 levels showed enhanced invasion and decreased host survival.ConclusionsIn conclusion, cells at the margin of glioblastoma, in comparison to tumor core cells, have enhanced expression of mediators of invasion. Galectin-1 is likely one such mediator. Previous studies, along with the current one, have proven galectin-1 to be important in the migration and invasion of glioblastoma cells, in GBM neoangiogenesis, and also, potentially, in GBM immune privilege. Targeting this molecule may offer clinical improvement to the current standard of glioblastoma therapy, i.e. radiation, temozolomide, anti-angiogenic therapy, and vaccinotherapy.
Highlights
MethodsPatient-derived glioblastoma lines have been propagated in our laboratories and orthotopically xenografted into the brains of immunocompromized mice
High-grade gliomas, including glioblastomas (GBMs), are recalcitrant to local therapy in part because of their ability to invade the normal brain parenchyma surrounding these tumors
Galectin-1 has been identified as a key player in GBM cell migration [15]
Summary
Patient-derived glioblastoma lines have been propagated in our laboratories and orthotopically xenografted into the brains of immunocompromized mice. Tumors expressing high galectin-1 levels showed enhanced invasion and decreased host survival. The use of human tissue to create these xenograft lines was performed in accordance with NIH guidelines and under approval of the Mayo Clinic Institutional Review Board (IRB protocol #802-04). Mouse orthopic xenografts All nude mice (Hsd:Athymic Nude-Foxn1nu- Harlan Laboratories, Indianapolis, IN) used in this project were treated in compliance with NIH and institutional guidelines. These protocols were reviewed and approved by the Mayo Clinic Institutional Animal Care and Use Committee (IACUC protocols #84-05, #A279-09, #A688-11). Glioblastoma cells were injected intracranially into anesthetized mice following our laboratory protocol [25]
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