Abstract
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Objectives Meningeal metastasis is a fatal complication of breast cancer affecting nearly 5% of breast cancer patients. Seeding of cancer cells in the meninges and their subsequent growth results in severe neurological complications reducing life span to 1 to 4 months. Treatment at present is largely palliative. A better understanding of the biology of the disease process will enable us to implement novel targeted therapy for these refractory metastases. Models that mimic this disease process are rare. We present a model of meningeal metastases in the mouse where the development of meningeal tumors is studied with molecular imaging over time.
Methods Meningeal metastases were created using the human breast cancer cell line MDA-MB-231 that expresses Rluc. Tumor cells (2x10^4 cells/10µl) were injected into the 4th ventricle of the brain in Balb/C mice using stereotactic coordinates. The development of metastases in the meninges of the brain and spinal cord were studied over time with bioluminescence imaging for Rluc to be confirmed with MRI. The brains were removed and processed for immunohistochemical confirmation of metastases and their markers.
Results Bioluminescence uptake indicative of Rluc expression by the tumor cells was detected in the mice brains as early as 10 days following metastases induction. On histology, the uptake corresponded to tumor cells that were in the 4th ventricle and those that had migrated to the meninges. By day 14 the signal in the brain increased while another was detected in the spine. These signals increased by day 18. The metastases expressed Wnt7, vimentin and TGFβ following immunohistochemical staining. By day 21 the mice had succumbed to the disease.
Conclusions We present a murine model of meningeal metastases studying the disease process with molecular imaging correlated to in vitro data. These features will serve as a bench mark for studying novel treatments for meningeal metastases.
Research Support DOD