Rodent models of brain metastasis in melanoma

Abstract

Metastasis of melanoma to the central nervous system (CNS) remains one of the major barriers to successful treatment of this disease. Available treatment modalities are of limited clinical efficacy. This problem is compounded by the presence of the blood-brain barrier (BBB), an important consideration in the development of new therapeutic agents. Only in animal models can the dual properties of experimental tumours and the BBB be explored in one system. A variety of rodent models have been developed, utilizing both murine and human melanoma cell lines. These models have highlighted the complex biology of cerebral metastasis, involving apparent disease progression through the selection of subclones at each stage, eventually leading to disease in the brain. As demonstrated in a number of animal studies, different subpopulations of metastatic melanoma cells are likely to be responsible for parenchymal and leptomeningeal CNS disease. In addition, these animal systems have been used to demonstrate the potential efficacy of new chemotherapeutic drugs, radiation treatments and immunotherapeutic approaches for the treatment of melanoma brain metastasis. Key biological questions remain to be answered. In particular, the molecular and cellular mechanisms responsible for establishing cerebral melanoma must be clearly delineated. Several molecules, including vascular endothelial growth factor (VEGF) and integrins, appear to play important, but not definitive, roles. Other, as yet undefined, molecules appear to be critical. The identification of these factors in experimental models, with confirmatory studies in humans, will expand our understanding of cerebral melanoma and provide valuable new therapeutic targets for intervention in this difficult clinical problem.

A small molecule cell-impermeant Hsp90 antagonist inhibits tumor cell motility and invasion

“…Metastasis from a primary tumor requires progression through a series of highly complex and interrelated events, including (1) promotion of angiogenesis; (2) invasion into the circulation; (3) detachment and embolization of tumor aggregates; (4) transport through the circulation; (5) adhesion and arrest in capillary beds of specific organs; (6) extravasation and (7) establishment at secondary sites (Cranmer et al, 2005). The mere presence of tumor cells in the blood does not necessarily indicate that metastatic disease will follow, as most blood-born malignant cells die rapidly in the circulation.…”

“…Ex vivo treatment with cell-impermeable Hsp90 inhibitors reduces lung colonization by intravenously administered B16 melanoma To examine whether cell-impermeable Hsp90 inhibitors affect aspects of cancer metastasis in vivo, we used the B16 murine melanoma lung colonization model (Fidler, 1973;Brunson et al, 1978;Cranmer et al, 2005). Since DMAG-N-oxide is structurally unstable in vivo, B16 cells stably expressing the luciferase gene were exposed to either DMAG-N-oxide (1 mM) or Hsp90 antibody (20 mg ml À1 ) ex vivo.…”

Applications of nanotechnology for melanoma treatment, diagnosis, and theranostics

“…In melanoma, the most common metastatic sites are brain, liver, lung, bone, and the gastrointestinal tract. 123 Brain metastasis is one of the major reasons for melanoma-caused deaths because the blood−brain barrier reduces treatment efficacy. An animal model has been established to mimic the metastasis of melanoma to the brain, and nanotechnology has been used to improve the model.…”

“…An animal model has been established to mimic the metastasis of melanoma to the brain, and nanotechnology has been used to improve the model. 123 At present, the model is made by injecting melanoma cells directly into the left cardiac ventricle to bring the cells to brain. 124 The model has been used to study the role of growth factor−induced signaling pathways in metastasis, and treatment efficacy.…”

Endothelial-melanoma cell interactions in the formation of brain metastases

“…RBECs in our culture system maintain the main in vivo characteristics of the brain endothelium, such as expression of von Willebrand factor, presence of a continuous line of tight junctions, high transendothelial electrical resistance (TEER) and low permeability values and high activity of P-glycoprotein. However, the fact that rodents develop in very rare instances spontaneous melanoma brain metastases (Cranmer et al 2005) points towards significant differences between the human and animal disease.…”