The seed and soil hypothesis: vascularisation and brain metastases

The development of a relevant mouse model for the establishment and growth of brain metastases is essential for study of the biology and therapy of brain metastasis. Injection of human tumour cells into the internal carotid artery of syngeneic or nude mice produces experimental metastases in specific regions of the brain; these are not due to patterns of initial cell arrest, motility, or invasiveness, but rather to the ability of metastatic tumour cells to grow. Whether the progressive growth of brain metastases depends on neovascularisation is not clear. Immunohistochemical and morphometric analyses show that the density of blood vessels within experimental metastases in the brains of nude mice, or within brain metastases derived from human lung cancer, is lower than in the adjacent, tumour-free brain parenchyma. However, blood vessels associated with brain metastases are dilated and contain many dividing endothelial cells. Immunohistochemical analysis also reveals that tumour cells located less than 100 mum from a blood vessel are viable, whereas more distant tumour cells undergo apoptosis. The blood-brain barrier is intact in and around experimental brain metastases smaller than 0.25 mm in diameter, but is leaky in larger metastases. Nevertheless, the lesions are resistant to chemotherapeutic drugs. The way in which the brain microenvironment influences the biological behaviour of tumour cells is a subject of intense investigation.