Elsevier

The Lancet Oncology

Volume 3, Issue 1, January 2002, Pages 53-57
The Lancet Oncology

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The seed and soil hypothesis: vascularisation and brain metastases

https://doi.org/10.1016/S1470-2045(01)00622-2Get rights and content

Summary

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 μm 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 chemo-therapeutic drugs. The way in which the brain microenvironment influences the biological behaviour of tumour cells is a subject of intense investigation.

Section snippets

Neoplastic angiogenesis

To produce metastases, tumour cells must complete a series of sequential and selective steps.4, 10 Failure to complete even one step eliminates the cells from the process.11 Previous studies have shown that to produce brain metastases, tumour cells must reach the vasculature of the brain, attach to the endothelial cells of the microvasculature, extravasate into the parenchyma, proliferate (in response to growth factors), and induce the formation of new blood vessels.12, 13

The growth and spread

Neovascularisation and vascular remodelling in brain metastases

Since the seminal observation of Weidner,28 many reports have suggested that the mean vessel density (MVD) within or at the periphery of spontaneous and artificially induced tumours in mice and rats, and within clinical specimens of human neoplasms, correlates with the aggressiveness of the disease. However, this generalisation does not extend to experimental brain metastases. In the tumour model we have used, tumour cells injected into the internal carotid artery of nude mice resulted in

Location of dividing tumour cells in relation to the vasculature

The diffusion coefficient of oxygen within tissues is about 150–200 μm.39, 40 Since cell viability depends on oxygen, we wished to find out whether the location of dividing or apoptotic tumour cells within brain metastases was related to distance from the nearest blood vessel. Because the growth of discrete, focal, experimentally induced brain metastases was associated with fewer but larger blood vessels per unit area, we also wanted to know whether the proximity of tumour cells to blood

Location of apoptotic tumour cells in relation to vasculature

To assess the distance of apoptotic cells from the nearest blood vessel, we sequentially labelled sections of tumour tissue for the CD31 antigen, and then used an end-labelling assay (terminal-uridine nick-end labelling, or TUNEL) to detect apoptotic cells.44 The distance of apoptotic cells from the blood vessel was assessed with the EDM.45 Apoptotic cells (TUNEL-positive) in autochthonous human lung-cancer brain metastases (Figure 3b) and KM12C brain metastases (Figure 3d) were mostly located

The blood-brain barrier in brain metastasis

The microvasculature of the brain parenchyma is lined with a continuous, non-fenestrated endothelium with tight junctions and little pinocytic vesicle activity.46, 47 This structure, designated the blood-brain barrier (BBB), limits the entrance of circulating macromolecules into the brain parenchyma. The BBB and the lack of a lymphatic system maintain the brain as an immunologically privileged site48 and protect the brain against the entry of most drugs and invasion by microorganisms.49

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