Selection and altered properties of brain-colonising metastatic melanoma

Abstract

Two of the least understood properties of malignant tumour cells are their abilities to invade surrounding normal tissues and to escape to form secondary tumours (metastases) at near and distant sites^1–3. Distant metastases can arise when invading malignant cells penetrate into and are disseminated in the lymphatics, coelomic cavities or blood circulatory system. The mere presence of tumour cells in the blood does not necessarily indicate that distant metastatic disease will follow⁴, for most blood-borne malignant cells die rapidly in the circulation with few surviving to form secondary tumours^2–5. In various experimental blood-borne metastatic tumour systems the location of gross metastases is nonrandom and does not correlate with the first capillary bed encountered^6–10. This suggests that other factors are involved in tumour cell arrest apart from nonspecific trapping^2,3,9,10. These would include cellular adhesive interactions of tumour cells with themselves^11–13 (homotypic aggregation), heterotypic aggregations with circulating^14–16 and non-circulating^12,17,18 host cells, interactions with blood clotting components^19–21, tumour cell deformability^22,23, release or display of malignant cell hydrolytic enzymes^24,25 and interactions with host immunological defences^{2,16,18,26,27}. Unique tumour cell surface properties probably determine malignant cell arrest and survival at specific sites^{3,12,17,18,28} and this has been demonstrated when enzymatic treatment of malignant tumour cells has modified experimental metastasis^26,29. We report here that variant cell lines of malignant melanoma can be selected in vivo²⁸ for brain-specific colonisation³⁰. These variants have cell surface characteristics that correlate with their brain specificity in vivo.