INVOLVEMENT OF NEUROTROPHINS AND GROWTH-FACTORS IN BRAIN METASTASIS FORMATION

The formation of brain metastases is an important clinical end point i n patients with cancer. The brain provides a unique microenvironment e nclosed by the skull, lacking lymphatic drainage and maintaining a hig hly regulated vascular transport barrier. In the brain microcirculatio n, brain-metastatic tumor cells must attach to endothelial cells, resp ond to brain-derived invasion factors, and invade the blood-brain barr ier. Neurotrophins are important brain invasion-stimulating factors in this process, and in responsive tumor cells neurotrophins can promote invasion by enhancing the production of basement-membrane-degradative enzymes (gelatinase and heparanase) capable of locally destroying the blood-brain barrier. We examined human melanoma variant lines that ex press low-affinity p75 neurotrophin receptor in relation to their brai n-metastatic potentials. Expression of p75 in these variants occurs in the absence of expression of trkA, the gene encoding the high-affinit y nerve growth factor (NGF) tyrosine kinase receptor. Brain-metastatic tumor cells can also produce factors and inhibitors that influence th eir growth, invasion and survival in the brain. We found that brain-me tastatic melanoma cells synthesize transcripts for tumor growth factor -beta, basic fibroblast growth factor, tumor growth factor-alpha, and interleukin-1 beta. Synthesis of these factors may influence the produ ction of neurotrophins by adjacent brain tissues. In support of this, we found increased amounts of NGF in tumor-adjacent tissues at the inv asion front of human melanoma tumors in the brain. These and other fac tors may determine whether metastatic cells can successfully invade, c olonize, and grow in the central nervous system.