THE ROLE OF TROPHIC FACTORS AND AUTOCRINE PARACRINE GROWTH-FACTORS INBRAIN METASTASIS

The brain is a unique microenvironment enclosed by the skull, lacking lymphatic drainage and maintaining a highly regulated vascular transpo rt barrier. To metastasize to the brain malignant tumor cells must att ach to microvessel endothelial cells, respond to brain-derived invasio n factors, invade the blood-brain barrier and respond to survival and growth factors. Trophic factors are important in brain invasion becaus e they can act to stimulate this process. In responsive malignant cell s trophic factors such as neurotrophins can promote invasion by enhanc ing the production of basement membrane-degradative enzymes (such as t ype IV collagenase/gelatinase and heparanase) capable of locally destr oying the basement membrane and the blood-brain barrier. We examined h uman melanoma cell lines that exhibit varying abilities to form brain metastases. These melanoma lines express low-affinity neurotrophin rec eptor p75(NTR) in, relation to their brain-metastatic potentials but t he variants do not express trkA, the gene encoding a high affinity ner ve growth factor (NGF) tyrosine kinase receptor p140(trkA). Melanoma c ells metastatic to brain also respond to paracrine factors made by bra in cells. We have found that a paracrine form of transferrin is import ant in brain metastasis, and brain-metastatic cells respond to low lev els of transferrin and express high levels of transferrin receptors. B rain-metastatic tumor cells can also produce autocrine factors and inh ibitors that influence their growth, invasion and survival in the brai n. We found that brain-metastatic melanoma cells synthesize transcript s for the following autocrine growth factors: TGF beta, bFGF, TGF alph a and IL-1 beta. Synthesis of these factors may influence the producti on of neurotrophins by adjacent brain cells, such as oligodendrocytes and astrocytes. Increased amounts of NGF were found in tumor-adjacent tissues at the invasion front of human melanoma tumors in brain biopsi es. Trophic factors, autocrine growth factors, paracrine growth factor s and other factors may determine whether metastatic cells can success fully invade, colonize and grow in the central nervous system.