Involvement of neurotrophins and growth factors in brain metastasis formation

D. G. Menter, J. L. Herrmann, D. Marchetti, G. L. Nicolson

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

The formation of brain metastases is an important clinical end point in patients with cancer. The brain provides a unique microenvironment enclosed by the skull, lacking lymphatic drainage and maintaining a highly regulated vascular transport barrier. In the brain microcirculation, brain-metastatic tumor cells must attach to endothelial cells, respond to brain-derived invasion factors, and invade the blood-brain barrier. 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 express low-affinity p75 neurotrophin receptor in relation to their brain-metastatic potentials. Expression of p75 in these variants occurs in the absence of expression of trkA, the gene encoding the high-affinity nerve growth factor (NGF) tyrosine kinase receptor. Brain-metastatic tumor cells can also produce factors and inhibitors that influence their growth, invasion and survival in the brain. We found that brain-metastatic melanoma cells synthesize transcripts for tumor growth factor-β, basic fibroblast growth factor, tumor growth factor-α, and interleukin-1β. Synthesis of these factors may influence the production of neurotrophins by adjacent brain tissues. In support of this, we found increased amounts of NGF in tumor-adjacent tissues at the invasion front of human melanoma tumors in the brain. These and other factors may determine whether metastatic cells can successfully invade, colonize, and grow in the central nervous system.

Original languageEnglish (US)
Pages (from-to)372-384
Number of pages13
JournalInvasion and Metastasis
Volume14
Issue number1-6
StatePublished - 1994

Keywords

  • Brain metastasis
  • Growth factors
  • Melanoma
  • Nerve growth factor
  • Neurotrophins
  • Site-specific metastasis
  • Tumor progression

ASJC Scopus subject areas

  • Cancer Research

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