Gene expression profiling of metastatic
brain tumors from primary
lung adenocarcinoma, using a 17k-expression array, revealed that 1561 genes were consistently altered. Further functional classification placed the genes into seven categories: cell cycle and DNA damage repair, apoptosis, signal transduction molecules,
transcription factors, invasion and
metastasis, adhesion, and angiogenesis. Genes involved in apoptosis, such as
caspase 2 (CASP2),
transforming growth factor-beta inducible early gene (TIEG), and neuroprotective
heat shock protein 70 (Hsp70) were underexpressed in metastatic
brain tumors. Alterations in
Rho GTPases (ARHGAP26, ARHGAP1), as well as down-regulation of the metastasis suppressor gene KiSS-1 were noted, which may contribute to
tumor aggression. Overexpression of the invasion-related gene
neurofibromatosis 1 (NF1), and angiogenesis-related genes
vascular endothelial growth factor-B (
VEGF-B) and placental
growth factor (
PGF) was also evidenced. Brain-specific
angiogenesis inhibitors 1 and 3 (BAI1 and BAI3) were underexpressed as well. Examination of cell-adhesion and migration-related genes revealed an increased expression of
integrins and extracellular matrices
collagen and
laminin. The study also showed alterations in p53
protein-associated genes, among these increased gene expression of p53, up-regulation of Reprimo or candidate mediator of the p53-dependent G2-arrest, down-regulation of p53-regulated
apoptosis-inducing protein 1 (p53AIP1), decreased expression of
tumor protein inducible
nuclear protein 1 (p53DINP1), and down-regulation of Mdm4 (MDMX). The results demonstrated that genes involved in adhesion, motility, and angiogenesis were consistently up-regulated in metastatic
brain tumors, while genes involved in apoptosis, neuroprotection, and suppression of angiogenesis were markedly down-regulated, collectively making these
cancer cells prone to
metastasis.