E. Tolnay et al., EXPRESSION OF TYPE-IV COLLAGENASE CORRELATES WITH THE EXPRESSION OF VASCULAR ENDOTHELIAL GROWTH-FACTOR IN PRIMARY NONSMALL CELL LUNG-CANCER, Journal of cancer research and clinical oncology, 123(11-12), 1997, pp. 652-658
Tumor growth and metastasis are angiogenesis-dependent processes initi
ated and regulated by a number of cytokines. Vascular endothelial grow
th factor (VEGF) is a potent angiogenic protein with a selective mitog
enic effect on vascular endothelial cells, known to be involved in phy
siological (embryogenesis) and pathophysiological (rheumatoid arthriti
s, tumor) angiogenesis. An increased expression of matrix metalloprote
inase type IV collagenase has been reported in invading endothelial ce
lls in vitro and in malignant cells, degrading structures of the basem
ent membranes in various human malignancies. In the present study we i
nvestigated the expression of the genes for type IV collagenase and va
scular endothelial growth factor (VEGF) in 40 cases of primary non-sma
ll-cell lung cancer (NSCLC). Specimens were immunostained by an antibo
dy directed against VEGF and mRNA transcripts of VEGF and type IV coll
agenase were localized by nonradioactive in situ hybridization. VEGF m
RNA was detected in 33 neoplasms, while in 23 cases transcripts of the
type IV collagenase gene were visualized by digoxigenin-labeled cDNA
probes. Transcripts of both mRNAs were detected in malignant cells. Fu
rthermore, anti-VEGF immunostaining was present in newly formed microv
essels close to the atypical cells, and mRNA of type IV collagenase wa
s present in stromal cells adjacent to the tumor. A statistically sign
ificant correlation was found between the expression of type IV collag
enase and VEGF (P = 0.0061), These data suggest a double role for type
IV collagenase in the metastatic process of NSCLC: (1) facilitating t
he invasion of tumor cells by the proteolytic cleavage of the basement
membrane and (2) similarly supporting the endothelial cell invasion e
ssential for tumor angiogenesis. Furthermore, our findings sustain the
hypothesis that metastatic spread and angiogenesis are associated wit
h a clonal expansion of highly angiogenic and invasive tumor cell clon
es.