EXPRESSION OF TYPE-IV COLLAGENASE CORRELATES WITH THE EXPRESSION OF VASCULAR ENDOTHELIAL GROWTH-FACTOR IN PRIMARY NONSMALL CELL LUNG-CANCER

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.