Sier C F, Quax P H, Vloedgraven H J, Verheijen J H, Griffioen G, Ganesh S, Lamers C B, Verspaget H W
Department of Gastroenterology and Hepatology, University Hospital, Leiden, The Netherlands.
Invasion Metastasis. 1993;13(6):277-88.
Human carcinomas of the oesophagus, stomach, colorectum, and their liver metastases were previously shown to have increased levels of the urokinase-type plasminogen activator (u-PA). The proteolytic activity of u-PA on the surface of tumour cells is thought to play a key role in invasion and metastasis of malignancies. Therefore, in this study we quantitatively determined the presence of specific u-PA receptors in human gastrointestinal carcinomas, premalignant colonic adenomas, liver metastases, and adjacent normal tissues. All carcinomas showed a 2- to 13-fold higher level of u-PA receptor than their corresponding normal tissues at both the antigen level (ELISA) and the mRNA level (Northern blotting). Colonic adenomas also showed enhanced levels of the u-PA receptor protein. The state of occupancy of the u-PA receptors was determined using a specific ligand-binding assay in which free u-PA receptors were cross-linked with 125I-u-PA and visualized by autoradiography. Colonic carcinomas and liver metastases contained higher levels of free u-PA receptor compared to their corresponding normal tissues. Acid treatment of the receptors prior to cross-linking did not enhance the u-PA/u-PA receptor complex formation. The free u-PA receptor levels in colonic adenomas and in oesophageal and stomach carcinomas showed less difference compared with their normal reference tissues. The increased presence of specific receptors for u-PA in gastrointestinal carcinomas, particularly primary colonic carcinomas and their metastatic lesions in the liver, emphasizes the involvement of the urokinase pathway of plasminogen activation in gastrointestinal carcinogenesis and renders it a putative target for clinical intervention.
