INCREASED UROKINASE RECEPTOR LEVELS IN HUMAN GASTROINTESTINAL NEOPLASIA AND RELATED LIVER METASTASES

Human carcinomas of the oesophagus, stomach, colorectum, and their liv er metastases were previously shown to have increased levels of the ur okinase-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 q uantitatively determined the presence of specific u-PA receptors in hu man 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 (Norther n blotting). Colonic adenomas also showed enhanced levels of the u-PA receptor protein. The state of occupancy of the u-PA receptors was det ermined using a specific ligand-binding assay in which free u-PA recep tors were cross-linked with I-125-u-PA and visualized by autoradiograp hy. Colonic carcinomas and liver metastases contained higher levels of free u-PA receptor compared to their corresponding normal tissues. Ac id treatment of the receptors prior to cross-linking did not enhance t he 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 incr eased presence of specific receptors for u-PA in gastrointestinal carc inomas, particularly primary colonic carcinomas and their metastatic l esions in the liver, emphasizes the involvement of the urokinase pathw ay of plasminogen activation in gastrointestinal carcinogenesis and re nders it a putative target for clinical intervention.