Increased urokinase receptor levels in human gastrointestinal neoplasia and related liver metastases.

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.