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Urokinase type plasminogen activator receptor expression in colorectal neoplasms.

ABSTRACT: BACKGROUND: The urokinase type plasminogen activator receptor (uPAR) may play a critical role in cancer invasion and metastasis. AIMS: To study the involvement of uPAR in colorectal carcinogenesis. METHODS: The cellular expression and localisation of uPAR were investigated in colorectal adenomas and invasive carcinomas by in situ hybridisation, immunohistochemistry, and northern and western blot analyses. RESULTS: uPAR mRNA expression was found mainly in the cytoplasm of dysplastic epithelial cells of 30% of adenomas with mild (19%), moderate (21%), and severe (47%) dysplasia, and in that of carcinomatous cells of 85% of invasive carcinomas: Dukes' stages A (72%), B (93%), and C (91%). Some stromal cells in the adjacent neoplastic epithelium were faintly positive. Immunoreactivity for uPAR was detected in dysplastic epithelial cells of 14% of adenomas and in carcinomatous cells of 49% of invasive carcinomas. uPAR mRNA and protein concentrations were significantly higher in severe than in mild or moderate dysplasia (p<0.05); they were notably higher in Dukes' stage A than in severe dysplasia (p<0.05), and significantly higher in Dukes' stage B than in stage A (p<0.05), but those in stage B were not different from those in stage C or in metastatic colorectal carcinomas of the liver. CONCLUSIONS: Colorectal adenoma uPAR, expressed essentially in dysplastic epithelial cells, was upregulated with increasing severity of atypia, and increased notably during the critical transition from severe dysplasic adenoma to invasive carcinoma. These findings implicate uPAR expression in the invasive and metastatic processes of colorectal cancer.

SUBMITTER: Suzuki S

PROVIDER: S-EPMC1727344 | biostudies-other | 1998 Dec

REPOSITORIES: biostudies-other

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Project description:BACKGROUND AND OBJECTIVES:Black Americans with and without APOL1 kidney disease risk variants face high risk of ESKD. Soluble urokinase-type plasminogen activator receptor (suPAR), a circulating signaling protein and marker of immune activation, constitutes a promising biomarker of CKD-associated risks. We aimed to quantify the associations between serum suPAR concentration and adverse outcomes in Black Americans with and without APOL1 kidney disease risk variants, over and above iodine-125 iothalamate measured GFR and proteinuria. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:Using data from the African-American Study of Kidney Disease and Hypertension, a multicenter clinical trial followed by a cohort phase with a median total follow-up of 9.7 years (interquartile range, 6.5-10.9 years), we examined the associations of suPAR with CKD progression (defined as doubling of serum creatinine or ESKD), ESKD, worsening proteinuria (defined as pre-ESKD doubling of 24-hour urine protein-to-creatinine ratio to ?220 mg/g), and all-cause death. RESULTS:At baseline, the median suPAR was 4462 pg/ml, mean measured GFR was 46 ml/min per 1.73 m2, and median 24-hour urine protein-to-creatinine ratio was 80 mg/g. After controlling for baseline demographics, randomization arm, GFR, proteinuria, APOL1 risk status, and clinical risk factors, there was a 1.26-times higher risk for CKD progression per SD higher baseline log-transformed suPAR (hazard ratio [HR], 1.26; 95% confidence interval [95% CI], 1.11 to 1.43; P<0.001). Higher suPAR was also independently associated with risk of ESKD (HR, 1.36; 95% CI, 1.17 to 1.58; P<0.001) and death (HR, 1.25; 95% CI, 1.08 to 1.45; P=0.003). suPAR was only associated with worsening proteinuria in patients with two APOLI risk alleles (HR, 1.46; 95% CI, 1.08 to 1.99; P=0.02). CONCLUSIONS:Higher suPAR was associated with various adverse outcomes in Black Americans with CKD, with and without APOL1 kidney disease risk variants, independently of proteinuria and GFR.

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Urokinase type plasminogen activator receptor expression in colorectal neoplasms.

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