Tumor Budding, uPA, and PAI-1 in Colorectal Cancer: Update of a Prospective Study

Abstract

Aims. The prognostic role of the proteases uPA and PAI-1, as well as tumor budding, in colon cancer, has been investigated previously. Methods. We provide 6-year follow-up data and results of the validation set. The initial test set and validation set consisted of 55 colon cancers and 68 colorectal cancers, respectively. Tissue samples were analyzed for uPA and PAI-1 using a commercially available Enzyme-Linked Immunosorbent Assay (ELISA). Tumor budding was analyzed on cytokeratin-stained slides. Survival analyses were performed using cut-offs that were determined previously. Results. uPA was not prognostic for outcome. PAI-1 showed a trend towards reduced cancer specific survival in PAI-1 high-grade cases (68 versus 83 months; P = 0.091). The combination of high-grade PAI-1 and tumor budding was associated with significantly reduced cancer specific survival (60 versus 83 months; P = 0.021). After pooling the data from both sets, multivariate analyses revealed that the factors pN-stage, V-stage, and a combination of tumor budding and PAI-1 were independently prognostic for the association with distant metastases. Conclusions. A synergistic adverse effect of PAI-1 and tumor budding in uni- and multivariable analyses was found. PAI-1 could serve as a target for anticancer therapy.

The Urokinase Plasminogen Activator System in Human Cancers: An Overview of Its Prognostic and Predictive Role

“…In a recent study, the same research group provided a follow-up of colon cancer patients who were analysed in previous study. 112 Their findings confirmed that uPA and PAI-1 were adverse predictive factors in colon cancer. Contrastingly to previous studies, they observed uPA to have lesser prognostic value than PAI-1, which, according to uni-and multivariate analyses, in tandem with tumour budding correlated independently with distant metastases in patients.…”

Compared to preoperative plasma levels post-operative urokinase-type plasminogen activator-1 levels are persistently elevated for 6 weeks after minimally invasive colorectal resection

“…If uPA levels are persistently increased postop, similar to the above-mentioned proteins with long duration plasma elevations, then further evidence will have been found to support the hypothesis that colorectal resection is associated plasma protein changes that are stimulatory to tumor growth. The level of uPA protein and/or mRNA has been noted to be elevated in a significant proportion of breast, ovarian, bladder, gastric, prostate, and CRCs (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23). Further, elevated tumor uPA levels have been associated with a worse outcome or more advanced disease for all of these cancers (13)(14)(15)(16)(17)(18)(21)(22)(23).…”

“…The level of uPA protein and/or mRNA has been noted to be elevated in a significant proportion of breast, ovarian, bladder, gastric, prostate, and CRCs (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23). Further, elevated tumor uPA levels have been associated with a worse outcome or more advanced disease for all of these cancers (13)(14)(15)(16)(17)(18)(21)(22)(23). Also, plasma levels of uPA have been shown to be significantly elevated in patients with ovarian, endometrial, non-small cell lung cancer (NSCLC), gastric, hepatocellular, pancreatic, colorectal, and bladder cancers (24)(25)(26)(27)(28).…”

Role of adipocytokines in endometrial cancer progression

“…PAI-1, a promising prognostic factor involving in selective degradation of extracellular matrix components ( Andreasen et al, 1997 ; Fredstorp-Lidebring et al, 2001 ), has been found to be associated with neovascularization, invasion, and migration in breast ( Schmitt et al, 2010 ), prostate ( Almasi et al, 2011 ), colorectal ( Markl et al, 2017 ), ovarian ( Zhang et al, 2013 ), and endometrial cancers ( Tecimer et al, 2001 ). Women with PAI-1 rs1799889 4G/4G genotype are more likely to be at risk for endometrial cancer and the susceptibility to cancer may be associated with the 4G allele.…”