Abstract
BackgroundThe protease uPA and its inhibitor PAI-1 play major roles in hemostasis and are also involved in cancer progression. This is mainly caused by their ability to degrade extracellular matrix-facilitating tumor cell migration. This study aimed to investigate the impact of uPA/PAI-1 and disseminated cytokeratin-positive cells (dCK+) on the outcome and the existence of synergistic effects.MethodsWe retrospectively analyzed a cohort of 480 breast cancer cases with known uPA/PAI-1 and dCK+ status. uPA/PAI-1 was tested on fresh tumor samples using a commercial ELISA test. Bone marrow aspirates were investigated immunocytochemically for CK18.ResultsDCK+ cells were identified in 23% of cases. uPA positivity was significantly associated with the occurrence of dCK+ cells (P = 0.028). uPA and PAI-1 were significantly associated with outcome in the subgroup of early-stage cases without chemotherapy. DCK+ cells alone were not prognostic. However, we found synergistic effects. In the subgroup of node-negative cases with and without chemotherapy, the prognostic impact of uPA and PAI-1 was enhanced in cases with additional dCK-positivity (triple +). In cases without chemotherapy, triple-positive status was independently prognostic (HR: 9.3 CI: 1.1–75) next to T stage.ConclusionsuPA and PAI-1 seem to influence the metastatic potential of dCK+ cells, which underlines its important role in tumor progression.
Highlights
The protease Urokinase-type plasminogen activator (uPA) and its inhibitor Plasminogen activator inhibitor (PAI)-1 play major roles in hemostasis and are involved in cancer progression
There was a trend toward a higher rate of dCK+ cells with increasing pT-stage (P = 0.100). uPA and PAI-1 levels were significantly associated with grade (P < 0.001 and P < 0.007) and progesterone receptor negativity (P = 0.01 and P = 0.023). uPA showed an association with estrogen receptor negativity (P = 0.04), while PAI-1 showed only a trend in this direction (P = 0.06)
Correlation of proteases and dCK+ cells with survival Complete cohort Analyzing the whole cohort (n = 480), we identified an association between uPA, grading, and dCK+ cells with dCK+ rates of 18.8% vs 27.7% in uPA-negative and -positive cases, respectively (P = 0.028; BHST 0.013)
Summary
The protease uPA and its inhibitor PAI-1 play major roles in hemostasis and are involved in cancer progression This is mainly caused by their ability to degrade extracellular matrix-facilitating tumor cell migration. While testing of circulating tumor cells has not yet been introduced into the clinical routine, many studies have shown its clinical relevance in several cancer entities, including breast cancer In the latter, it was shown to be prognostic and helpful in monitoring the response of adjuvant therapy [8]. Given the function of proteases in cancer, an association between the level of uPA and PAI-1 and the occurrence of disseminated tumor cells could be assumed The aim of this retrospective study was to evaluate the relationship and potential interaction of the biomarkers uPA/PAI and disseminated cytokeratin-positive (dCK+) cells in the bone marrow
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