Network of Mediators for Vascular Inflammation and Leakage Is Dysbalanced during Cytoreductive Surgery for Late-Stage Ovarian Cancer

Abstract

Background: Cytoreductive surgery (CS) in late-stage ovarian cancer patients is often challenging due to extensive volume shifts, and high fluid intake may provoke postoperative complications. Expression of vasoactive mediators is altered in cancer patients, which may affect systemic vascular function. We sought to assess how serum levels of vasoactive markers and mediators change during CS in ovarian cancer.

Methods: Following IRB approval and informed consent, pre- and postoperative serum samples were analyzed in 26 late-stage ovarian cancer patients using multiplex protein arrays and ELISA.

Results: The proinflammatory cytokines and chemokines IL-6, IL-8, and CCL2 were significantly elevated after 24 hrs compared to the baseline values, with IL-6 and IL-8 being most prominently increased. While ANGPT1 remained unchanged after surgery, its competitive antagonist ANGPT2 was significantly increased. In contrast, serum levels of the ANGPT receptor TIE2 were decreased to 0.6 of the baseline values. While VEGF-D, E-selectin, P-selectin, ICAM-1, and PECAM-1 remained unchanged, serum activity of both thrombomodulin and syndecan-1 was significantly increased following surgery.

Conclusion: We identified a regulatory network of acute-phase reaction during CS in late-stage ovarian cancer. This suggests that IL-6 exerts positive regulation of other proinflammatory mediators and, by upregulating ANGPT2 and suppressing ANGPT1, induces a serum profile that promotes vascular leakage. This may contribute to the observed hemodynamic alterations during CS procedures.

Figure 1

Dynamics of cytokines and chemokines during CS. Serum was collected prior to cytoreductive surgery (CS) as well as after 24 hrs, and a panel of cytokines and chemokines was measured by multiplex analysis and ELISA. Median with 25^th and 75^th percentiles (boxes) and minimum and maximum (whiskers), n = 26, Wilcoxon signed-rank test.

Figure 2

Dynamics of leakage-related mediators during CS. Serum was collected prior to cytoreductive surgery (CS) as well as after 24 hrs, and a panel of mediators of endothelial leakage was measured by multiplex analysis and ELISA. Median with 25^th and 75^th percentiles (boxes) and minimum and maximum (whiskers), n = 26, Wilcoxon signed-rank test.

Figure 3

Dynamics of endothelial adhesion molecules during CS. Serum was collected prior to cytoreductive surgery (CS) as well as after 24 hrs, and a panel of endothelial adhesion molecules was measured by multiplex analysis. Median with 25^th and 75^th percentiles (boxes) and minimum and maximum (whiskers), n = 26, Wilcoxon signed-rank test.

Figure 4

Dynamics of markers of blood coagulation during CS. Serum was collected prior to cytoreductive surgery (CS) as well as after 24 hrs, and a panel of peptides modulating local blood coagulation was measured by multiplex analysis. Median with 25^th and 75^th percentiles (boxes) and minimum and maximum (whiskers), n = 26, Wilcoxon signed-rank test.

Figure 5

Regulatory network of mediators and markers of vascular inflammation and leakage following CS. The figure shows the interactive association of the analyzed peptides. Proteins being upregulated following cytoreductive surgery (CS) are depicted in red, while those that were downregulated are shown in green. Peptides that are detectable but remained unchanged after 24 hrs are given in light red. Red arrows indicate positive regulation, while green arrows show suppression of expression. The dashed line indicates activation of the TIE2 receptor by its natural ligand ANGPT1.