PB1413 - Multifaceted antimetastatic mechanisms of a natural low-anticoagulant heparin

Background: Metastasis lacks targeted therapeutic interventions. While heparin effectively treats cancer-associated thrombosis and improves prognosis, its potent anticoagulant properties hinder its use as an anticancer agent. In our recent study, we introduced a naturally occurring low-anticoagulant heparin derived from bovine mucosa (LA-hep), demonstrating potent antimetastatic effects, particularly in disrupting interactions between tumor cells and platelets through P-selectin blocking. Notably, we observed a significant attenuation of metastatic foci in P-selectin-depleted mice, indicating an additional effect unrelated to microemboli formation. Inspired by these findings, we explored the heparin's impact on tumor cell interactions with the endothelium, a crucial event in the metastatic cascade occurring subsequent to platelet-tumor cell interactions.

Aims: Our study aims to elucidate the multifaceted antimetastatic mechanisms of this low-anticoagulant heparin, focusing on its anti-adhesive properties related to the endothelium.

Methods: The ability of LA-Hep to inhibit the adhesion of tumor cells to the endothelium was assessed through an assay where melanoma MV3 cells or lung carcinoma A549 cells, labeled with the red fluorochrome PKH26, were added onto a confluent monolayer of HUVECs, in the absence and presence of LA-hep. Additionally, we evaluated the effect of LA-hep on the adhesion of MV3 melanoma cells to immobilized V-CAM1.

Results: The results demonstrated a noteworthy reduction in the adhesion of MV3 cells to HUVECS. Extending our investigation to A549 cells confirmed the broad applicability of the heparin's antimetastatic effects. Furthermore, we explored the inhibition of melanoma cell adhesion to immobilized VCAM-1, a crucial adhesion molecule on activated endothelium, revealing a significant inhibitory effect.

Conclusion(s): Our study provides comprehensive insights into the mechanisms underlying the antimetastatic effects of LA-hep. By disrupting multiple stages of the metastatic cascade, from platelet-tumor cell interactions to tumor cell adherence to the endothelium, this heparin emerges as a promising candidate for further development as an anticancer therapeutic agent