Background: Platelets migrate from bloodstream into tumor microenvironment and support tumor growth. But the full understanding of trans-endothelial platelet extravasation in cancer remains limited. The complex interactions between blood cells, endothelium and tumor that take place in vivo require dissectible analysis and visualization that animal models don’t always provide. Therefore, a humanized experimental model that predicts tumor-vascular signaling, includes blood constituents, and provides mechanistic insight is required.

Aims: We established an ovarian tumor-vessel-blood-flow integrated in vitro biosystem (OvCa-Chip) and evaluated critical platelet-mediated processes in ovarian cancer. We tested the hypothesis that tumor cells release signals that result in nearby vascular endothelium to lose its barrier integrity, following which platelets extravasate into the tumor. Additionally, platelets interact with tumor Galectin-3 through their GP-VI receptors and this interaction results in tumor proliferation.

Methods: The OvCa-Chip consisted two adjacent microfluidic chambers separated by extracellular matrix. One chamber was lined with ovarian cancer cells and in the second chamber, we cultured primary endothelial cells on all sides thus forming a vessel constituting perfusion of platelet-rich-plasma at physiological flow rates for 5 days. We performed live-cell imaging along with analysis of cytokines in effluents, transcriptomics, cell cycle analysis of tumors and biochemical investigation of surface-receptor protein interactions.

Results: OvCa-Chip revealed key role of tumor-shed cytokines in activation of vascular Src/FAK/Akt signaling, that eventually downregulated transcription-factor VE-PTP and inhibited formation of VE cadherin-βcatenin complex, crucial for endothelial barriers. Platelets transmigrated into tumors via communication with endothelial Tie-2, Pyk-1 and Rac-1 and post extravasation, interacted with tumor Galectin-3 via GPVI that triggered secretion of tumor growth factors and metastasis. Correspondingly, atorvastatin treatment and inhibition of Galectin3-GP-VI interaction resulted in reduced platelet extravasation and tumor growth.

Conclusions: Subsequent confirmation of these data with cancer patient biopsies altogether established OvCa-Chip as a platform to model platelet & vascular function in cancer and new therapeutics.

[OvCa-Chip: A new experimental model to investigate platelet and vascular function in cancer]

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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/ovca-chip-a-new-organ-on-a-chip-experimental-model-to-dissect-platelet-vascular-dysfunction-in-ovarian-cancer/