Metastatic cancer cell attachment to endothelium is promoted by endothelial glycocalyx sialic acid degradation

Abstract

While it is known that cancer cell interactions with vascular endothelial cells (ECs) drive metastatic cancer cell extravasation from blood vessels into secondary tumor sites, the mechanisms of action are still poorly understood. Here, we tested the hypothesis that neuraminidase‐induced degradation of EC surface glycocalyx (GCX), particularly the sialic acid (SA) residue components of the GCX, will substantially increase metastatic cancer cell attachment to ECs. To our knowledge, our study is the first to isolate the role of GCX SA residues in cancer cell attachment to the endothelium, which were found to be differentially affected by the presence of neuraminidase and to indeed regulate metastatic cancer cell homing to ECs. We hope that this work will eventually translate to identification of EC GCX‐based cancer markers that can be therapeutically targeted to hinder the progression of metastasis.

Endothelial Glycocalyx-Mediated Intercellular Interactions: Mechanisms and Implications for Atherosclerosis and Cancer Metastasis

“…To our knowledge, our study is the first to isolate the role of GCX SA residues in cancer cell attachment to the endothelium, which were found to be differentially affected by the presence of neuraminidase, in correlation to variations in metastatic cancer cell homing to ECs. Reported in a recent paper, 71 this study provides an improved understanding of the effect of GCX degradation on the attachment of cancer cells to the endothelium, which is very much needed for creating therapeutic measures that will combat the spread of cancer via strengthening of GCX against GAG degrading cytokines released by cancer tumors.…”

“…We recently showed that both enzymatic and flow induced degradation of the GCX, which exposes the adhesion molecules, significantly increases EC adhesiveness to circulating cells. 70,71…”

“…We also investigated the importance of GCX in concealing or uncovering receptors that mediate cancer-endothelial cell interactions. 71 While it is known that cancer cell interactions with vascular ECs drive metastatic cancer cell extravasation from blood vessels into secondary tumor sites, the mechanisms of action are still poorly understood. This investigation added fundamental information to the body of knowledge about the mechanisms underlying cancer-EC interactions.…”

Flow‐regulated endothelial glycocalyx determines metastatic cancer cell activity

“…To our knowledge, studies investigating the activities of CTCs in relation to the degradation of the GCX as a whole, or in relation to the degradation of its SA sub‐component, are limited. Recently, we performed a study in which ECs were treated with the GCX degradative enzyme, neuraminidase (Neur), to cleave various SA residues of the GCX and to determine their correlation to enhance cancer attachment to the endothelium . We concluded that the ∝‐2,6‐linked residue of SA is the first to be degraded in the presence of Neur, resulting in the vulnerability of the GCX layer, which is sufficient to initiate CTC attachment to the endothelium .…”

“…Recently, we performed a study in which ECs were treated with the GCX degradative enzyme, neuraminidase (Neur), to cleave various SA residues of the GCX and to determine their correlation to enhance cancer attachment to the endothelium . We concluded that the ∝‐2,6‐linked residue of SA is the first to be degraded in the presence of Neur, resulting in the vulnerability of the GCX layer, which is sufficient to initiate CTC attachment to the endothelium . Whether DF will have the same effects as Neur, by degrading SA and leading to the enhanced attachment of CTCs to the endothelium, is unknown.…”