Circulating tumor cells exit circulation while maintaining multicellularity augmenting metastatic potential

Abstract

Metastasis accounts for the majority of all cancer deaths, yet the process remains poorly understood. A pivotal step in the metastasis process is the exiting of tumor cells from the circulation, a process known as extravasation. However, it is unclear how tumor cells extravasate and whether multicellular clusters of tumor cells possess the ability to exit as a whole or must first disassociate. In this study, we use in vivo zebrafish and mouse models to elucidate the mechanism tumor cells use to extravasate. We found that circulating tumor cells exit the circulation using the recently identified extravasation mechanism, angiopellosis, and do so as both clusters and individual cells. We further show that when melanoma and cervical cancer cells utilize this extravasation method to exit as clusters, they exhibit an increased ability to form tumors at distant sites through the expression of unique genetic profiles. Collectively, we present a new model for tumor cell extravasation of both individual and multicellular circulating tumor cells. This article has an associated First Person interview with the first author of the paper.

The Complexities of Metastasis

“…Whether CTC clusters equally extravasate by endothelial remodeling in flow-permissive regions remains to be further elucidated. A recent study conducted in the zebrafish embryo, that requires further validation, demonstrates that clusters of CTCs mostly extravasate upon endothelium remodeling [164]. It has become evident that clustering increases CTC resistance to shear stress and protects from immune cell clearance [103,165].…”

Impairing flow-mediated endothelial remodeling reduces extravasation of tumor cells

“…Based on this, we previously discovered that extravasation occurs mainly through an active endothelial-dependent process that we named endothelial remodeling (Follain et al, 2018a). Our findings were recently extended to human melanoma and cervix cancer lines (Allen et al, 2019), suggesting that it is not a cell line specific mechanism. Incidentally, a similar process had also been linked to extravasation of stem cells (Allen et al, 2017) and is at play during the important step of blood clot removal, through angiophagy (Lam et al, 2010;Grutzendler et al, 2014).…”

Identification of Cancer-Associated Circulating Cells in Anal Cancer Patients

“…In addition, multicellular, CC microclusters, sometimes including neutrophils, have been identified as a small percentage of the CCs. These microclusters are able to undergo extravasation (via angiopellosis); they have distinct survival and secondary tumour formation abilities, exceeding those of any single CC [ 36 ].…”