The gate to metastasis: key players in cancer cell intravasation

Abstract

WES -whole exome sequencing ROS -reactive oxygen species mtDNA-mitochondrial DNA i.v -intravenous injection assay CAF -cancer associated fibroblast ECM -extracellular matrix NETs -neutrophil extracellular traps TAM -tumor associated macrophage Mena -actin-regulatory protein mammalian enabled IFP -interstitial fluid pressure

EGFR is a pivotal player of the E2/ERβ – mediated functional properties, aggressiveness, and stemness in triple‐negative breast cancer cells

“…EMT is a complex dynamic process that occurs normally during embryonic development but also drives cancer progression [16]. EMT is considered as one of the metastatic cascade's driving forces as it bestows tumor cells the proper traits necessary for tumor dissemination and distant metastasis, namely, increased motility, invasion, intravasation, and extravasation [17,18]. Still, for metastatic colonization to occur, cells mostly follow the reverse to EMT process, namely, mesenchymal-to-epithelial transition (MET), in order to proliferate and form the secondary tumor [19].…”

Physical Forces and Transient Nuclear Envelope Rupture during Metastasis: The Key for Success?

“…Metastasis is extremely inefficient; it is estimated that less than 1% of cells that intravasate into the blood stream will ultimately succeed in the generation of distant metastasis [ 7 ]. This inefficiency maybe be the result of the mechanical stress excess.…”

“…Several studies have established the importance of proteases-mediated degradation of the BM during invasion [ 3 , 4 , 5 ], notwithstanding, protease-independent mechanisms have also been implicated [ 6 ]. In the latter, the invading tumor cells can form invadopodia protrusions to mechanically open up micron-sized channels in the matrix to then squeeze and migrate through them [ 7 , 8 , 9 ]. This migration can be of single cells or of groups of cells that then form CTC clusters within the blood stream [ 10 ].…”

“…In order to shuttle in (denoted as intravasation) and out (denoted as extravasation) of the blood stream, invading tumor cells need to cross the endothelial walls of blood vessels and as such are confronted by several mechanical challenges. These steps rely on the intrinsic properties of cancer cells such as the epigenetic state, the composition of the microenvironment, and the mechanical cues associated with this process (reviewed in [ 7 ]).…”

“…Importantly, this constricted migration imposes extreme nuclear shape changes that involve the formation and insertion of a nuclear lobe and nuclear squeezing [ 19 ]. In a similar way during intravasation, invading tumor cells generate protrusions that are initially aligned along endothelial cell–cell junctions and are then inserted between the endothelial cells to disrupt their connection allowing transendothelial migration [ 7 , 8 , 9 , 20 ]. The presence of macrophages in the proximity of the intravasation sites suggests that these immune cells may play a role in the opening of the endothelial wall [ 9 , 13 , 20 ].…”