The movement of metastatic cells through the blood circulation, their adhesion to vessel walls and their release into new tissues are closely linked to blood flow force. Inserm researchers have just described these links following a study performed in vivo in two animal models (zebrafish and mice), and confirmed in humans.
The development of metastases is not linked purely to the intrinsic properties of metastatic cells, but also to environmental conditions and, in particular, the mechanical pressures exerted on them. Studies have already demonstrated, for example, that these cells adapt to the rigidity of a tissue to more effectively invade it. In this case, an Inserm* team has just proved that their dissemination is associated with blood flow force.
To study this phenomenon, researchers worked in vivo with zebrafish embryos. “This is a simple model, with stereotypical vascularization, that can be used to inject metastatic cells and then observe their fate in terms of space and time under the microscope. It’s also possible to modify the blood flow in this model by injecting different substances regulating cardiac activity,” explains Jacky Goetz*, who led the research.
Arrest, adhesion, extravasation
The researchers demonstrated that the speed of displacement of metastatic cells was slowed in the capillaries, highly ramified zones with bends and bifurcations, where the blood flow itself is slower. In these areas, the cells stop preferentially in certain locations, called hotspots by the researchers. They also observed that it is possible to move these hotspots by altering the blood flow force. This observation is consistent with the fact that, in patients, metastases preferentially appear in organs presenting a highly ramified and complex vascular network, such as the lungs, liver or brain.
But to be aggressive, cells need to do more than simply stop: they also need to adhere to the vascular wall and cross it. Once again, the force of the blood flow plays a key role. “When we modify it, we observe that there needs to be a certain blood flow velocity for the metastatic cells to adhere to the endothelial cells.” This adhesion involves a protein expressed by metastatic cells, integrin ß1. Experiments conducted in mice have shown that if the cells are deprived of this protein, they remain mobile in the blood circulation.
Finally, once they have adhered to the vessel wall, the cells need to be expelled from the vascular system. This phenomenon is known as extravasation. Once again, a certain blood flow force needs to be maintained to obtain remodeling of the endothelial cells around the tumor cell, this being necessary for expulsion. "If the blood flow is too weak, there is no extravasation and metastases cannot form,” explains Jacky Goetz
Reducing the metastatic risk?
In a second phase, working in collaboration with a German team, the researchers confirmed the link between blood flow and metastatic regions in the brain in around one hundred patients with different cancers. To do so, they used CT scans in order to map the degree of perfusion throughout the brain, providing information on blood flow force. A correlation was thus demonstrated between blood flow force and the preferential location of metastases detected by MRI.
Does this mean that these studies might help us find solutions to reduce the metastatic risk in cancer patients? ”Unfortunately, trying to alter the blood flow force to limit this risk would be too complex,” admits Jacky Goetz. “However, we are focusing very closely on the endothelium remodeling stage at the moment of extravasation of the tumor cells. Treatments exist to limit the growth of vessels in the event of cancer, by asphyxiating the tumor. And these also affect this remodeling. Consequently, we are currently looking at whether they may be able to inhibit the extravasation step. Theoretically, this could reduce the risk of metastasis development,” he hopes.
*unit 1109 Inserm/Université de Strasbourg, Tumor Biomechanics team, Faculty of Medicine, Strasbourg
G. Follain et al. Hemodynamic forces tune the arrest, adhesion and extravasation of circulating tumor cells. Dev Cell, April 9, 2018 edition