E51 Vascular transport of tumor cells

Topic

When a tumor cell leaves the primary tumor and enters the bloodstream, it becomes what is known as a circulating tumor cell. From that moment on, the circulating tumor cell must survive its transit through the bloodstream and eventually exit it to settle in a distant organ—a process comprising several successive stages: departure from the primary tumor, entry into the bloodstream, survival during transit, and extravasation (exiting the blood vessel once it reaches the distant organ).

Of all the circulating tumor cells that enter the bloodstream, the vast majority die during transit; only an extremely small fraction—far fewer than one in ten thousand—manages to complete the entire process, survive the journey through the bloodstream, and successfully colonize a new site in the body. This high mortality rate during transit explains why most tumor cells that break away from the primary tumor never go on to form a metastasis.

The reason so few circulating tumor cells survive this transit is that, while in the bloodstream, they face three distinct types of physical and biological challenges. The first challenge is purely mechanical: blood flow itself generates shear forces on the circulating tumor cell—specifically, friction and drag forces acting on its surface as blood flows around it—which can directly damage or destroy the cell.

The second challenge arises when the circulating tumor cell—assuming it survives those shear forces—approaches the wall of a blood vessel; to extravasate and leave the bloodstream, the cell must adhere to the endothelium, the layer of cells lining the inner wall of the blood vessels. This adhesion relies on specific cell-binding mechanisms between the circulating tumor cell and the endothelium; if the circulating tumor cell fails to adhere to the endothelium, it remains swept up in the bloodstream, unable to exit it.

The third challenge is biological in nature: while circulating in the bloodstream, the tumor cell is a target for the patient's immune system, which can recognize and destroy it. Furthermore, upon detaching from the primary tumor, the circulating tumor cell is separated from the extracellular matrix—the supportive environment that normally surrounds tumor cells and provides signals for their survival. Without contact with the extracellular matrix, the circulating tumor cell loses these survival signals, and many die precisely due to this absence while adrift in the bloodstream.

It is the combination of these three challenges facing the circulating tumor cell—blood flow shear forces, the need to adhere to the endothelium, and the loss of survival signals normally provided by the extracellular matrix—that explains why the development of metastasis from a circulating tumor cell is such a rare event. Gaining a physical understanding of the circulating tumor cell's transit through the bloodstream helps explain why, even though the primary tumor continuously sheds cells into the blood, most patients do not develop a metastasis from every single one of those cells, but rather only from the very few that manage to survive the entire journey.

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