Cancer is one of the leading causes of death worldwide and more than 1.6 million new cases are expected to be diagnosed in the United States alone in 2016. Tumor cells are able to spread to distant sites within the body, a process known as metastasis, which is responsible for 90% of cancer-related deaths. Metastasis was previously believed to involve the travel of individual tumor cells through the bloodstream or lymph system; however, researchers at Massachusetts General Hospital have recently published a paper in the Proceedings of the National Academy of Sciences (PNAS) describing novel cell behavior and the movement of clusters of tumor cells through the blood.
Metastasis and host defense
Metastasis is a complex process where tumor cells separate from the primary tumor to invade the circulatory or lymphatic system, allowing travel to other organs in the body. Within the primary tumor, only certain cells are capable of surviving this process. Circulating tumor cells (CTCs) that are detached from the primary tumor may undergo anoikis, programmed cell death following detachment from the extracellular matrix, or may die as they encounter host defenses such as T cells, natural killer cells, and macrophages. CTCs that circulate through the blood face further challenge in surviving the harsh environment of the blood stream and high velocity of blood. CTCs that successfully relocate to other organs may not initiate secondary tumor formation if the surrounding tissue does not support their growth. One factor believed to play an important role in promoting secondary tumor formation is the formation of clusters of circulating tumor cells. The metastatic potential of CTC clusters may be 50 times greater than that of an individual circulating tumor cell and is likely due to the ability of CTC clusters to prevent anoikis and protect against immune cell attacks.
CTC clusters and the circulation
Research on CTC clusters in the circulation is limited, and the general consensus is that they are too large to pass through capillaries despite confounding evidence of CTC clusters in the peripheral blood of cancer patients. In order to determine the ability of CTC clusters to travel through the circulation, Dr. Mehmet Toner at Massachusetts General Hospital utilized a microfluidic constriction device to mimic human capillaries. Dr. Toner found that CTC clusters isolated from the blood of cancer patients and cultured CTC clusters were indeed capable of transiting through the microfluidic device under physiologic temperature and pressure. Furthermore, Dr. Toner identified a novel tumor cell behavior where CTC clusters “unfolded” into single-file chains at constrictions and then refolded after the constrictions explaining how seemingly large clusters can pass through small capillaries.
CTC clusters and clinical implications
The metastatic potential of CTC clusters and their ability to be isolated from the blood indicate that they may be valuable cancer markers and potential therapeutic targets. Given the results of Dr. Toner’s research, targeting CTC clusters in their unfolded state and likely, most vulnerable state, may be a promising therapeutic target to prevent cancer metastasis.