Circulating Tumour Cells (CTC)
Once intravasation has occurred, the cancerous cell enters the circulatory system and is referred to as a circulating tumour cell (CTC) (1,2). This section will focus on tumor cell survival following intravasation into the circulatory system or the lymphatic system. Cancer cells can also disseminate via mucosal surfaces, such as in ovarian carcinomas (2). The CTC has several challenges to face once it is in the new environment.
Challenges CTCs Face
1) Lack of stromal support
The first challenge to overcome is the lack of stromal support. As the CTC is now completely free from stromal support, it no longer receives growth, mitogenic or trophic factors from the stromal cells (1,2). Without these signals, most cells undergo a special form of apoptosis called anoikis (1-3). Anoikis is a type of programmed cell death that occurs when cells no longer interact with the matrix. Most cancer cells are subject to anoikis and so many CTCs die off (1-3). However, a few have developed mechanisms to avoid the anoikis process. For example, interference with an anti-apoptosis factor such as Bcl-2 can protect a cell from this form of programmed cell death. Recent studies have found that this could be through a protein called 'Bcl2-inhibitor of transcription' or 'Bit1' (3).
Cancer cells vary in the amount of time spent in circulation. CTCs can spend a few seconds in circulation before they get embedded in a capillary, some can last minutes at a time or even longer (1,2). Therefore, the threat of anoikis varies between CTCs. This has lead to a debate in the importance of anoikis in the success of invading tumour cells (1).
2) Geometric constraints
Another challenge CTCs must face is geometric constraints. CTCs are not geometrically suited for the circulatory or lymphatic systems.
Note that capillaries range from 3-8µm wide, and red blood cells (RBCs) are 7 µm in diameter. RBCs manage to squeeze through one at a time due to their flexibility (1,2). This ability to deform and bounce back into shape is not common in most cells. Now imagine a CTC. Relative to an RBC, it is on average a whopping 20µm diameter. Imagine such a large cell trying to lumber through the narrow passages of the capillaries. Clearly, the sheer size of CTCs will inhibit their transport!
So how does a CTC travel long distances? The clever CTCs intravasate into larger vessels of the venous system. The venous system is a sequence of larger and larger vessels that lead to the heart. Deoxygenated blood goes from the heart to the lungs where it hits a large network of capillaries. Due to their size, most CTCs get stuck in the first capillary network they run into, and so a large number of CTCs end up in the lungs (1,2,4). CTCs entering veins draining the digestive system go a different route: first they must travel through the hepatic-portal system, and then they will encounter the capillaries of the liver. Because CTCs usually get trapped in the first capillary bed they run into, there is a disproportionate amount of metastases that end up in the lungs and liver. This preferential metastasis to particular organs is known as organotroposism.
3) Withstanding shearing force
Once in the capillaries or lymphatic vessels, the CTC has to withstand a beating from the fluid contained in these vessels. A large cell will occupy a large amount of the capillary cross-sectional area, and so it will be exposed to a range of fluid velocities and pressures, even within one vessel. If the fluid is flowing faster on one side of the vessel than the other for example, the CTC will experience a shearing force. As CTCs are not designed to withstand shearing forces, often they can literally be ripped apart (1,2,4) To help them travel through the bloodstream without dying, CTCs can recruit platelets. Often tumour cells have been found with platelets and even red blood cells adsorbed to their surface within blood vessels. These complex bundle of cells are sometimes referred to as microemboli, microthrombi, or thromboemboli (2). The platelets and red blood cells form a shield around the CTC protecting it from shearing forces, NK cells, and macrophages. Microthrombi are triggered by a factor on the CTC membrane called 'tissue factor'. Tissue factor activates a clotting cascade which results in platelets binding to the CTC (2).
4) Overcoming capillary beds
If CTCs can get trapped in the first capillary bed they run into (usually in the lungs or liver), how then do metastatic cancers form in other places in the body? One way is that CTCs sometimes avoid capillary networks altogether. The circulatory system has back-alleys for the CTC to sneak through, called arteriovenous anastamosis or "shunts". These shunts are connections between arteries and veins, or more commonly arterioles and venules. Through these passages CTCs can bypass capillary networks. Another way is that the cancer cell can try and squeeze through the tiny capillaries. For this to happen the CTC has to pinch of much of its cytoplasm to greatly reduce its size.This will often result in non-viable cells, however on some occasions the vastly reduced cell can actually be viable, make it through the capillary network it is stuck in, and find a new target site (1,2). Lastly, the circulatory system is not the only place cancer cells can intravasate into, as vessels of the lymphatic system are also common destinations. CTCs in the lymphatic system only usually get as far as the closest set of lymph nodes however. If the CTC is going to travel further usually it has to transfer into the circulatory system. CTCs will eventually exit the circulatory system and affect new organs, progressing down the metastatic cascade. This will require further interactions with chemokines and endothelial surface receptors in the next step of metastasis: extravasation.
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3. Jenning, S., Pham, T., Ireland, S.K., Ruoslahti, E., Biliran, H., Bit1 in anoikis resistance and tumor metastasis. Cancer Letters. [Epub ahead of print - Jan 31] (2013)
4. Reymond, N., Im, J.H., Garg, R., Vega, F.M., Borda d'Agua, B., Riou, P., Cox, S., Valderrama, F., Muschel, R.J., Ridley, A.J., Cdc42 promotes transendothelial migration of cancer cells through β1 integrin. J Cell Biol. 199(4):653-68 (2012).
5. Gay, L. J., & Felding-Habermann, B. (2011). Contribution of platelets to tumour metastasis. Nature Reviews Cancer, 11(2), 123-134.