Platelets are small cell fragments which circulate in our blood. We make a lot of them, with the average human producing 100 billion every day. These plate-shaped fragments are vital for the clotting of blood; at injury sites, they become activated and aggregate together to stop bleeding. They also have an array of important functions within the immune system, including roles in diseases such as cancer. Much of the research into platelets and cancer has shown platelets to worsen the disease, enabling the spread of tumour cells. As a result, some cancer treatments which interfere with platelet function have been trialled. But some findings contradict the idea that platelets exacerbate cancer and question the use of drugs which target platelets. They are crucial in blood clotting, but when it comes to cancer; are platelets a help or a hindrance?
Cancer cells are extremely good at evading recognition by the immune system, and they can recruit platelets to help them do so. Tumour cells can release chemicals such as thrombin, which is an important platelet activator in the blood clotting cascade. Thrombin released by cancer cells activates platelets, causing them to clump together on the tumour cell surface. The platelets “shield” the tumour cell, protecting it from attack by white blood cells such as natural killer (NK) cells. By recruiting platelets to activate and stick to their surface, tumour cells can effectively “hide” from the immune system, and avoid triggering an immune response.
As well as helping cancer cells to avoid immune recognition, platelets can aid their metastasis (spread to secondary sites in the body). For instance, platelets can facilitate the movement of tumour cells out of blood vessels and into surrounding tissues; a process called extravasation. If cancer cells can extravasate from blood vessels, then tumours can develop at new sites. Platelets promote this extravasation by facilitating the binding of tumour cells to the blood vessel wall, ready to migrate out of the blood altogether. This partly occurs because tumour-platelet aggregates, formed when tumour cells activate platelets, “slow down” the cancerous cells as they travel through the blood. Additionally, platelets are capable of binding to both cancer cells and endothelial cells of the blood vessel wall, through a platelet receptor called P-selectin. P-selectin molecules on platelets can bind to both endothelial and tumour cells at the same time. They can therefore bring tumour cells into close contact with endothelial cells, which helps the tumour cells attach to the blood vessel wall, and subsequently escape to new sites. Through these mechanisms of retarding tumour movement in the blood and facilitating binding to endothelial cells, platelets allow cancer cells to adhere to the blood vessel wall and migrate to new parts of the body.
But new research has shown that platelets might not be all bad when it comes to cancer. Platelets were cultured with different tumour cell lines, and the subsequent proliferation of the tumour cells was measured. Surprisingly, the platelets inhibited the growth of the cancerous cells.
In order to replicate, and therefore grow, tumour cells undergo DNA synthesis and a cycle which results in the splitting of a tumour cell into two “daughter” cells. Scientists found that in the experiment, platelets were interrupting the cell cycle of the tumour cells. Through contact with the tumour cells and release of chemicals, platelets caused the cell cycle to arrest during its first phase, preventing the tumour cells from replicating and proliferating. DNA synthesis within the tumour cells was also decreased by the presence of platelets.
Another research group found that platelets are capable of causing the controlled death of tumour cells – a process known as apoptosis. Platelets were found to express the “death inducing” receptor Fas Ligand (FasL) on their surface. The complementary receptor to FasL is called Fas, and is present on tumour cells. Platelet FasL was able to bind to tumour cell Fas, which initiates a cell signalling pathway within the tumour cell which results in its programmed death.
These findings of the effects that platelets have on tumour cells indicate that platelets may in fact help stop the spread of cancer. This contrasts with the roles of platelets previously discussed, and suggests that these tiny fragments may have a more complex role in cancer than first thought. Importantly, the conflicting findings have implications for drug therapies and treatments for cancer.
It has been previously documented that preventing platelet-tumour cell interactions can diminish or eliminate the metastasis of cancer. Platelet numbers can be depleted for example, or their activation blocked. This can stop them from facilitating the extravasation of tumours from blood vessels, and shielding the cancerous cells from immune recognition.
But treatments such as these carry considerable risks. Platelet activation is crucial for the clotting of blood, as platelets aggregate together at injury sites to arrest bleeding. If platelet numbers are decreased, blood clotting is also adversely affected. Therefore, cancer treatments targeting platelets could result in side effects such as the inability to clot blood and haemorrhaging. Furthermore, with new research pointing to platelets having advantageous functions in cancer, it may be necessary for these treatments to be rethought. If platelets have the ability to slow the proliferation or even directly kill tumour cells, their role in cancer may not be as straightforward as previously suggested.
The role of platelets in cancer may need to be re-examined, and the balance of their negative and positive actions determined. If the net impact of platelets in cancer can be established, it may be possible to develop novel cancer therapies accordingly. Platelets, despite their size, have demonstrated their potential to exert all manner of effects on tumour cells. If we can accurately assess their role in the disease, we may be able to apply the knowledge to develop new therapies for cancer.
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