Are Endothelial Cells A Good Target For Cancer Treatment?

Introduction

In order to tackle the question at hand we must first understand what cancer is. Cancer is a disease, caused by the malfunctioning of our own tissues (contrary to the longstanding belief that it was caused by a foreign body). A cancer is generally made up of a group of monoclonal tissues which cannot control their growth. They can be characterised by six key hallmarks , these include proliferative signalling, the evasion of growth suppressors, the ability to resist cell death, replicative immortality, activating invasion and metastasis and finally angiogenesis (Hanahan and Weinberg, 2011). In this essay we shall be focussing in on the final hallmark of the list- angiogenesis. All cancers fall into one of two categories, benign (contained) or malignant (can fragment and produce secondary tumours). Most deaths from cancer are caused by malignant tumours- the main cause of death often being hormone imbalances e.g. hyperthyroidism, where a thyroidadenoma leads to excess thyroid hormones leading to symptoms such as weight loss, loss of sleep and weakness. The fact the majority of deaths come from this type of tumour is because with a benign tumour the main issue is its size, causing it to push against organs or block ducts, which generally have less severe effects.

Cancers are most often triggered by a mutation on an oncogene leading to an alternative protein being produced at a key site e.g. v-src triggers a cascade of events by acting as a kinase (phosphorylating) to many compounds, showing how a single mutation can lead to vast changes in the cells functioning, a mechanism explored further by Tammela, T., Zarkada, G., Nurmi, H., et al. (2011). But many of the original cells properties are retained, therefore dependent on the type of original cell, the tumour will have different properties, leading to different types of cancer. Further mutation is also likely due to the unstable nature of a cancer cell s genome. However not all cancerous cells arise purely through mutation as shown by Ames, B.N., McCann, J., Choi, E., et al. (1975) who showed that up to 40% of carcinogens weren t mutagens, therefore implying that there are triggers for cancer other than mutation.

The endothelium is the name given to the tissue lining blood vessels, however in this essay we will be focussing on capillaries. Their primary purpose is to allow the transport of small molecules (e.g. glucose and carbon dioxide) between the circulatory system and the cells of the body. They also carry out angiogenesis (the formation of new blood vessels). This is controlled by angiogenic factors such as VEGF (vascular endothelial growth factor). Angiogenesis has a naturally occurring purpose, that is to provide new vasculature to new tissues during growth and to replace old vasculature during repair after a wound among other reasons.

Angiogenesis in cancers

Whilst angiogenesis is a necessary process for survival, it is also one of the six key hallmarks of cancer. Angiogenesis is required to allow the growth of a tumour beyond 2-3mm in length as it prevents hypoxia and also delivers vital nutrients to the cancer cells that are further away from blood vessels (N.S. Vasudev and A.R. Reynolds, 2014). Increased vascularisation also provides a means by which malignant tumours can metastasise to produce secondary tumours elsewhere in the body.

Tumours trigger angiogenesis by over-expressing genes for pro-angiogenic growth factors. This is most commonly seen in tumours as VEGF over-expression, which can be seen in most solid tumours (N.S. Vasudev and A.R. Reynolds, 2014). This comes about through a mechanism triggered by the hypoxic conditions found further away from blood vessels. Under hypoxic conditions HIF-1 transcri ption factor accumulates, this transcri ption factor then activates the angiogenic genes. The growth factors produced by the targeted genes work by acting as ligands to the tyrosine kinase receptors on the capillary membrane, which in turn, triggers proliferation of the capillaries as well as for their cytoplasm to contort in order to form branches towards the highest concentrations of VEGF (figure 1). It then follows that cancers may be treatable by inhibiting this pathway. Many treatments focus on the angiogenic switch this is the point at which the stroma surrounding the tumour can t continue to sequester the excess VEGF being produced by the tumour. It is described as a switch as it is a relatively sudden event which occurs upon the production of the enzyme MMP-9 which releases the sequestered VEGF triggering a rapid spike in VEGF concentration (Weinberg, 2006).

The primary danger with gaining vasculature is that the size of the tumour will no longer be limited by the effects of hypoxia, exacerbating the already existing negative effects of the tumour such as the hormonal imbalances or crush damage described earlier. The secondary issue is, however, that the vasculature produced is erratic (often with `dead ends`) and the lumen of these capillaries is also much larger than that of normal capillaries causing excessive leakage. This leads to very high hydrostatic pressure within the tumour that can t be corrected naturally due to a lack of lymphatic vessels within the tumour (Weinberg, 2006). This is an issue because high hydrostatic pressure makes drug delivery very difficult because the high pressure within the tumour can prevent the drugs from entering the tumour. This makes many aspects of the cancer hard to treat by removing/ lessening the effects of many of the most common treatments of cancer.

VEGF- Vascular Endothelial Growth Factor

Treatment of cancer based on VEGF

Despite the difficulty caused by high hydrostatic pressure, knowledge of the processes of angiogenesis can still help us to develop alternative treatments. Cancer is primarily treated either surgically or by chemotherapy in most cases. This is generally because they lead to effects which are seen more quickly, an important trait when dealing with a rapidly intensifying disease. Whilst anti-angiogenic drugs aren t used as a main treatment they can be used alongside other treatments (usually chemotherapy). Anti-angiogenic drugs generally act in one of two ways, they either supress the growth factor directly e.g. Avastin, a monoclonal antibody that binds to VEGF-A (figure 2) (Hicklin and Ellis, 2005). Alternatively, they can target the receptor, for example by blocking the site of tyrosine kinase. In both of these cases, they work by reducing the amount of growth factor (VEGF) that binds to the plasma membrane of the capillaries.

Evaluation of anti-angiogenic treatment

One preferable feature of anti- angiogenic drugs is that there are many which are naturally occurring as the body needs them to prevent over-vascularisation for example after a wound it has also been shown that primary tumours release such chemicals into the blood stream in order to supress secondary tumours. This has been evidenced anecdotally by many doctors who have noticed that after surgically removing a patient s tumour there has been a notable increase in the number/ size of secondary tumours shortly afterwards (Weinberg, 2006). The presence of natural anti-angiogenic drugs means that less money needs to be spent researching to find new drugs and the molecules are less likely to have unexpected side effects as they originate within the target organism. However unfortunately, this hasn t been proven clinically with Chen and Cleck (2009) showing multiple side effects of VEGF targeted therapy such as hypertension and impaired wound healing. Also, synthesising biological molecules is very expensive due to the complex nature of chemical synthesis because of having to account for the many chiral variations of a polypeptide among other reasons, therefore it may not hold up against cheap alternative treatments such as a surgical procedure.

Whilst tumours can often become refractory to a new drug due to their unstable genome s rapid mutation, anti-angiogenic drugs target the microenvironment of the tumour, specifically the capillaries, which will have a stable genome and are therefore less likely to become refractory. However, this effect has not been evidenced clinically to a large degree, with varying results with respect to the type of cancer being treated for example FDA approval of bevacizumab, whilst being a leading anti-angiogenic drug, has been removed for breast cancer as it is ineffective, illustrating the vast differences between different types of cancer. A key explanation of this is that cancers use a variety of angiogenic molecules, so cancer cells will therefore mutate and be selected for if they begin to produce less of the molecule being inhibited and more of the others (Welti, J., Loges, S., Dimmeler, S., et al., 2013).

As tumour associated endothelium has a very short life cycle it is more vulnerable to drug induced killing by cytotoxic therapies (Weinberg, 2006). Whilst this is promising, due to the high hydrostatic pressure described earlier it is currently difficult to exploit this weakness. Promisingly, Avastin has been shown to reduce vascularity of tumours. This in turn reduces hydrostatic pressure, allowing other treatments to be used more effectively. It could therefore be asserted that anti-angiogenic drugs may be best used synergistically with other drug treatments (figure 3).

Anti-VEGF drugs have been shown to be much more effective in early stages of the tumour, whilst more developed tumours are less dependent on VEGF, this is concordant with the theory that anti-VEGF drugs can offset the angiogenic switch. This is an issue as most drug treatments are used in the adjuvant setting within which the tumour is much more likely to have lost its high dependency on VEGF in situations like this it would be much more effective to tackle areas away from the endothelium such as the pericytes or smooth muscle to achieve the same outcome by using anti-PDGF drugs. However, the other side of this argument is that anti-VEGF treatment could be ideal in the adjuvant setting after surgical procedures as the smaller secondary tumours (which would otherwise flourish as described above) may respond in a similar way to early tumours as they will, generally, be small in size.

One of the greatest downfalls of targeting endothelial cells is that reducing the vasculature around the tumour only limits its size by either halting further growth or causing regression in the tumour. Whilst halting growth is a strong positive point on the surface, it follows that when the anti-angiogenic treatment is stopped, growth will continue. This is exactly what was shown clinically, when anti-angiogenic treatment is stopped, the progress of treatment was rapidly reversed (Mancuso, M.R., Davis, R., Norberg, S.M., et al., 2006) meaning the treatment, if used, would have to be lifelong. Consequently, it could be seen as less convenient than other treatments as well as being very cost-ineffective.

Conclusion

In conclusion I think that targeting endothelial cells has a great deal of potential. I have come to the conclusion because of their potential malleability. They can be used to improve the situation of many stages of cancer patient dependant on the way in which they are used. Anti-angiogenic drugs could be effective in the neoadjuvant setting, by giving them to patients on surgery waiting lists for example. In this case they would serve to halt/ slow the development of the tumour in the days/ weeks preceding the operation. However, I think that their greatest potential use is to be used synergistically with other drugs or treatments such as chemotherapy in order to maximise their effectiveness. Of course side effects should be deeply considered though, as some are very serious, such as the increased rate of gastrointestinal perforation leading to death (Giantonio, B.J., Catalano, P.J., Meropol, N.J., et al., 2007). Therefore, combatting these side effects should be at the forefront of research into endothelial targeted drugs, as it could lead to anti-angiogenic treatment being a key method of combatting cancers. This potential benefit is best exemplified in those types of cancer which are less easily surgically accessible such as pancreatic and lung cancer, which are already primarily treated with chemotherapy/ drug treatments.

References

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