Bacteria Led to the Fridge so Cancer Will Lead to the…?
‘When will we beat cancer?’ is a question asked of a lot of scientists who work in cancer research. It was a question I was asked intermittently, when friends-of-friends heard that I was (nominally) involved in cancer research as a PhD student. To begin with, I took a sagacious approach, explaining that cancer is really several conditions, which can differ markedly from one another. I also mentioned what I thought to be fun facts, that the disease can change during its course within individuals and so beating it was a difficult thing to pin down. This was rather an effort and often made people look at their glass whilst I was speaking. So after a while, I replied with a question ‘Have we beaten infection?’
This manages to hint that we probably never will beat cancer entirely, but we can find out a lot about it and exercise a good deal of control over it. The battle with infection has seen diseases that were once widespread, like polio and tuberculosis, largely disappear (anti-vaccination campaigning notwithstanding). Many of these disappearances were unimaginable at the turn of the 19th century. The fight against infections such as these has also affected us in more subtle ways. Not only do we live longer, but we understand how to manage and prevent non-life threatening infection, such as a lot of food poisoning. This has led to had a considerable effect on how we eat—refrigeration is a good example.
So, if tackling cancer is like the fight against infection, it too will affect us in ways we cannot imagine at present. This makes broader examples rather interesting—not only do they contribute to the desire to meet challenge of controlling cancer, but they offer tantalising possibilities of other things. One recent development, that may have the potential to influence other things, is an anti-cancer therapy that interferes with a whole metabolic pathway. This type of treatment affects a number of biochemical reactions and therefore the breadth of its effect is wide.
At first glance, this sort of approach seems a bit unrealistic, even cowboyish. Disturbing a whole molecular pathway, rather than a clear, narrow target has many potential dangers. There is a lot going on and it is easy to imagine that some of those effects may be undesirable or even harmful. It may even be that it creates a situation in which the cure is worse than the illness. Despite such pitfalls, recent evidence shows that it may be possible to use a broad tool for just such a purpose. This involves a known drug called Tamoxifen.
A recent study by Morad et al. showed that Tamoxifen can increase the death of cancer cells when given as part of a set of drugs [1, 2]. It does this by blocking the production of fully-fledged sphingolipids from ceramide, and by blocking the destruction of ceramide. This double-effect of ceramide not being broken up, nor made into other lipids, means that it can accumulate in cells. The effect of this result has a firm background: the presence of ceramide has been known for at least a decade to lead to programmed cell death (apoptosis) in cancer cells.
Despite this clear result, it is not yet clear how the drug achieves this . One suggestion is that it has a few concurrent effects that have yet to be assessed together. The effects of Tamoxifen are still being discovered: another recent study, Khadka et al., details the effect Tamoxifen has on the physical behaviour of membranes. This study indicates that the barrier properties of membranes appear to change in the presence of tamoxifen ; cell membranes are weakened, causing greater leakage. This means the cell cannot maintain its internal environment and almost literally falls to pieces.
Thus, where tamoxifen can be targeted to cancer cells, it has real potential as a tumour-killing drug. This adds to its use as an established anti-cancer treatment; it is currently used in treating breast cancer, in which it works by modulating the activity of oestrogen receptors in the system . The discovery of a second use for tamoxifen is also convenient because its clinical use means that it is already an accepted and available drug.
It is appealing to speculate about the broader impact of this understanding. Perhaps it will be possible to have a multi-drug broad-spectrum tablet or injection that can tackle a variety of cancers at once. This might mean that some of the most dangerous cancers, such as those at later stages when the cancer has spread (metastasis) become treatable. This may influence the desire for cancer screening, either reducing it (because cancers are easier to treat) modifying it (some cancers do not need to be screened for, others will be screened for more carefully) or extending it (catch it all early and minimise drug administration).
Any of these might be expected to have a knock-on effect on screening technology and its secondary uses. For example, if cancers that Tamoxifen may not be used for are screened for more carefully, for example in a given organ or organ system, our understanding of that organ or organ system may increase. Lung disease may be understood better as a result and thus how we condition air and what we consider ‘good air’ may therefore change. Screening for cancers in reproductive systems may be understood better, giving an insight into infertility or contraception.
These possibilities are of course guesswork at present. Readers, as always, are encouraged to comment, but particularly on this occasion: what might the fringe or unexpected benefits of treating cancer more fully, be?
 S. A. F. Morad, S. F. Tan, D. J. Feith, M. Kester, D. F. Claxton, T. P. Loughran Jr., Brian M. Barthd, Todd E. Fox, Myles C. Cabot, Biochimica et Biophysica Acta, 2015, 1851, 919–928.
 S. A. F. Morad, Myles C. Cabot, Biochimica et Biophysica Acta, 2015, 1851, 1134–1145.
 T. A. Taha, T. D. Mullen, L. M. Obeid, Biochimica et Biophysica Acta, 2006, 1758, 2027–2036.
 N. K. Khadka, X. Cheng, C. S. Ho, J. Katsaras, J. Pan, Biophysical Journal, 2015, 108, 2492–2501.
 V. C. Jordan, British Journal of Pharmacology, 1993, 110, 507–517.
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