It’s been a strange couple of weeks in the world of oncology. First of all, a humble naked mole rat has been found to possess potentially life-saving capabilities with it’s resistance to developing cancer. Second of all, the Cancer Research Institute has reported on the major success of using HIV to combat particularly aggressive forms of cancer in a remarkably efficient way. And just when you thought it couldn’t get any more strange, Paul Davies – a cosmologist and author in his field – decides to radically change the outlook on cancer by proposing a completely new theory to how we fall victim to it.

Mole Rat Magic

There are a few features of the naked mole rat that are already relatively unique. For example, it is the only cold-blooded mammal known to man, it can survive when deprived of oxygen and it does not feel pain through its skin. You’d think that would be enough, however, on top of this, it has been found to possess the incredible feature of never developing cancer.

The team that made the remarkable discovery were already investigating the naked mole rat and made the observation that in many cases, the rodents would live for around 30 years (the normal life-span of a similar creature is around 4 years) with no incidence of  cancer. Upon further inspection, they found that naked mole rats produce a particularly large sugar called hyaluronan.

In most creatures, hyaluronan is found in epithelial and connective tissues between cells, contributing to tissue elasticity. It is thought that the sugar is produced in such large quantities to allow naked mole rats to navigate the tight underground tunnels that comprise their natural habitat. As a result, it seems that naked mole rats produce the sugar in an alternative form; five times larger and in much higher volumes than that found in humans.

In order to determine whether this actually was the reason behind the supposed cancer resistance, the team grew up cell colonies harvested from the rodents. Some of these cells were genetically altered to deactivate a major inhibitor of cancer called p53 whilst at the same time activate an oncogene called Ras. The cells continued to demonstrate a resistance to cancer. Other diagnostic tests showed the same result: combining naked mole rat cells with an enzyme that destroys hyaluronan produced large masses of cells reminiscent of tumour masses. When the enzyme was then deactivated, the cells stopped growing, suggesting it was indeed hyaluronan that was preventing tumour formation.

All of the evidence found regarding hyaluronan is compelling to say the least, however, how exactly is it that a sugar can prevent cancer? The answer is through something called “contact inhibition“. The process involves a gene called p16 that is activated when cells become too tightly packed. In maked mole rats, the same team that discovered hyaluronan found that p16 was present in a hyper-sensitive form, suggesting cells would never get too close together before it was activated. This new data suggests that high levels of hyaluronan is the reason behind this hyper-sensitivity as it gives the impression of a highly congested tissue environment.

Hyaluronan and Cancer

It is already known that hyaluronan contributes to skin elasticity but in terms of cancer development, it also contributes to cell proliferation and migration. As we know cancer is at its most deadly when it has metastasised and effected major organs. Developing a way of targeting and manipulating the sugar in humans way well produce similar effects to those demonstrated in naked mole rats. Perhaps a means of increasing hyaluronan production in cancer cells? Or administering an inhibitor of enzymes that break down the sugar? Right now it is too early to tell whether this is a legitimate player in the fight against cancer.

Hyaluronic acid/hyaluronan (HA), hyaluronic acid synthase (HAS), hyaluronic acid receptors (HAR) and hyaluronase (HAase) all play vital roles in the different stages of cancer metastases, ranging from migration to angiogenesis (formation of new blood vessels).

 

Fighting Fire with Fire

Moving on from our hairless rodent friend to a much more fear-inducing and deadly player in the game of life: the human immunodeficiency virus aka HIV. When thinking about HIV, it is easy to conjure up images of short lives lived by those unfortunate to have come across the virus. However, the truth of the matter in this day and age is that most people infected with it live perfectly normal lives, dying from natural causes while modern medicine manipulates the virus into state of dormancy. In terms of cancer, HIV can be manipulated further into engineering immune cells to attack cancer cells.

Now before conclusions are inevitably jumped to, it should be said that the form of HIV that is being used in this practice is a disabled version, much like those given in vaccines against influenza or measles. The difference in this example is that the virus can not multiply but instead introduces a gene of interest into a patient’s T cells that have been harvested from their own immune system. The virus “infects” the T cells with the gene but then can not multiply as it has a particular sequence from its own genome deleted. The gene that is inserted into the patient’s T cells enable them to target cancer cells much more efficiently, essentially re-arming their immune system once they are reintroduced into the patient’s bloodstream.

Multiple variants of this kind of treatment already exist and the most up-to-date versions of viral therapy fall under the category of third-generation viruses where three parts of the genetic sequence of the virus are deleted through genetic engineering. These genes can encode for such things as structural proteins that form the shell of the virus or receptor proteins that allow new viruses to penetrate cells. First and second generation viruses failed as viruses have the ability to “steal” parts of its hosts DNA and use them as replacements for any of its own that is missing.

The Curative Power of Viruses

The Cancer Research Institute (CRI) specialises in immunotherapy and is the organisation that funded this research carried out at the University of Pennysylvania. Not much has been revealed as to the workings behind this treatment but needless to say that when it works, it works incredibly efficiently. The video below was posted on the CRI website along with the news of this treatment. Examples like Emma are why it is so exciting to see a working form of a new treatment.

The Physicist’s Point of View

Finally we come to the week’s most curious development. As previously mentioned, Paul Davies is a highly-respected cosmologist and author in his field. Two weeks ago, Davies conducted a lecture in London at a New Scientist event describing how cancer may well be the result of a form of “ancient awakening” within our own cells.

The concept that Davies puts forward is something that he has been promoting for a while now and the lecture is a fascinating insight into the thinking behind his theory. By comparing cells to physical objects, Davies believes that comparing the development of cancer to the example of a genie in a bottle may well revolutionize how we treat the disease.

Davies theorises that cancer is not the result of uncontrollable cell growth caused by cells gone haywire, but rather as an activation of an ancient cancer program that silently lies within our DNA. When regarding the cell as the bottle and an ancient cancer-coding genome as the genie, the theory he puts forward emphasises that cancer results from a broken bottle that allows the genie to escape. The bottle may be broken by a form of environmental stress, activating a cancer genome. Because of this, Davies suggests that repairing the bottle instead of trying to defeat the genie may be a more successful treatment hypothesis.

An Ancient Awakening

Further simplifying Davies’ theory results in the clarification of his theory. The almost universally accepted theory behind cancer suggests that a cell undergoes mutations over its lifetime that eventually enable the cell to exhibit cancerous behaviour – the so-called “error theory“. The alternative theory that Davies puts forward suggests that an environmental stress activates an already present cancer genome which then activates mutations in cells to produce tumours – the “stress response theory“.

The idea is indeed fascinating and Davies uses examples of atavisms to enhance his theory. Atavisms are representations of ancestral physical attributes in modern man, for example webbed feet. If modern man’s genome contains coding for ancient physical attributes then perhaps cancer is just another representation of it? Whether this theory turns out to be valid or not, its nice to see the point of view from a scientist from a different field.

References:

Research into the naked mole rat: http://www.nature.com/nature/journal/vaop/ncurrent/full/nature12234.html

‘Cancer Immunotherapy Goes Viral’ article by the Cancer Research Institute: http://www.cancerresearch.org/news-publications/our-blog/june-2013/cancer-immunotherapy-goes-viral

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