Immunological Turncoats Ward off Tumour Eradication

Confocal microscope image of a spontaneous breast cancer tumor in a mouse. (Credit: Image courtesy of University of California - San Francisco)

This news report from ScienceDaily highlights how much progress has been made in our understanding of cancer. The picture is beautiful because it presents an image of what has long been suspected. 

As the news article states ....

Instead, these immune cells are headed off at the pass. A completely separate set of healthy cells that are already in contact with the tumor effectively establish a defensive perimeter around it.

This is very important information, it provides insight into one of the fundamental mysteries of cancer: why the immune system can both recognise and mount a T cell attack that gets headed off at the pass. Cancer Immunotherapy began long ago with a chap named Steven Rosenberg ...

Weinberg on the Big Science Crisis

I was directed to an article by the acclaimed physicist Steven Weinberg through a link in this blog. In the article Weinberg is arguing that in the USA Big Science has already missed some golden opportunities, including building a collider much more powerful than the Cern Large Hadron Collider. The story in about that funding fiasco is sad but common, once again indicating that political concerns too often dominate spending decisions.

The picture is not a pretty one but what really surprised me is that towards the end of the article Weinberg lays out his cards in no uncertain fashion. He is not happy with the economic settings of the USA. Thus ...

I am not an economist, but I talk to economists, and I gather that dollar for dollar, government spending stimulates the economy more than tax cuts. It is simply a fallacy to say that we cannot afford increased government spending. But given the anti-tax mania that seems to be gripping the public, views like these are political poison. This is the real crisis, and not just for science.

It is a difficult issue because the dividends of Big Science can be far into the future. A good example of this is the concept of "spin" in quantum mechanics. During the mid-20's the bods in Copenhagen did realise that they needed more metrics to understand the behavior of an electron and so did find a little known branch of mathematics praise be to drunken Irish mathematicians that allowed them to come up with the property of "spin". Some 60 years later a bod realises that we can use the concept of spin to creating an imaging device that will revolutionise modern medicine, as it has done. MRI is impossible without the concept of "spin".

Read the article by Weinberg. He goes through a long history of major breakthroughs in science and highlights the changing nature of the challenge over the century. This is not the economic time to establish Big Science projects but if we tarry too long that is time irreversibly lost. It reminds me of the challenge to the meta-mathematician Paul Erdos, who used amphetamines for the last 20 years of his life because claimed he could not do mathematics without those drugs. A friend challenged him to stop for one month on the grounds that he had become addicted. Paul Erdos immediately and easily met the challenge. His response to his friend was: you have put off the progress of mathematics by one month. You'll find that story in a great biography of Paul Erdos, The Man Who Loved Only Numbers. How long can we wait? I don't know but I have a sneaking suspicion it could be a very long time because in the coming decades our intellectual energies will be directed to more immediate practical concerns.

Cancer: Death by Suicide or Death by Execution?(Rommel's Dilemma)

Apoptosis, programmed cell death, is a central issue in cancers and the failure of apoptosis allows pre-cancerous cells to become very dangerous. As the article notes ...

Cancer cells can die in several ways, Weiner says. One is a natural process called apoptosis, or programmed cell death, which is a way that the body keeps the cells growing within an organ or body in check. "This is a normal process, so the immune system ignores those cells," Weiner says. Manycancer drugs are designed to promote apoptosis.

See the problem? Apoptosis is way of ensuring that the process of cell death does not lead to nearby cells being attacked by the immune system. The failure of apoptosis may enable tumours to grow but that does not mean increasing apoptosis is always the best way to kill the cells. I even vaguely recall studies suggesting apoptosis can lead to humoral factors that limit the immune response.

The Evolving Tumour

Some people wonder why the challenge of cancer has not been met. Even with the advanced techniques of today the principle strategy for defeating cancer remains personal behavior. The treatments are improving but at a slow rate. This news item highlights that despite all we have learnt about cancer at the molecular level, there are some very important information that we simply fail to discover. Fortunately with so much research going on the representations we can create are increasingly accurate, much more detailed, and slowly but surely coalesce into fruitful schemas that facilitate the development efficacious therapies. This news item calls for a some serious reconsideration of our strategic imperatives.

A tumour can be a hotbed of diversity, British scientists have discovered. Just as different types of tumours have distinct genetic mutations, so do separate parts of the same tumour.

This "Magic Bullet" is Critical for Future Cancer Treatment

Bright future ahead for antibody cancer therapyMarch 15, 2012 in CancerAntibodies, once touted as the "magic bullets" of cancer care, are now fulfilling that promise and more advances are on the way, say cancer researchers at the Georgetown Lombardi Comprehensive Cancer Center

When we think of antibodies we typically think of an immune response. The reference here is different and is an excellent example of how molecular biology can provide insights that revolutionize clinical treatment.

Stay Hungry to Fight Cancer and Dementia

This is a good news article by David Liu on the Food Consumer website. It relates to how fasting can have significant anti-cancer benefits and is protective of the brain. Latter the article references Professor Mattson, who long ago wrote a fascinating little article entitled, "Starve me and watch my brain run". He is now investigating the possibility of intermittent fasting as an anti-dementia strategy. After reading his previous work and that of others I long ago decided that intermittent fasting is one of the best things we can do for our health in general and cancer and cognitive function in particular. This is good epidemiological, physiological, and cellular data to support this contention. Three levels of analysis confirmation is good enough, especially given the strength of the primary data.

If you are at all serious about maintaining good health you must think very seriously about fasting as an integral part of your lifestyle. For another example of that have a look at the previous post on the news report, Short fasting cycles work as well as chemotherapy in mice. In relation to the other benefits of fasting you'll have to read on. 

Cancer, heat shock protein 90, and adaptation

I read about this quality of heat shock protein 90 a long time ago and was always puzzled by it because it challenged our conventional view of protein production control.  It means the capacity for adaptation does not require de novo mutations, that the potential for adaptation is often present but suppressed by hsp90, which can let this adaptive potential loose when conditions change or stress occurs. Fascinatingly, hsp90 also binds the key stress receptors, GCs and MRs, and their function requires a dissassociation from the two. So from single cell creatures to us, hsp90 has a strongly conserved evolutionary role, this being rather typical of most heat shock proteins.

Prions and chaperones: Outside the fold

Susan Lindquist has challenged conventional thinking on how misfolded proteins drive disease and may power evolution. But she still finds that criticism stings.

Carbs and Cancer

I've just finished reading an interesting review article on the relationships between carbohydrate intake(sugar!) and cancer incidence and metabolism. There are some important lessons here and worth giving serious thought to. For example:

Cancer, which might be considered a disease of civilization, has consistently been reported to be very rare among uncivilized hunter-gatherer societies [1-4].

... 

Data from 229 hunter-gatherer societies included in the revised Ethnographic Atlas indicate
that hunter-gatherer diets differ from typical Western ones in basically two aspects: first, a
strong reliance on animal foods (45-65% of energy or E%) and second, the consumption of
low-GI plant foods such as vegetables, fruits, seeds and nuts [7]. This is consistent with stable
isotope studies of human fossils [8, 9].

Full details of the paper overleaf.

Starving Cancers

This news item is interesting because it represents a novel strategy to delay tumour progression but that strategy is also unlikely to eradicate the tumour.

Short fasting cycles work as well as chemotherapy in mice
Even fasting on its own effectively treated a majority of cancers tested in animals, including cancers from human cells.

It touches on the Warburg Effect. You can read the Wiki entry on this but it has some errors. Notably:

• Glycolysis is not just anaerobic, it can also be aerobic. Hence the claims by some that oxygen therapy should kill cancers is just plain wrong. As I said to a friend recently, if oxygen is the enemy of cancer then explain lung and brain cancer. Can't be done. 
• The collapse of mitochondrial function still remains a mystery. Any cell may contain hundreds of mitochondria so we can rule our mtDNA changes, the causal agents here must be humoral. One possible candidate is UCP proteins, these proteins uncouple mitochondrial respiration from producing ATP. Brown adipose tissue uses this property to generate heat in our bodies. So we have a situation where this is a specific class of normal cells with UCP being ubiquitous but not driving cancer. That may be irrelevant because to my knowledge in adulthood we do not produce new fat cells, only make existing fat cells fatter. So fat cells may be oncologically disabled. 

Why Does Fasting Have This Effect?

The Warburg Effect, which is surprisingly common if not pervasive in cancer cells, makes the cell entirely dependent on sugar. Caloric Restriction does very much lower the incidence of cancer but comes at a big cost. That being:

• Compromised fertility
• Potentially reduce immunological status. 
• Hypoglycemia
• In humans I suspect over the long term it damages cognition(Neurons are entirely dependent on sugar, astrocytes absorb sugar from the bloodstream, convert it to pyruvate, which is then excreted to the extra cellular space, where it is then picked up by neurons. 

Caloric Restriction is impractical and unnecessary. Short intermittent fasting can do provide many of the same benefits. It is my view that if you are concerned about cancer prevention then learning to fast is a good idea. Stop the cancer before it stops you because nearly all of us have nascent tumours. It is a probability game and intermittent fasting helps stack the odds in your favour by promoting cell death in pre-cancerous and cancerous cells.

Fasting can induce sugar loss but keep in mind that despite all the hype about the dangers of sugar we'd be dead without it. Our brains our critically dependent on sugar, whether it be from glucose, fructose, or carbs(reduced to sugar via our bodies), we need that sugar in our bodies, hence the large reserves stored in our liver and muscles as glycogen. It therefore becomes problematic that collapsing sugar levels is a key component in the anti-cancer effects of CR and fasting. In fact, without experiencing hypoglycemia, which knocks you to the floor and carries its own risks, including brain damage, I'm not sure how collapsing sugar intake can be beneficial in treating cancers. So .... .

A very notable effect found in Caloric Restriction studies is that very substantial decline in Insulin Growth Factor prodn. We are talking about multiple declines in concentration here, not just a dip but a big decline. Sugar levels play an important role in regulating insulin growth factor levels. Insulin growth factor, stimulated for release and production from the liver by Human Growth Hormone, is the key growth factor. This addresses the above quandary because reducing sugar levels will have an immediate impact on growth factor production. As there is an increasing view that cancers are being driven by cancer stem cells, and these cells are signalled by growth factors, and the recent trend towards identifying inhibitors of growth factor receptors in cancerous cells, this suggests that real benefit of fasting is not sugar restriction per se but rather its impact on growth factor production.

This study highlights an ongoing and mysterious problem with cancers treatments:

As with any potential cancer treatment, fasting has its limits. The growth of large tumor masses was reduced by multiple fasting and chemotherapy cycles, but cancer-free survival could not be achieved. Longo speculated that cells inside a large tumor may be protected in some way or that the variety of mutations in a large mass may make it more adaptable.

Clonal selection, somatic evolution, what a damned nuisance! It large tumours it may even be the case that the surviving cells are feeding off the debri from all those dead cells! Don't know. Alternatively, even in apoptosis, there is some degree of inflammation present and this may drive increased blood supply when large numbers of apoptotic cells are present as inflammation generally increases blood and nutrient flow to a given region. That is the primary purpose of inflammation, it "opens up" the blood vessels to allow in various immune cells, growth factors, and nutrients to enter into the damaged tissue. Don't friggin know!

New Approach to Cancer Stem Cells

This will be the most important focus of future cancers research.

Collaborative Research Sheds Light On New Cancer Stem Cell Therapies

...

A collaborative anti-cancer research jointly conducted by The Hong Kong Polytechnic University (PolyU), Peking University Shenzhen Graduate School and Nevada Cancer Institute has led to the development of a novel class of chemical inhibitors that specifically target cancer cells with pluripotency.

1. Felix Cheung. Cancer biology: Ridding the seeds of evil. Nature China, 2012; DOI: 10.1038/nchina.2012.1
2. J. Wang, F. Lu, Q. Ren, H. Sun, Z. Xu, R. Lan, Y. Liu, D. Ward, J. Quan, T. Ye, H. Zhang. Novel Histone Demethylase LSD1 Inhibitors Selectively Target Cancer Cells with Pluripotent Stem Cell Properties.Cancer Research, 2011; 71 (23): 7238 DOI: 10.1158/0008-5472.CAN-11-0896