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

IDO, ITO, tryptophan, and Cancer Immunotherapy

One for the archives but this is interesting because it has long been known that tumours often express proteins that inhibit immune responses. http://medicalxpress.com/news/2012-01-cancer-therapy-preclinical.html ...

Scientists from the Ludwig Institute for Cancer Research (LICR) in Brussels identified a new target for cancer therapy, an enzyme which prevents the immune system from recognizing and destroying certain types of tumors. Called tryptophan 2,3-dioxygenase or TDO, the enzyme works by depriving immune cells of tryptophan, an amino acid essential to their activity. TDO is produced by a significant number of human tumors. Scientists also show that blocking TDO activity with a novel TDO inhibitor promotes tumor rejection in mice. The study findings were published online today in the January 30 issue of the Proceedings of the National Academy of Sciences (PNAS).