Cancer and autophagy
A cancer cell is a damaged cell where the damage allows the cell to replicate without constraint. There are as many types of cancer as there are ways to damage a cell in this way. The damage must be to the genetic machinery of the cell else it would not transmit to all daughter cells. Likely all fatal cancers trace back to a single cell among the 50 to 75 trillion cells of the adult human body that has acquired the ability to replicate without constraint, to evade the body’s cancer defenses, to convince the body to feed it and/or to spread throughout the body.
This genetic damage is usually from an external source such as tobacco for lung cancer, UV rays for skin cancer, or viruses for cervical cancer. These common cancers often strike at an early age and the incidence varies greatly between regions. Other cancers are more characteristic of old age and are said to be senescent.
Cancer and cardiovascular disease are the quintessential senescent diseases in that their general incidence rises exponentially as an organism approaches the maximum lifespan characteristic of its species. A 20-year old dog will be as cancer riddled as a 90-year old human despite their similarities at the cellular level.
The question then arises as to what mechanism accounts for the exponential rise and the differences among species? Depending on definitions, it has been estimated that around 5000 cells per day out of 50 to 75 trillion total cells of the body become cancerous. Normally these cells are destroyed by the body’s cancer fighting mechanism, the immune system. Cancer rates therefore depend on two opposing factors: the rate of mutagenesis producing cancer cells versus the efficiency of the immune system in killing them.
A mutagen is anything that causes a mutation: an alteration in the DNA of the cell that materially and permanently changes the cell. X-radiation is an example that directly damages DNA. The chemicals associated with tobacco use are the most prominent direct mutagens. Other mutagens are produced by the body itself in reaction to what may be termed indirect mutagens; alcohol, obesity and inactivity, all known causes of cancer, probably work this way by causing an increase in ROS (reactive oxygen species) that then do the actual damage.
One can minimize but not entirely eliminate exposure to external mutagens. Further there are internal mutagens such as genetic predispositions independent of behavior. Some genes, for example, detach from their original position in the chromosomes and reinsert into some other position. Other genes make copies of themselves that then insert into somewhat random positions on the chromosomes. This jumping gene process, though likely beneficial to the evolution of the species, can create cancers to the detriment of the individual. It is thought that something similar to this jumping-gene mechanism is used by the body to create the large random assortment of antibodies produced by the immune system.
Antibodies are proteins that bind specifically to other substances, their antigens, for the purpose of signaling their presence. An antibody producing cell is genetically altered to make just one species of antibody. The body generates hundreds of thousands if not millions of species of such cells by a random process early in development. Then those cells whose antibodies are currently binding their antigens are culled and eliminated. After the culling period, the remaining cells wait for the remaining life of the organism for their antigens to appear. If and when they do, the particular cell proliferates producing more antibodies that now signal other cells to destroy the antigen and/or whatever is displaying the antigen.
All cells are required to display pieces of their internal proteins on their outside membranes. Those that display antigens for existing antibodies are destroyed by the immune system as are those who fail to display anything. Only those proteins present at the time of the antibody cull are allowed (or those by chance not recognized by any of the body’s remaining antibody species – presumably a rare event perhaps more common in old age). An invading virus, for instance, is thus recognized by the “foreign” proteins it encodes and its host cell is killed to limit the infection.
Cancer cells are usually killed by the same process. The genetic damage that makes a cell cancerous in the first place often causes the cell to make proteins not present during the cull. These may be fetal proteins only required for early development or others normally not ever produced at all. Or a mutation may alter a protein sufficient to make it appear foreign. Either way the cell is seen as producing illegal substances and is killed.Very few cells with major genetic damage make it this far (a mere 5000 a day) to be eligible for an external attack. Most die from internal processes many of which are likely designed just to prevent cancers from forming. These internal detection systems command an orderly death when triggered.
About 50-70 billion cells normally die every day in the human body. Usually when a cell knows its time is up, it packages itself up into bite-size pieces and hangs eat-me signs on its outer membranes. Its neighbors and passing macrophages then consume the dying cell. This orderly process is called programmed cell death or apoptosis and the cell maintains a system of enzymes just for this purpose, the caspases. If a cells dies without apoptosis, a so-called necrotic death, its contents spill out and provoke an inflammatory response, a less desirable outcome from the point of view of the entire organism.Sometimes a cell dies from excessive autophagy and that is then called autophagic cell death. This dual role of autophagy, preserving the cell or killing the cell, creates many problems of interpretation especially in cancer studies where the goal of treatment is to selectively kill human cells. It is a current controversy whether autophagic cell death is programmed or accidental. It is certainly messier than apoptosis and one would wonder why the body would sometimes select it when a better mechanism is available. More likely autophagic cell death reflects the cells heroic but futile rescue efforts in response to a fatal stress.
In some cancers, the apoptosis mechanism is broken and the cell fails to respond to internal or external signals that apoptosis should initiate and complete. The damage can occur at any point in the complex apoptosis system and cancers will behave differently depending on where the damage has occurred. Some, for example, will not respond to external requests to kindly die such as provided by immune cells when they detect that the cancer cell is producing unusual proteins. Others may simply be unable to complete the apoptosis program regardless of who initiates it.
As autophagy is likely involved in all cell processes including apoptosis and antigen presentation, drugs or other treatments that affect autophagy might be expected to affect cancer growth as well. Indeed this is seen: autophagy enhancers promote some cancers and retard others, and the converse is seen for autophagy blockers.
A cancer cell with a broken autophagy system may thereby avoid apoptosis but then not get the benefits of autophagy, namely the ability to survive a period of starvation and stress. Many conventional cancer treatments are thought to work in just this way, by stressing all cells to the point where the weaker cancer cells die. Some autophagy enhancers might then be expected to override the breakage and allow some cancer types to better survive the treatment, making things worse. For other cancer types, overriding the breakage may then allow apoptosis to complete, making things better. Other cancers have intact autophagy systems and would show no affect. Cancer is complicated…
The question then arises concerning protein cycling, an autophagy enhancer; does it promote or retard cancer generally? From an earlier chapter it was seen that cancer underlies far more deaths than neurodegenerative diseases and this is not a trivial concern. Many cancers though have known environmental causes (smoking, obesity, sun exposure, alcohol, etc.) and are mostly preventable. To subscribe to protein cycling while not dealing with these known cancer causes is disproportionate to say the least. Certainly if one is currently under treatment for cancer, that is perhaps not the time to practice speculative diet measures. If otherwise one might look to the data.
Though protein cycling has not been studied in this context, intermittent fasting including ADCR has and the results have been encouraging86,104. At least in mice and rats, alternate day fasting (ADF) in the few studies available showed lower values of cancer markers or longer survivability compared to the controls. Though it may be premature to practice protein cycling for the sole purpose of diminishing cancers, one can be reasonably confident from studies so far that it would not make cancer incidence worse.