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Friday, March 13, 2015

How Did Cancer Evolve?

Cancer seems to exist as a different form of life.  But unlike a virus, a bacterium, or even the rogue proteins called prions, cancer (in humans) does not propagate from victim to victim.  Rather, cancer is simply a cellular disorder, a wrench in the works of cellular reproduction caused by damage to chromosomes.  Each case of cancer should be unique, and ill-adapted in comparison to the body’s defenses which have been honed through the ages by the survival of the fittest.

However, cancer possesses adaptive traits which enable the disease to evade the body’s immune response and promote the growth of the cancer.  Such adaptive traits would seem unremarkable in any form of life which changes through the process of evolution.  Evolution allows a species to pass successful traits to subsequent generations.  But cancer originates, develops, and dies with its host.  So how did cancer evolve, and how did it acquire adaptive traits?  It seems to me that this is quite a puzzle in evolutionary theory.  If we understood how adaptive traits have developed in cancer, we might have a better understanding of what cancer is, how it came to exist, and how to defeat it.
Adaptive Traits in Cancer
There are over 100 known cancers that affect humans.  Cancers are also common among animals that live more than 10 years.  Cancers affect a variety of species, and are caused by a number of known environmental triggers and susceptibilities.  The great majority of cancers, about 90% to 95% , are caused by environmental factors causing cellular damage and resulting in cancer.  There are also genetic susceptibilities to cancer, of which a few types are known in humans.  Genetic susceptibility to specific types of cancer has been bred into laboratory mice as a means of studying cancer and potential cures.  A few types of cancer in the animal kingdom are known to be communicable, but in general, cancers originate and die in individuals.

In 2000, Douglas Hanahan and Robert Weinberg published a landmark paper in the Journal Cell, titled “The Hallmarks of Cancer”.    The authors suggested that all cancers share six common hallmarks which characterize the disease.  In 2010, author Hanahan proposed four additional hallmarks.

The hallmarks of cancer include a number of sophisticated adaptive characteristics, which interfere with the body’s defensive efforts and promote the survival of the cancer.  Benign tumors also include these characteristics, with the exception of the tendency to metastasize, or spread to other areas of the body.

The hallmarks of cancer, as described by Hanahan and Weinberg, include the following traits.
A small table shown in Wikipedia summarized the six traits:

Simple analogy
Self-sufficiency in growth signals
"accelerator pedal stuck on"
Insensitivity to anti-growth signals
"brakes don't work"
Evading apoptosis
won't die when the body normally would kill the defective cell
Limitless replicative potential
infinite generations of descendants
Sustained angiogenesis
telling the body to give it a blood supply
Tissue invasion and metastasis
migrating and spreading to other organs and tissues

These traits are described in more detail below. 

>  Self-sufficiency in Growth Signals
Normal cells require chemical growth factors to multiply.  Cancers can grow and multiply without external growth signals, and sometimes produce their own chemical growth factors, such as the platelet derived growth factor (PDGF).  The receptors for growth factors in cancer can also be overexpressed, or mutations of the receptors can provide growth signals to the tumor in the absence of growth factors.

>  Insensitivity to Anti-growth Factors
The growth of normal cells is kept in check by growth inhibitors in the environment surrounding the cell.   Cancer cells are generally resistant to the signals in the body regulated cell replication.

>  Evading Apoptosis.
Apoptosis is the process of programmed cell death, in the event of cellular damage or malfunction.  Though processes involving a number of chemical signals and receptors, cancer cells disable the chemical signals which would signal the damaged cells to die.

>  Limitless Replicative Potential
Normal cells age and die.  The number of times a normal cell can divide is limited to about 40 to 60 times.  The process is the essence of aging.  Telemeres at the ends of the chromosomes are removed with each cell division; when the telomeres are consumed, no more cellular division is possible, and the organism dies of old age.   Cancer cells disable tumor suppressor proteins, and regulate telomerase, the enzyme that maintains telomeres.  Cancer cells circumvent the limits on replication, and can produce “immortal” cells which can reproduce indefinitely without limit.

>  Sustained Angiogenesis
Tumors require a blood supply for growth.   Angiogenisis is term describing how new blood vessels are formed.  Through processes that are not completely understood, cancer cells promote the growth of blood vessels which will feed a tumor.  In certain cancers, cancer cell produce growth factors which encourage the growth of new blood vessels. 

>  Tissue Invasion and Metastasis
Cancer tumors spawn “pioneer cells”, which invade neighboring tissues, or can travel through the bloodstream to other parts of the body.

In 2010, following on the original work, Douglas Hanahan proposed four additional hallmarks of cancer.  Again, several of these hallmarks appear to be adaptive in nature.

>  Deregulated Metabolism
Most cancer cells use abnormal metabolic processes to generate energy.
>  Evading the Immune System
Cancer cells appear to be invisible to the immune response from the body.

>  Unstable DNA
Cancer cells generally have chromosomal abnormalities, which progressively increase through the course of the disease.

>  Inflammation
Cancer cells are believed to produce local inflammation.  Recent studies have also identified chronic inflammation as a factor in promoting the occurrence and growth of many types of cancer.

Considerations from Evolutionary Biology
Over-interpretation is common in evolutionary biology.  For a time, it seemed that evolutionary biologists will propose an adaptive purpose for every trait in the animal kingdom.  In truth, many traits are simply the random dispersion of biological variation.  A cardinal is red and a bluebird is blue, but there is no particular reason why either color is adaptive to either species.  Indeed, if snow were a species, evolutionary biologists would undoubtedly declare that snow is white, because it is an adaptive trait.  White snow reflects sunlight as an adaptive characteristic for self-preservation and survival of its genes…except that it has no genes.  Snow is simply white by an accident of chemistry.

Author David Servan-Schreiber writes that cancer hijacks the body’s natural process for healing wounds.  Inflammation, angiogenesis and growth factors all critical elements of the body’s response to injury.  Still, although cancer may represent the body’s healing processes gone wrong, cancer also possesses a number of other specialized traits seemingly engineered to defeat the body’s natural defenses.  How and why did the complete suite of traits develop, and occur over and over again in different ways, in different cancer victims?

Survivorship bias may be another way to account for adaptive traits in cancer.  If I take a wrench and throw it into the engine of a Chevrolet, it is unlikely that the car will go faster.  If I throw a wrench into 10,000 Chevrolets, it is possible that one of them may actually be improved by the mutation.  And if we only study the instances of cars which are improved, it may seem that throwing wrenches into car engines is a consistent way to make cars go faster.  Thus, there may be many breakdowns of cells, most of which are successfully handled by the body, but only a few of which become cancer.   These would represent certain random collections of characteristics.  It is impossible for me to whether the incidence of cancer in its standard forms is merely the result of survivorship bias or a more organized and coordinated disease.

The only genetic heritage that cancer cells have is the human genome.  If cancer possesses sophisticated adaptive traits, it may be because cancer cells have inherited those traits from people in whom those traits were an evolutionary advantage.  How could a process for causing death be an evolutionary advantage?  By clearing out the elderly for the next generation.  (Thanks and credit to to my friend Greg Brown, who suggested this line of thinking and the key phrase.)  If true, this would be an example of group evolution, i.e. natural selection on the level of breeding populations rather than individuals.  That concept has been debated for decades and is still controversial among evolutionary theorists.  The idea of group evolution is currently out-of-favor.  But if cancer has acquired adaptive traits by improving the overall survival of a population, it would be the perfect example of group evolution.

Many things about evolution are not as we believed 40 years ago.   Genes have been shown to “jump” from individual to individual and from species to species.  Environmental factors have proven to affect inheritance through epigenetics, in a way that has sometimes been compared to Lamarkism, the long discredited theory of direct environmental influence on evolution.  It is not unreasonable to suspect that something unknown or not understood may account for the accumulation of adaptive traits in cancer.

The Puzzle of Cancer
So, the mystery is this.   Cancer exists as a set of over 100 different cellular disorders in humans, and many more varieties in other species.  These disorders are caused by a wide variety of environmental triggers and genetic predispositions.  And yet most cancers share a set of common characteristics. 

Eight of the ten hallmark characteristics of cancer appear to be adaptive.  Three of these traits* thwart the body’s attempts to control and remove the cancer.  Five of the hallmark traits promote the survival and growth of the cancer.   How did this suite of highly adaptive traits develop in a set of organisms that have no heredity, cannot evolve, and cannot transmit favorable traits to the next generation?   How did cancer evolve?

* Insensitivity to anti-growth factors, evading apoptosis, and evading the immune system.
* Self-sufficiency in growth signals, limitless replicative potential, promotion of angiogenesis, tissue invasion and metastasis, and inflammation.

David Servan-Schreiber, 2007, 2009, Anti-Cancer, A New Way of Life, 274 p.

Animal Cancers
Cancer is common among animals that live more than 10 years.

Cancer hallmarks
90% to 95% of cancers are caused by environmental triggers.

Hallmarks of Cancer, Hanahan and Weinberg

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