Hallmarks of Cancer

Ca Rectum

Adenocarcinoma under the microscope. Cells with a multiplicity of mutations leading to uncontrolled growth.

Cancer is the Result of Cellular Genetic Mutation

Every cell in our body (except red blood cells   forget them) is controlled by its own complicated blueprint in the form of DNA which forms genes, genes in chromosomes, 48 chromosomes to the cell. We have about 30,000 genes controlling each cell. As cells divide, the DNA and genetic structures can, and very commonly do, become mutated. Every second there are thousands, in fact. The cell’s repair mechanisms fix the defects, or marks the cell for disposal.

Since these mutations occur primarily in cells as they divide, the faster the dividing process, the greater the chance of mutation. Cancer cells gather these mutations as they develop in clumps, and multiple mutations are required for the cell to gain all the defects it needs to become malignant. Usually seven of eight and very often, many more.

So, What Mutations are Required? What Do Those Mutations Do?

One of the best references to understand what Cancer truly is can be found in this article from the journal Cell in 2011, by Hanahan and Weinberg (reference below) an improved review of the evidence from their original article in 2001.

All cancer results from mutations in a cell’s DNA, leading to propagation of cells of the tissue in a disorganized and uncontrolled manner. Cancers share the characteristic of uncontrolled growth, but the number and variety of typical characteristics is variable from one cancer to another. Ultimately it leads to tissue and organ destruction by the invasion of malignant cells into body tissues, the co-opting of food and energy resources, and the production of detrimental substances that adversely affect body function.

The key to controlling and defeating cancer is to understand the characteristics of cells that make the cancer in the first place. Hannah and Weinberg’s well known article is one of the first and best in the comprehensive description of the changes required, but it is bloody hard to read if you are not a biochemist. In fact, it’s bloody hard for an oncologist with forty years of experience. So let’s try:

Keep on Truckin’ (Sustained Signaling of Proliferation)

Many changes in the coding of the cell’s blueprint, the DNA, result in such intense trouble for the cell that the cell does not survive. This is a usual and probably frequent protection of the organism against uncontrolled sustained growth by a small family of cells (clone) which is stimulated to grow by several mutational changes within the clone’s DNA: chemical signals telling the cells to grow are produced by changes in DNA governing the pathways normal in the cell, and failure of the usual negative feedback controls within the cell that normally stop such growth. Basically, the cell’s mutations lead to excessive signals to keep proliferating.

Side-Stepping Trouble (Evading Growth Suppressors)

The normal cell machinery often contains controls to cell proliferation; the cancer cell must develop methods of evading these controls. This often involves tumor suppressor genes that can stop the development of the cancer cell. Typical examples are the Retinoblastoma gene and the TP53 gene.  These provide gatekeepers to the cell’s continued growth, and even lead to the cell committing suicide (apoptosis). Mutational damage to these mechanisms allow the cancer cell to continue unabated. Some of these changes involve contact inhibition that normally helps to mold tissues into appropriate shapes and structures; when lost, the groups of cells grow into patterns that are unhelpful, damaging to other tissues, and uncontrolled.

A previous post referenced Immune Checkpoint Inhibition, where the tumor cell actually ‘learns’ to produce a signal telling the host immune system not to eat it, thus avoiding growth suppression.

Keeping the Bad Apples (Resisting Cell Death)

As mentioned before (above and in a previous post), the organism can protect itself from cancer by inducing cell death, a natural barrier to malignancy. Dead cells don’t replicate. Bad ones do. There are normal genetic mechanisms that maintain this type of control, and these mechanisms can be damaged by mutation. But additionally important is the method of dying. Cells that undergo programmed cell death, as opposed to cells that die from over-reaching their own supportive resources (food, oxygen), do not exude as much stimulus or growth factors for other surrounding cells in the malignant tissue. Thus, when programmed cell death is avoided, and the cancer cells die from outstripping their supplies, the resulting inflammation can stimulate cancer production.

Forever Young (Enabling Replicative Immortality)

Most normal cells are capable of only a defined number of replications. After a while, they just can’t do it anymore. Basically the cell line gets old (senescence) and reproduces no more, or goes into crisis and ups and dies. Cancer cells lose that mechanism of control and keep on reproducing forever. The biochemistry of this is somewhat better known to the lay public who have heard of telomeres, protein structures at the end of chromosomes which shorten with each division, keeping count, if you will, like an abacus. After a pre-defined number of divisions, they stop. Mutations in the cell can sabotage this control mechanism.

Irrigation (Inducing Angiogenesis)

Cancers cannot simply grow without blood vessels providing for delivery of nutrients, much like irrigation channels for agriculture. Generating blood vessels is a necessity, and cancer cells must gain that ability to stimulate the necessary vascular growth or die from starvation/suffocation. Such a function is enabled in normal tissues by vascular endothelial growth factors, proteins produced as a result of gene control that must be increased in the cancer cell to support the increased growth.

Building Landing Craft (Activating Invasion and Metastasis)

For cancers to do the damage they do to the large variety of tissues in the body, they must develop the ability to travel through the body and take up shop somewhere else. This is not a natural function of normal cells. Your lung cells do not normally take a trip to the kidneys and transplant themselves there. Such a project requires more talents than the typical lung cell has at it’s disposal. Genetic mutation within the cell must produce the ability to relocate.

The reprise article which built on the work done up until 2001, was published in 2011, and contained several other enabling characteristics of cancer.

Compound Interest (Genomic Instability and Mutation)

Mutations occur during proliferation. Mutations that induce greater proliferation thus result in more mutations which then result in greater proliferation, which results in…

Well, you get the idea.

It becomes a cascade, a snowball. It is like compound interest working for the cancer. The more unstable the genetic material (the genome) within the cell, the greater the chance of a mutation resulting in more of the same. Failure of DNA repair mechanisms within the cell leads to more fragile DNA that can be mutated more easily. Genes which maintain these repair mechanisms fail when they become mutated, leading to more damage and more mutations. Indeed, some of these failings of DNA repair mechanisms lead to family clusters of cancer when they occur in the genetic patterns within members of the family, such as the BRCA 1 and 2 genes that lead to breast and ovarian cancer.

Spoils of War (Tumour-Promoting Inflammation)

The detritus in the wake of uncontrolled tumor proliferation is not neat and orderly. There is a lot of inflammatory material which can promote further genetic damage. Inflammation in the body can result in the collecting of repair enzymes, growth stimulants and destructive proteins which can aid new cancer cells, as well as the new normal cells which result from the normal repair process.

Faulty Emission Control (Reprogramming Energy Metabolism)

Curiously, the cancer cell often develops a failure of metabolism of glucose, the prime fuel for the cell. Coincidentally, however, this results in greater building blocks for subsequent cellular proliferation. Many non-physicians and non-biochemists out there will remember high school science classes in which they studied, however superficially, the Kreb’s or Tri-carboxyllic Cycle, now known also as the Citric Acid cycle. In this chemical pathway,  glucose is ‘burned’ step by step from a six carbon molecule down to carbon dioxide and water, simply with the addition of the oxygen we breath. You may remember the straight line part at the top of this pathway, entering into the circular path at the bottom in the usual representations.Citric

Some will even know that during high out put states of exercise, such as in sprinting, the muscle cells of the body chew up glucose into pyruvate, rapidly producing the energy required for the short term high output effort. The pyruvate then gets burned down to the basics of carbon dioxide and water in the tri-carboxyllic cycle, producing a lot more energy (about 8 times what is produced getting to the lactate stage); but that takes a lot more time, and more oxygen, and so the accumulated pyruvate gets diverted into lactate when there is not yet quite enough oxygen (the oxygen debt), which produces the burn (‘Feel the Bern’).

That lactate or pyruvate can be used in the building of more cancer cells, however, starting from three carbon building blocks, instead of just single carbon molecules, and producing energy (in the form of ATP and other energy transporting molecules) without the need of oxygen, which in rapidly growing tumors is often at short supply.

While this adds to the growth advantage of cancer cells as a group, in terms of proliferation, it also results in tumor tissue absorbing ten to a hundred times the amount of glucose that the surrounding tissues absorb. Cancer cells don’t know it, of course, but this leads to our ability to find those cancers using a PET Scan.

Hah. Too clever by half, cancer cell.

Our increasing understanding of the biology of cancer is leading to improved therapies. The old days of the nasty cyto-toxic chemotherapies with their attendant side effects and dangers may soon be behind us, what with hormone manipulation, Tyrosine Kinase inhibitors, vascular endothelial growth factor inhibitors, other drugs which disrupt cancer biochemical pathways, monoclonal antibodies and now immune checkpoint inhibitors.

What Bad Luck, For One Cell to Become Malignant

Well, there it is. These are examples of mechanisms by which a normal cell gradually becomes a cancer cell. Probably one of the common responses to all this is the wonder at how the cancer knows what to do, what mutations to create.

It doesn’t know. The secret is in huge numbers and Darwinian evolution.

It is all by accident that they come up with the right mutations. It seems way too much coincidence. But think of it: one cancer, a centimeter in size, can contain 10,000,000,000 cells. Dividing and splitting chromosomes all the time, many mutations lead to the individual cell’s death. But one in a million might lead to a mutation that does not stimulate programmed cell death, but gets constantly replicated in the progeny. As the clone becomes more damaged, more nasty mutations occur, and more frequently.

Still to much coincidence for you? Think of this thought experiment in the power of statistics and chance. I can ALWAYS find a person who can win ten games in a row of a coin toss.

ALWAYS. Two people toss a coin and call it, I can produce someone who wins ten times in a row, EVERY TIME.

This is reminiscent of a cell becoming a cancer by having the right series of mutations.

Just gather 1024 people together in a large room, have them pair off and play a coin flip. Then have the winners do it. And again. An again. Each cycle there is only half the number of players left, and at the end, one guy has remained standing having just won ten coin tosses in a row. Every time. (I forget where I read this first, but it might have been Richard Dawkins)

Thousands of cells die in the mutation process, but in the end, one nasty one is left, and that’s all it takes.

What Do We Do Now?

The future is slowly getting better in cancer care, admittedly with repeated little baby steps. But the progress is slow in human terms, as too many patients suffer even today, and too many lives are being lost. We are getting there, certainly, but there is a lot we can do while waiting for the relentless progress of medical science.

Lifestyle: don’t smoke, eat healthy, get your exercise, drink in moderation.

Environment: save the planet by changing our energy source and controlling our catastrophic population growth.

Social structure: reduce the gap, educate the people, ensure health care access for everyone.

And rid yourself of mystical thinking. Unethical or immoral behavior (or what others think is unethical or immoral) does not produce cancer; bad luck does.

Curing cancer will still take a long time. We can work on these last three things right now.

The Bern is not due to excessive lactate!

 

Hallmarks of Cancer: The Next Generation, Hanahan, D., and Weinberg, R., Cell 144, March 4, 2011

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