Biology - Molecules and Cells

 Terms and Concepts 

SECTION 6

CANCER

 If we can __________, why can’t we cure cancer?

It seems like a simple question, and if you look at cancer broadly, it seems reasonable.  In cancer, some type of body cell (almost always cells whose job involves mitosis, and these are almost always stem cells that produce replacements in various organs) divide out of control and fail to differentiate;   instead of becoming functioning body cells, they form pockets of almost embryonic cells, tumors.  Some cancer risk factors increase stem cells' division workload, like lung or digestive irritants, toxins processed in the liver, response to sex hormones, or addition of many new fat cells;   more divisions increase the odds of cancerous changes.  In dangerous cancers, cells at the edges invade surrounding tissues, the tumor largely evades clearance by the body’s defenses, and cells or cell clusters break free, migrate to new locations, and form new tumors elsewhere (metastasis).  This description makes cancer sound simple, and it’s easy to believe that a single treatment could be the answer.

But a cancer cell is abnormal, and the abnormalities come in a multitude of flavors.  Disruptions of the normal cell cycle, problems with the proofreading systems at work during DNA replication, refusal of damaged cells to kill themselves through apoptosis, disrupted interactions that could allow the immune system to recognize and remove cancerous cells, these are just some of the systems that go wrong to initiate cancer.

Populations of replacement cells are a basic feature of multicelled systems, so evolution has provided a number of safeguards to prevent or remove dangerously-altered cells.  Inside the cells, DNA copying is checked for errors and repaired;  if DNA is too damaged, it won't be copied and the cell won't divide;  cells showing too much damage are given commands for apoptosis, and they kill themselves.  Controls come from outside the cells as well.  A relatively new hypothesis, tissue organization field theory, is based on the idea that cell interactions within the tissues are critical in making the cells "behave," and small local changes are necessary for cells to get out of control.  In some epithelial tissues, damaged cells that try to detach are literally eaten by a neighbor.   Immune response, possibly to cell components being released from damaged cells, or cell markers altered enough by mutations to be what are called neo-antigens, is an area where much current treatment research is focused.  A small area of research is trying to determine if microbiome interactions with the immune system can have negative or positive effects on cancer.

Mutations.   Cell division and differentiation is a complex process that involves a tremendous number of proteins in timely interactions.  This system is so prone to errors that there are proteins that just prevent a cancerous change, coded by what are called tumor suppressor genes.  These genes may keep new divisions from starting too quickly, they may be involved in repairing DNA copying mistakes, they may initiate apoptosis if a cell is too damaged to trust anymore, or they may keep cells from becoming mobile.  A cell with mutations that produce non-working or barely working versions of these proteins loses much of its anti-cancer protection.   Cancer-causing mutations usually require that both copies of a suppressor gene go “bad,” so cancer in a cell is generally recessive;  an old cancer allele may be passed along many times before the second allele mutates to a non-functional version.  This is part of the reason why risk of cancerous changes is higher in systems that generate a lot of cells and the risk increases with age.  About 2% of the population is diagnosed with cancer before age 40;  by age 80, that number is 50%.  It has been found that cultured stem cells generate mutations associated with cancer, more in older cultures, although cancer itself has not appeared in the cultures.  In stem cells that respond to hormones, such as estrogen, the hormones and cell responses are associated with cancer risk.  Some cancers, such as aggressive prostate cancers, show widescale chromosome rearrangements that seem to follow a pattern driven by evolution, preserving the "good" (for a cancer) combinations.

A common type of mutation in cancers, especially advanced cancers, is aneuploidy, an abnormal number of chromosome copies, which changes the number of gene codes available for all of the genes on the extra or missing chromosomes.

Mutagens are a broad category of chemicals that can increase mutations in cells.  The affected genes are typically called oncogenes.  Many of the well-known cancer risks, such as tobacco, oxygen radicals, and many organic solvents, can interfere with DNA replication, often by causing patterns of point substitutions. Estrogen metabolism produces mutagens that affect purine nucleotides.  Radiation of various frequencies can be absorbed by DNA, destabilizing it and causing multiple breaks.  Ionizing radiation, such as x-rays and gamma rays, can cause breaks either directly or by causing changes in nearby molecules that interact with DNA;  ultraviolet radiation tends to cause a particular substitution of cytosine for thymine.  Viruses, such as the human papillomavirus, can cause disruption as its own DNA inserts itself into host cells.  Some research suggests that bacteria like E. coli might produce mutagenic products.

There are many different genes whose mutation can lead to cancerous changes.   The Cancer Gene Census Database lists some 600+ genes associated with cancers.  Roughly 20% may be mutations inherited from parents.  Many inherited mutations (or mutations occurring in early stages of the embryo) are associated with childhood cancers, and have recently been found to increase risk for adult cancers that were thought to be unrelated to those genes.  As mentioned, there are several classes of tumor suppressor genes.  Some other genes associated with cancer code for histones or other structural elements of chromatin, changing the epigenetics of whole regions (see more below).  Destabilization of so-called insulated neighborhoods on a chromosome can drastically affect expression of genes in those previously little-used neighborhoods.  Mutations may change proteins involved in transcription, producing proteins that attach to tumor suppressor promoter sequences, effectively shutting them off.  Mutation in proteins associated with spindle formation can prevent differentiation of damaged cells.  A new area of research is investigating code changes for microRNAs, important nuclear processing molecules.  Other changes can affect the splicing of messenger RNA that is an important part of the final code;  some splicing changes may be associated with particular cancer types. 

Summary of changes needed in cell populations to produce cancer.

Basics of cancers as surviving systems.

Cancer risk and age.

List of known carcinogens.

Mutations in childhood cancers are associated with later cancers as well.

Fusion mutations may play a role.

Cancer Gene Census site.


Cancer epigenetics.

Too many centrosomes.

How do mitochondria figure in?

Epigenetic Disruptions.   There is a growing list of discoveries in this area, where the main effect is on the expression or suppression of unmutated genes initiates the cancer.  These changes can be in the DNA, in non-gene expression factors such as promoters or enhancers, which can be hijacked from other genes.  The changes can be in the methylation “clips” that control gene activation:  proteins called epigenetic erasers may be affected.  As mentioned above, changes that affect histones and chromosome integrity can drastically affect the ease / difficulty of using genes in the affected regions.

Non-differentiation.    A critical detail of cancer initiation is a basic change in the normal stem-cell process.  Stem cells are a population of potential replacement cells;  they are non-differentiated, but the replacement process requires them to activate the proper genes to make them work in their new jobs.  Cancers can arise when that system is compromised:  the starting process, cell division, is activated, but the changeover to usefulness is compromised, producing a population of cells somewhat like an early embryo.  In fact, it has been found that some of the active genes in cancers would also be found activated in embryos.  In one case, embryonic genes were not only active but were the target of what the researchers called “super-enhancers.”

Inflammation, a local release of immune-system chemicals (mostly histamines), is a known risk factor to initiation of cancers.  It is thought to destabilize the stem cells, but how, the mechanism of its role, is not understood.  Certain inflammation-prone tissues and conditions, and cells involved in inflammation, seem to be associated with cancer initiation.

Early Tumor Formation.  As mentioned above, mutations accumulate in stem cells, and there may need to be a critical theshold of mutations to produce a legitimately cancerous cell.  One study of advanced cancers found on average 1000 - 2000 point mutations.  Among those were a few hundred insertions, deletions, and rearrangements, those mutations most likely to completely shut down the coded proteins' functions.  Stem cell populations may produce precancerous lesions. Colon polyps, breast ductal carcinoma in situ, acid damage to the esophagus, and the changes looked for in pap smears reveal cells that have some, but not enough, mutations to become cancerous.  Mutations that are necessary to certain progression points of cancer are called driver mutations.  Some researchers have claimed that normal mutation rates are not fast enough to produce the several known driver mutations;  they may be miscalculating, or the rate increases with the production of many damaged cells in lesions, or a cancer may need to go through a hypermutation event, producing multiple DNA alterations very quickly. As cancers progress, normal mitosis processes get more and more chaotic, resulting in chromothripsis, major chromosome fragmentation, rearrangements, fusions, and other larger-scale mutations, sometimes even the formation of extra micronuclei.

Evolution and Selection.  The idea that one cell changes, and all of the cells in a tumor are descendants of that cell, may be true, but the production of more and more genetically damaged cells drastically raises the odds that new subpopulations with different alterations will arise in the tumor.  Are the cells equivalent to separate unicellular organisms, or does the tumor become, essentially, a multicellular unit?  The answer to that probably varies (and many cancers could be considered colonial), but an established tumor no longer is performing a function for the body;  it has effectively become a parasite, with the body as its ecosystem.  One good thing is that, unlike parasitic species, cancers are terrible at spreading to other individuals.  That's not impossible, though:  cancer viruses spread from host to host, and there have been a few instances in nature where actual cancer cells move to a new host and establish cancers there.

These cancers are just as affected by the principles of evolution as any parasite population.  Changes almost certainly select out ineffective cancer cells from the population - who knows how many tiny clusters of cancer cells just die out?  That question may be critical to the discovery that early detection programs for breast cancer have found lots of cancers but have had virtually no effect on longterm survival rates:  many now-treated cancers might never have gotten large enough to be detected if they had not been found.

As a tumor grows, it develops needs it did not have as a cluster or layer of stem cells.  For instance, the core of a tumor gets further and further from the surrounding blood vessels, becoming starved for oxygen and nutrients.  Here's where major driver mutations are critical, as certain abilities buried in the genome but not used by the original stem cells must activate, either through mutation or epigenetic alterations.  One common driver mutation is a strong activation of glycolysis, effectively starting up the oxygen debt system.  It is controlled through a gene that is actually a neighbor of a commonly-mutated tumor suppressor gene, so it may be easier to access as a result of that alteration.  It has been found that hypoxia, oxygen starvation, can promote progression of cancer, even spurring on other driver mutations.  This dependence on glycolysis means that cancers depend upon the presence of glucose, while other potential energy molecules, such as proteins or lipids, are not accessible (although metastatic cells might be using fatty acids).  Some attempted treatments based on carbohydrate restrictions have seen limited success.

In some cases, tumors activate genes used during early development and growth that "call in" extensions of the circulatory system;  blood vessels grow into the tumor (this is called angiogenesis, and some chemotherapies block this action, so its metabolic needs are different from glycolysis-reliant cancers.  Recent evidence suggests that neighboring nerve cells may help the tumor recruit blood vessels.

As a tumor grows, it is not just a mass of cells;  a matrix of fibrous material somewhat like a wound develops, called the stroma.  Features of the stroma seem to resist invasion of immune systems cells, and may even help to recruit such cells from bone marrow production processes to prepare eventual colonization sites for the cancer to spread to.  Cells in the tumor release exosomes, which may also adhere to tissues elsewhere and prepare that area for eventual invasion.  Exosomes can facilitate eventual migration through the fluid drainage system (lymph system), and there is some evidence that they can transport microRNAs into normal cells and spur cancerous changes there.

Tissue Invasion.   Some precancerous lesions, like moles, tend to be self-limiting;  the tumor stops expanding and stabilizes (although those cells are more at risk for cancerous changes).   In the colon, stem cells remain in microregions called crypts, but cancerous cells do not.  An early step of true cancer is for the margins (edges) of the tumor to begin to form extensions into the surrounding tissues.  The name cancer comes from the crab-like appearance of these truly cancerous tumors.

Metastasis.  The developing tumor is a mixture of distinct populations of cells, often cooperating to support the tumor and resist the body's control efforts (and medical treatments).  The truly life-threatening aspect of most cancers is a transition to malignancy, when cells or clusters of cells activate genes used by cells like white blood cells to migrate around the body.  These cells must also loosen their connection to the initial tumor, get free into and through the tissues, and move elsewhere.  Migration may increase DNA damage as cells (and their nuclei) squeeze through tight places, physically stressing already compromised chromosomes.  Movement from the tumor site often follows the pathway that white blood cells follow:  once WBCs have left blood vessels into the tissues, they can't really squeeze back in, and they move into the lymph system (which drains fluid that has also leaked from the blood vessesl), which will eventually return them to the circulating blood.  This is why lymph nodes, white blood cell repositories along the system, are sometimes checked when tumors are removed.  In tumors where local blood vessels have been compromised, however, that is an available migration route;  in some cases, clumps of tumor cells loose in the circulation eventually lodge in small blood vessels and grow into new tumors there.

By this stage, the genetic profiles of cancer cells show some basic similarity, as there are a limited number of changes (mutation profiles) that can move the tumor down the progression needed to survive and spread.  Secondary tumors have very little resemblance to the types of cells they originally started as, and the evolution of these parasitic clusters continues.  Among the cells may be a small population of what have come to be called cancer stem cells, cells that have gone quiet (and therefore are not using chemistry targeted by chemotherapies), which may not die when the other cells do but which may become active later.

In 1914, chomosomal abnormalities were recognized in cancer cells.  Later, carcinogens, chemicals that could cause cancerous changes, were recognized, and these were often found to be mutagens, causing changes in the DNA of the cells.   Moving DNA from cancer cells to normal cells could change them into cancer cells.  Specific genes, oncogenes, were discovered, and many of those were found when active not to cause cancer but to prevent it - tumor suppressor genes.

Much of what is described here has been discovered by dedicated researchers who probably themselves were frightened by the prospect of cancer.  Just as the causes and mechanisms of cancer are many and varied, the areas of discovery and study cover the whole spectrum of cellular biology.   New treatments are being proposed, tested, and administered every year, but the going is slow, since every cancer is to one extent or another a unique population of cells.

Many cancer researchers have pointed out that the most successful area of research has found many risk factors for cancer, including steps that can be taken to prevent the occurrance of cancerous changes in our cells.  Our greatest defense against cancer is to reduce the odds of ever getting it, but even the researchers who recognize the risks find that they have difficulty changing their habits in line with these preventions.

Some risk factors, like tobacco exposure (smoking or chewing), are well know.  One controllable risk factor, obesity, is know to many as increasing risk of things like diabetes and heart disease, but it also increases cancer risk as well.  Weirdly, obesity might increase the odds of developing cancer, but it might also amplify the effects of some anticancer drugs.

Terms and Concepts

In the order they were covered.

   Tumor
Metastasis
Cancer Causes
Tissue Organization Field Theory
Neo-Antigens
Mutations and Cancer
Tumor Suppressor Genes
Mutagens
Oncogenes
Aneuploidy & Cancer
Cancer Gene Census Database
Epigenetics and Cancer
Differentiation & Cancer
Super-enhancers
Inflammation & Cancer
Early Tumor Formation
Driver Mutations
Hypermutation Event
Evolution & Cancer
 Oxygen Debt & Cancer
Angiogenesis & Cancer
Tumor Matrix (Stroma)
Exosomes
Micro RNAs
 Tissue Invasion
Metastasis Progression
Secondary Tumors
Cancer Stem Cells
Treatments
Radiation & Cancer
Chemotherapy
Telomerase
Cocktails
Immunotherapy
Microbiome & Cancer
Cancer Prevention