New view of cancer development focuses on subtle, combined effects
Rethinking Carcinogens: “Hallmarks of Cancer:” How Normal Cells Turn into Cancer Cells
Cancer develops over time as mutations and genetic changes accumulate in cells. The traits a normal cell acquires as it slowly transforms into a precancerous one and ultimately into cancer are called the “Hallmarks of Cancer”.30,31 They are the characteristics that distinguish cancer cells from normal cells. Although each hallmark contributes to cancer, it is not until a cell exhibits the complete set of characteristics that cancer has fully developed. This framework illustrates that cancer develops through a set of discrete transformations (genetic changes). This is known as the multi-hit model of carcinogenesis because it takes multiple alterations or “hits” to cellular processes for cancer to develop.
To fend off cancer, the human body has many layers of safeguards to control cell division and prevent DNA damage. A chemical that interferes with a single cancer-related hallmark process, therefore, is unlikely to cause cancer. But combine a chemical that interferes with the cell division cycle with one that interferes with the cellular death cycle and you begin to see how exposures to chemical mixtures have the potential to overwhelm the body’s defenses. Understood in this way, it is easy to see how chemicals that interfere with one or more hallmark processes could combine to form carcinogenic mixtures that apply multiple “hits” to cellular processes.
The Hallmarks of Cancer
In two landmark scientific papers, Douglas Hanahan of the University of California, San Francisco and Robert Weinberg of the Massachusetts Institute of Technology described the Hallmarks of Cancer this way:30, 31
1. Self-sufficient cell division
Cells are organized into tissues and tissues are organized into organs with specific functions, such as the heart, lungs and skin. The cells of each organ must work and communicate as a team to function properly. When growth is necessary, cells collectively send signals to other cells to divide. Cancer cells, on the other hand, do not behave as team members. They control their own proliferation by producing growth signals themselves or by having overactive signal receptors.
2. Insensitivity to signals to stop cell division
Just as there are signals that stimulate cell proliferation, there are signals that put the brakes on cell growth and proliferation. Cancer cells are able to interrupt or ignore these inhibitory messages. Usually this is a result of mutations or alterations to genes known as tumor suppressor genes, which normally control a cell’s response to external and internal cues to exit the cell division cycle.
3. Resisting cell death
When cells become old or damaged they are programmed to die in a process called apoptosis. This is the body’s way of limiting growth and discarding cells with damaged DNA in order to prevent propagation of DNA errors. Cancer cells are dangerous because they avoid the normal cell death cycle and continue to accumulate in the body. Apoptosis signals can be disrupted when tumor suppressor genes suffer mutations or other damage.
4. Limitless reproductive potential
The accumulation of the billions of cells it takes to form a tumor requires uncontrolled cell division, avoidance of apoptosis and the ability to replicate an unlimited number of times. In normal cell division, a small portion of the end of each chromosome, in a region called the telomere, is lost every time DNA is copied. Eventually the loss of telomere reaches a critical point and the cell can no longer divide and replicate. In this way, healthy cells self-limit their replication, but activation of an enzyme called telomerase can maintain telomeres and allow the cell to continue to replicate indefinitely. More than 90 percent of “immortalized” cancer cells have activated telomerase, while most normal cells do not.
5. Creating their own blood supply
In order for a tumor to grow it needs a greater and greater blood supply to provide oxygen and nutrients to the increasing number of cells. A tumor is able to stimulate formation of new blood vessels, a process known as angiogenesis, to supply it with adequate nutrients and promote its growth.
6. Ability to invade other organs
Cancer cells, unlike normal cells, can metastasize – break through tissue barriers and spread from one organ to another. Sometimes they do this by entering the newly formed blood vessels created by the tumor.
7. Ability to survive with little oxygen
Even with an increased blood supply, cells in the interior of a tumor may be oxygen- and nutrient-deprived. This would be detrimental to normal cells, which use oxygen to convert glucose to energy through the process of aerobic metabolism. Cancer cells have the ability to switch from aerobic to anaerobic (oxygen-free) glucose metabolism (glycolysis) to allow oxygen-deprived cells to continue to produce energy and survive.
8. Evading the immune system
When functioning properly, the body’s immune system detects and destroys foreign and abnormal cells. Although the process is not fully understood, there is evidence that cancer cells are able to evade destruction by the body’s immune defenses to some degree, allowing them to proliferate and invade other tissues.
These eight hallmark characteristics that distinguish cancer cells from normal ones are made possible by two final characteristics that enable the alterations necessary for a cell to become cancerous:
9. Genomic instability
Genes are segments of DNA that provide the instructions for all cellular activity. The accumulation of changes to specific genes that promote cell proliferation (e.g., activating oncogenes) or disrupt control mechanisms (e.g., tumor suppressor genes) can result in normal cells acquiring hallmark characteristics and transforming into cancer cells.
Chronic inflammation can result in conditions that promote proliferation, cell survival and angiogenesis. Inflammation can also enhance production of free radicals that can damage DNA.
Table 3 lists chemicals found by the Halifax Project team to alter the cancer-related hallmark processes. The list represents just a sample of potentially hundreds of chemicals that may interfere with these processes. Many of the chemicals are in pesticide residues on the foods we eat or are ingredients in personal-care products we use daily. These chemicals are ubiquitous in the environment and many can cause potentially harmful effects at low doses.
Table 3. Chemicals with evidence affecting cancer hallmark processes
|Self-sufficient cell division||
Low Dose Effect: bisphenol A (BPA), etoxazole, imazalil, methoxychlor, perfluorooctane sulfonate (PFOS), phthalates, polybrominated diphenyl ethers (PBDEs), prochloraz, trenbolone acetate (anabolic steroid)
Threshold effect (no low dose effect): cyprodinil, edible oil adulterants, pyridaben
Low Dose Effect Unknown: lactofen, maneb, phosalone
|Insensitivity to signals to stop cell division||Low Dose Effect: atrazine, BPA, chlorpyrifos, dichlorodiphenyltrichloroethane (DDT), folpet|
|Resisting cell death||
Low Dose Effect: BPA, dibutyl phthalate, dichlorvos, methoxychlor
Threshold effect (no low dose effect): chlorothalonil, diethylhexyl phthalate, lindane, oxyfluorfen
Low Dose Effect Unknown: linuron
|Limitless reproductive potential||
Low Dose Effect: acetaminophen, cotinine, diethylstilbestrol, lead, nickel-derived compounds, nitric oxide, phenobarbital, sodium selenite
Threshold effect (no low dose effect): reserpine
Note: potential compounders (limited research available)
|Creating their own blood supply||
Low Dose Effect: chlorothalonil, 2,2-bis-(p-hydroxyphenyl)-1,1,1-trichloroethane, PFOS
Threshold effect (no low dose effect): diniconazole, ziram
Low Dose Effect Unknown: biphenyl, bisphenol AF, C.I. solvent yellow 14, tributyltin chloride, methylene-bis(thiocyanate)
|Ability to invade other organs||
Low Dose Effect: hexachlorobenzene, phthalates, tetrabromobisphenol A (and metabolites: BPA, tetrabromobisphenol A dimethyl ether)
Low Dose Effect Unknown: biorhythms/melatonin, iron, sulfur dioxide
|Ability to survive with little oxygen||
Low Dose Effect: acrolein, cadmium, copper, cypermethrin, diazinon, iron, nickel, rotenone
Low Dose Effect Unknown: hexythiazox, malathion
|Evading the immune system||
Low Dose Effect: BPA, maneb, triclosan
Threshold effect (no low dose effect): diethylhexyl phthalate, pyridaben
Low Dose Effect Unknown: atrazine, azamethiphos, fluoxastrobin, pyraclostrobin
Low Dose Effect: alloys (containing: tungsten, nickel, and cobalt), carbon nanotubles, cobalt, mercury, nickel
Threshold effect (no low dose effect): benomyl, BPA, lead
Low Dose Effect Unknown: acrylamide, halobenzoquinones (quinones), titanium dioxide nanoparticles
Low Dose Effect: BPA
Threshold effect (no low dose effect): PBDEs
Low Dose Effect Unknown: 4-nonylphenol, atrazine, phthalates, vinclozolin
Source: Goodson WH, Lowe L, et al. (2015).
* Dose-response effects (low dose, threshold-level effect, unknown dose-response) specific to each hallmark process
A Short Primer on Cancer Biology
The hallmarks of cancer provide a framework for the idea that chemicals that interfere with discrete cancer-related mechanisms may combine to create carcinogenic combinations in a manner consistent with the multi-hit model of carcinogenesis. In order to better understand the role that chemical exposures, specifically chemical mixtures, play in the risk of developing cancer, it is helpful to understand the biology of cancer and how the disease develops.
Cells divide (i.e. replicate) in order for the body to grow and maintain itself. Cancer happens when abnormal cells begin to divide and proliferate uncontrollably. Unlike normal cells, cancer cells do not respond to the signals that control cell division. Because cancer cells grow and divide uncontrollably, they rapidly accumulate. In most cases, tumors eventually form as cancer cells become crowded within tissues and organs. In the late stages of cancer, malignant tumors can metastasize – break through tissue boundaries and form new tumors in other organs. It is the growth and spread of tumors that can lead to the shutdown of vital organ systems, which is the primary cause of death from cancer.
The process of cell division is carefully regulated by two main categories of genes. One category provides signals that stimulate cell proliferation, while the other provides signals that inhibit it. These genes also detect damaged cells and signal them to enter apoptosis, or programmed cell death. A proper balance between growth and inhibitory signals is critical to ensure that tissues and organs function as they should. Mutations or other changes in these two categories of genes are the major cause of healthy cells transforming into cancerous ones.
Our current understanding of cancer is that it is a multistep process and not a disease that develops all at once – the multi-hit model. For example, a mutation to a gene that promotes cell growth can allow a cell and all its offspring to replicate faster than normal. A second mutation to a gene that inhibits proliferation can allow a cell to break free from the normal constraints on cell division. One by one, this accumulation of mutations and gene alterations causes a normal cell to take on the traits of a cancer cell until eventually the transformation is complete.