How cancer can be linked to overactive positive cell cycle regulators (oncogenes) or inactive negative regulators (tumor suppressors).
Does cell cycle control matter? If you ask an oncologist – a doctor who treats cancer patients – she or he will likely answer with a resounding yes.
Cancer is basically a disease of uncontrolled cell division. Its development and progression are usually linked to a series of changes in the activity of cell cycle regulators. For example, inhibitors of the cell cycle keep cells from dividing when conditions aren’t right, so too little activity of these inhibitors can promote cancer. Similarly, positive regulators of cell division can lead to cancer if they are too active. In most cases, these changes in activity are due to mutations in the genes that encode cell cycle regulator proteins.
Here, we’ll look in more detail at what's wrong with cancer cells. We'll also see how abnormal forms of cell cycle regulators can contribute to cancer.
What’s wrong with cancer cells?
Cancer cells behave differently than normal cells in the body. Many of these differences are related to cell division behavior.
For example, cancer cells can multiply in culture (outside of the body in a dish) without any growth factors, or growth-stimulating protein signals, being added. This is different from normal cells, which need growth factors to grow in culture.
Cancer cells may make their own growth factors, have growth factor pathways that are stuck in the "on" position, or, in the context of the body, even trick neighboring cells into producing growth factors to sustain them.
Diagram showing different responses of normal and cancer cells to growth factor presence or absence.
- Normal cells in a culture dish will not divide without the addition of growth factors.
- Cancer cells in a culture dish will divide whether growth factors are provided or not.
Cancer cells also ignore signals that should cause them to stop dividing. For instance, when normal cells grown in a dish are crowded by neighbors on all sides, they will no longer divide. Cancer cells, in contrast, keep dividing and pile on top of each other in lumpy layers.
The environment in a dish is different from the environment in the human body, but scientists think that the loss of contact inhibition in plate-grown cancer cells reflects the loss of a mechanism that normally maintains tissue balance in the body.
Another hallmark of cancer cells is their "replicative immortality," a fancy term for the fact that they can divide many more times than a normal cell of the body. In general, human cells can go through only about 40-60 rounds of division before they lose the capacity to divide, "grow old," and eventually die.
Cancer cells can divide many more times than this, largely because they express an enzyme called telomerase, which reverses the wearing down of chromosome ends that normally happens during each cell division.
Cancer cells are also different from normal cells in other ways that aren’t directly cell cycle-related. These differences help them grow, divide, and form tumors. For instance, cancer cells gain the ability to migrate to other parts of the body, a process called metastasis, and to promote growth of new blood vessels, a process called angiogenesis (which gives tumor cells a source of oxygen and nutrients). Cancer cells also fail to undergo programmed cell death, or apoptosis, under conditions when normal cells would (e.g., due to DNA damage). In addition, emerging research shows that cancer cells may undergo metabolic changes that support increased cell growth and division.
Diagram showing different responses of normal and cancer cells to conditions that would typically trigger apoptosis.
- A normal cell with unfixable DNA damaged will undergo apoptosis.
- A cancer cell with unfixable DNA damage will not undergo apoptosis and will instead continue dividing.
How cancer develops
Cells have many different mechanisms to restrict cell division, repair DNA damage, and prevent the development of cancer. Because of this, it’s thought that cancer develops in a multi-step process, in which multiple mechanisms must fail before a critical mass is reached and cells become cancerous. Specifically, most cancers arise as cells acquire a series of mutations (changes in DNA) that make them divide more quickly, escape internal and external controls on division, and avoid programmed cell death.
How might this process work? In a hypothetical example, a cell might first lose activity of a cell cycle inhibitor, an event that would make the cell’s descendants divide a little more rapidly. It’s unlikely that they would be cancerous, but they might form a benign tumor, a mass of cells that divide too much but don’t have the potential to invade other tissues (metastasize).
Over time, a mutation might take place in one of the descendant cells, causing increased activity of a positive cell cycle regulator. The mutation might not cause cancer by itself either, but the offspring of this cell would divide even faster, creating a larger pool of cells in which a third mutation could take place. Eventually, one cell might gain enough mutations to take on the characteristics of a cancer cell and give rise to a malignant tumor, a group of cells that divide excessively and can invade other tissues.
Diagram of a hypothetical series of mutations that might lead to cancer development.
In the first step, an initial mutation inactivates a negative cell cycle regulator.
In one of the descendants of the original cell, a new mutation takes place, making a positive cell cycle regulator overly active.
In one of the descendants of this second cell, a third mutation takes place, inactivating a genome stability factor.
Once the genome stability factor is inactivated, additional mutations accumulate rapidly in the cell's descendants (because mutations are no longer prevented or repaired as efficiently).
Once a critical mass of mutations affecting relevant processes is reached, the cell bearing the mutations acquires cancerous characteristics (uncontrolled division, evasion of apoptosis, capacity for metastasis, etc.) and is said to be a cancer cell.
As a tumor progresses, its cells typically acquire more and more mutations. Advanced-stage cancers may have major changes in their genomes, including large-scale mutations such as the loss or duplication of entire chromosomes. How do these changes arise? At least in some cases, they seem to be due to inactivating mutations in the very genes that keep the genome stable (that is, genes that prevent mutations from occurring or being passed on).
These genes encode proteins that sense and repair DNA damage, intercept DNA-binding chemicals, maintain the telomere caps on the ends of chromosomes, and play other key maintenance roles. If one of these genes is mutated and nonfunctional, other mutations can accumulate rapidly. So, if a cell has a nonfunctional genome stability factor, its descendants may reach the critical mass of mutations needed for cancer much faster than normal cells.
Cell cycle regulators and cancer
Different types of cancer involve different types of mutations, and, each individual tumor has a unique set of genetic alterations. In general, however, mutations of two types of cell cycle regulators may promote the development of cancer: positive regulators may be overactivated (become oncogenic), while negative regulators, also called tumor suppressors, may be inactivated.
Positive cell cycle regulators may be overactive in cancer. For instance, a growth factor receptor may send signals even when growth factors are not there, or a cyclin may be expressed at abnormally high levels. The overactive (cancer-promoting) forms of these genes are called oncogenes, while the normal, not-yet-mutated forms are called proto-oncogenes. This naming system reflects that a normal proto-oncogene can turn into an oncogene if it mutates in a way that increases its activity.
Mutations that turn proto-oncogenes into oncogenes can take different forms. Some change the amino acid sequence of the protein, altering its shape and trapping it in an “always on” state. Others involve amplification, in which a cell gains extra copies of a gene and thus starts making too much protein. In still other cases, an error in DNA repair may attach a proto-oncogene to part of a different gene, producing a “combo” protein with unregulated activity.
Oncogenic form of the Ras protein.
Normal Ras is activated when growth factors bind to growth factor receptors. When active, Ras switches to its GTP-bound form and triggers a signaling pathway leading to cell division and proliferation. Normal Ras then exchanges GTP for GDP and returns to its inactive state until the cell perceives more growth factors.
An oncogenic form of Ras becomes permanently locked in its GTP-bound, active form. The oncogenic Ras protein activates a signaling pathway leading to growth and proliferation even when growth factors are not present.
Many of the proteins that transmit growth factor signals are encoded by proto-oncogenes. Normally, these proteins drive cell cycle progression only when growth factors are available. If one of the proteins becomes overactive due to mutation, however, it may transmit signals even when no growth factor is around. In the diagram above, the growth factor receptor, the Ras protein, and the signaling enzyme Raf are all encoded by proto-oncogenes.
Overactive forms of these proteins are often found in cancer cells. For instance, oncogenic Ras mutations are found in about 90% of pancreatic cancers. Ras is a G protein, meaning that it switches back and forth between an inactive form (bound to the small molecule GDP) and an active form (bound to the similar molecule GTP). Cancer-causing mutations often change Ras’s structure so that it can no longer switch to its inactive form, or can do so only very slowly, leaving the protein stuck in the “on” state (see cartoon above).
Negative regulators of the cell cycle may be less active (or even nonfunctional) in cancer cells. For instance, a protein that halts cell cycle progression in response to DNA damage may no longer sense damage or trigger a response. Genes that normally block cell cycle progression are known as tumor suppressors. Tumor suppressors prevent the formation of cancerous tumors when they are working correctly, and tumors may form when they mutate so they no longer work.
One of the most important tumor suppressors is tumor protein p53, which plays a key role in the cellular response to DNA damage. p53 acts primarily at the G checkpoint (controlling the G to S transition), where it blocks cell cycle progression in response to damaged DNA and other unfavorable conditions.
When a cell’s DNA is damaged, a sensor protein activates p53, which halts the cell cycle at the G checkpoint by triggering production of a cell-cycle inhibitor. This pause buys time for DNA repair, which also depends on p53, whose second job is to activate DNA repair enzymes. If the damage is fixed, p53 will release the cell, allowing it to continue through the cell cycle. If the damage is not fixable, p53 will play its third and final role: triggering apoptosis (programmed cell death) so that damaged DNA is not passed on.
Diagram showing normal p53 and nonfunctional p53.
In response to DNA damage, normal p53 binds DNA and promotes transcription of target genes. First, p53 triggers production of Cdk inhibitor proteins, pausing the cell cycle in G1 to allow time for repairs. p53 also activates DNA repair pathways. Finally, if DNA repair is not possible, p53 triggers apoptosis. The net effect of p53's activities is to prevent the inheritance of damaged DNA, either by getting the damage repaired or by causing the cell to self-destruct.
When a cell contains only nonfunctional p53 that cannot bind DNA, DNA damage can no longer trigger any of these three responses. Although p53 is still activated by the damage, it is helpless to respond, as it can no longer regulate transcription of its targets. Thus, the cell does not pause in G1, DNA damage is not repaired, and apoptosis is not induced. The net effect of the loss of p53 is to permit damaged DNA (mutations) to be passed on to daughter cells.
In cancer cells, p53 is often missing, nonfunctional, or less active than normal. For example, many cancerous tumors have a mutant form of p53 that can no longer bind DNA. Since p53 acts by binding to target genes and activating their transcription, the non-binding mutant protein is unable to do its job.
When p53 is defective, a cell with damaged DNA may proceed with cell division. The daughter cells of such a division are likely to inherit mutations due to the unrepaired DNA of the mother cell. Over generations, cells with faulty p53 tend to accumulate mutations, some of which may turn proto-oncogenes to oncogenes or inactivate other tumor suppressors.
p53 is the gene most commonly mutated in human cancers, and cancer cells without p53 mutations likely inactivate p53 through other mechanisms (e.g., increased activity of the proteins that cause p53 to be recycled).
Check your understanding: viruses and cancer
Some forms of cancer are linked to specific types of viruses. For instance, infection with certain strains of human papillomavirus can lead to cervical cancer. This virus encodes a protein called E6, which binds to the p53 protein. Which of the following explains why papillomavirus can cause cancer?
Want to join the conversation?
- Could you make a cancer-like cell, or rather a cell that has a mutation that makes it and its offspring grow into a neoplasm, and have their mutation be GOOD? The article says that cancer cells are known to be immortal, so if that's the case, could you use "good" neoplasms to fight cancerous ones that would later form tumors? Thanks to anyone who can understand my question :-)(15 votes)
- It is feasible, however the main issue is you don't want to introduce some foreign type of human mutated and immortal cancer without the full ability to knock it out and rein it in. Probably there will be treatments that revolve around this whether is be putting drug producing genes in cells that surround a cancer, although it wouldn't exactly be wise to use a cancer cell to fight a cancer cell by definition, since there are better cell options out there. However if such a cell was discovered tomorrow that didn't grow very fast, only grew near tumors, somehow produced weapons to fight it, no doubt it would become a very popular therapy, however a non-cancerous cell may do the trick better without the risk of it turning into actual cancer.(16 votes)
- How does DNA get damaged in the first place?(14 votes)
- As far as I know - don't take my word for it - exposure to carcinogens (things that cause cancer, like radiation) forces your DNA out of place (it's separated or jumbled around), often causing it to have to repair and replace itself, which can lead to mistakes, which can cause mutations. Cells get mutations all the time, but normally detect such and either fix the problem or self-destruct.(3 votes)
- It might not be directly related to this topic, but I have a question. Can cancer be inherited? or does it just depends on your normal habits?(7 votes)
- Some people are born with a gene mutation that they inherited from their mother or father. This damaged gene puts them at higher risk for cancer than most people. When cancer occurs because of an inherited gene mutation, it is referred to as "hereditary cancer."
Although this is often referred to as inherited cancer, what is inherited is the abnormal gene that can lead to cancer, not the cancer itself.(14 votes)
- Why not engineer a retrovirus to insert an extra copy of the P53 gene? First as a treatment for people with a dangerous cancer, then try it on people who have only one working copy of P53?(11 votes)
- I think there are several reasons why this isn't a treatment (yet). I'm sure there's a lot you have to figure out before you can get a virus to successfully insert a copy of the gene. There may be some epigenetic factors that would make this technique not work very well and nobody has figured out how to get around that yet.(4 votes)
- So, I was wondering what could happen if P53 is introduced to cancer cells, once they have mutated. May be, introducing a functional P53 to cancer cells before they progress so far, could prevent them. Is it possible ? What do you say? Please answer(6 votes)
- I was thinking the same thing! except maybe giving immunization shots to fix the DNA in earlier stages like when you are just born. But it would definitely be interesting to see if it worked after the patient had cancer. I think it could possibly work afterwards, but the only problem is, if the cancer is already affected large parts of the body, and the P53 activates the apoptosis, then you could kill of a large amount of cells in your body, too much to live. Other than that, I think this would completely work.(3 votes)
- Besides chemo and radiation, what other cures are there for cancer?(5 votes)
- here is a website that can show you more examples and what they mean
- So, how long does cancer cell cycle take compared to normal cell?(4 votes)
- That depends if it is a benign tumor (not to bad) or a bad tumor (I cannot spell its name). If the tumor is benign the cells it contains will split only slightly faster than a normal cell. If it is a dangerous cancerous tumor, then the cells in it will split much faster and more uncontrollably than a normal cell would.
If a normal cell takes a second to divide and then waits a week and divides again (this is just an example, this is not accurate information) a bad cancer cell might take a second to divide and then wait an hour. If this is the case you will have two good cells from one good cell and 168 bad ones from the cancerous cell. NOTE: this is just an example I made up, real cells divide much quicker and can wait much shorter or longer amounts of time before dividing again, some cells never even divide again.(5 votes)
- Is it possible to completely reverse the damage done by cancer cells to the host's DNA? Few form of cancers, which occur due to mutation in DNA, leading to uncontrollable growth of cells, may be treatable by gene therapy by targeting the mutated gene.(3 votes)
- That sounds like a nice idea but in reality, many mutations cause cancer. Plus there is that variability among cancer cells. What do I mean by that?
I mean that even within cancerous tissue not all of them are clones. there are genetic variants among them.
If you prepare gene therapy, how do you know which one to traget? Let's suppose you know which one, - cell variant A. Then you are left off B, C, D.
If there is left the only one of let's say D, that's enough to regrow and reoccur - several years later. Without you even knowing you left that one cell.(4 votes)
- Can cancer become so cancerous that kills itself? Could so many mutations accumulate that it would not be able to divide anymore?(4 votes)
- Interesting question!
Definitely, yes. But do not rely on that. Once there are too many mutations accumulated it is too late and it will affect healthy cells as well. You mean, mutations which trigger apoptosis, right? In that case, cancer would resemble an auto-immune disease.
Other than that it is not possible for cancer to just 'kill itself', moreover it thrives really well and always finds a way to grow and spread.(2 votes)
- What would be the difference between a benign tumor and a non-metastatic, non-invasive cancer?(3 votes)
- Benign tumors grow locally and do not spread. As a result, benign tumors are not considered cancer.
Non-metastatic cancer is cancer which does not metastasize.
While all benign tumors are non-invasive and non-metastatic,
some malignant tumors also can be non-metastatic.
It means they grow in situ and harm surrounding tissue, such as basal cells carcinoma.(3 votes)