Introduction

Does cell cycle control matter? If you ask an oncologist — a doctor who treats cancer patients — they 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 (see Unit 4, Topic 3). For example, cell cycle inhibitors keep cells from dividing when conditions are incorrect, 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.

One critical process monitored by the cell cycle checkpoint surveillance mechanism is proper DNA replication during the S phase. Even when all cell cycle controls are fully functional, a small percentage of replication errors (mutations) pass on to the daughter cells. For example, if changes to the DNA nucleotide sequence occur within a coding portion of a gene and are not corrected, a gene mutation results. All cancers start when a gene mutation gives rise to a faulty protein that plays a key role in cell reproduction.

The change in the cell that results from the malformed protein may be minor, perhaps a slight delay in the binding of Cdk to cyclin or an Rb protein that detaches from its target DNA while still phosphorylated (see Unit 4, Topic 3). Even minor mistakes, however, may allow subsequent mistakes to occur more readily. Over and over, small uncorrected errors pass from the parent cell to the daughter cells and amplify as each generation produces more non-functional proteins from uncorrected DNA damage. Eventually, the pace of the cell cycle speeds up as the effectiveness of the control and repair mechanisms decreases. Uncontrolled growth of the mutated cells outpaces the growth of normal cells in the area, and a tumour (“-oma”) can result.

In Unit 4, Topic 4 will cover what is wrong with cancer cells and how abnormal forms of cell cycle regulators can contribute to cancer.

What is Wrong with Cancer Cells?

Cancer comprises many different diseases caused by a common mechanism: uncontrolled cell growth. Despite the redundancy and overlapping levels of cell cycle control, errors do occur. One critical process that the cell cycle checkpoint surveillance mechanism monitors is proper DNA replication during the S phase. Even when all cell cycle controls are fully functional, a small percentage of replication errors (mutations) pass on to the daughter cells. If changes to the DNA nucleotide sequence occur within a coding portion of a gene and are not corrected, a gene mutation results. All cancers start when a gene mutation gives rise to a faulty protein that plays a key role in cell reproduction.

Cancer cells behave differently than normal cells in the body. Many of these differences are related to cell division behaviour. For example, cancer cells can multiply in culture (outside of the body in a dish) without adding any growth factors or growth-stimulating protein signals. This differs from normal cells, which need growth factors to grow in culture (Figure 1). Cancer cells may make their own growth factors, have growth factor pathways stuck in the “on” position, or, in the context of the body, even trick neighbouring cells into producing growth factors to sustain them.¹

Cancer cells also ignore signals that should cause them to stop dividing. For instance, when normal cells grown in a dish become crowded by neighbours 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.¹

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. Recall that human cells can generally go through only about 40 to 60 rounds of division before they lose the capacity to divide (see Unit 1, Topic 4), “grow old,” and eventually die.² 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 division¹. Most (85 to 90%) cancers express telomerase — at least in the population of cancer stem cells that divide uncontrollably, causing the tumour to grow. Perhaps agents that prevent the expression of the gene for telomerase — or prevent the action of the enzyme — will provide a new class of weapons in the fight against cancer. Treating the cancer this way must be done carefully. If telomerase activity, however brief, is essential for all cells and if lack of telomerase hastens replicative senescence, it may also hasten the aging of the tissues that depend on newly-formed cells for continued health — a trade-off that may not be worth making.

Cancer cells also differ from normal cells in other ways that are not directly related to the cell cycle. These differences help them grow, divide, and form tumours. For instance, cancer cells gain the ability to migrate to other parts of the body, a process called metastasis, and to promote the growth of new blood vessels, a process called angiogenesis (which gives tumour 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) (Figure 2). In addition, emerging research shows that cancer cells may undergo metabolic changes that support increased cell growth and division.

How Cancer Develops

Cells have many different mechanisms to restrict cell division, repair DNA damage, and prevent cancer from developing. Because of this, it is thought that cancer develops in a multi-step process in which multiple mechanisms must fail before reaching a critical mass where 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.³ How might this process work? In a hypothetical example, a cell might first lose the activity of a cell cycle inhibitor (see Unit 4, Topic 3), an event that would make the cell’s descendants divide a little more rapidly. These descendants would be unlikely to be cancerous, but they might form a benign tumour, a mass of cells that divides too much but does not have the potential to invade other tissues (metastasize).⁴

Over time, a mutation might take place in one of the descendant cells, causing increased activity of a positive cell cycle regulator (Figure 3). 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 tumour, a group of cells that divide excessively and can invade other tissues.⁴

As a tumour 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.³

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.¹ If one gene mutates and becomes nonfunctional, other mutations can accumulate rapidly. Therefore, 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.

Benign and Malignant Tumours

As previously mentioned, a single mutated cell in a tissue can become the growth point of a tumour, essentially a mass of cells cloned from the original mutated one. Benign tumours or growths are tumours comprised of cells that divide rapidly but are otherwise normal (Figure 4, Top). In some cases, benign tumours stop growing and are not life-threatening. Benign tumours are not considered cancerous; examples of these include breast and uterine fibroids in women or common moles, which can often surgically be removed for the comfort of the patient. In other cases, cells in benign tumours can accrue more mutations and develop into a more dangerous tumour type called a malignant tumour.

Malignant tumours (also called malignant neoplasms) (Figure 4, Bottom) are cancerous and the result of multiple mutations. They can grow beyond the boundaries of the tumour itself. They achieve this by stopping a process called contact inhibition, which refers to contact-dependent signals between adjacent cells within a tissue that prevent cells from growing on top of each other. As tumours grow, they deplete their available nutrients. To continue growing, they release signalling molecules that stimulate the growth and reorganization of nearby blood vessels. The process of blood vessel formation is called angiogenesis (not unique to cancer), which allows the cancer to continue growing by acquiring the necessary nutrients. In addition to providing nutrients, the blood vessels serve as a conduit to travel to a secondary location in the body, the phenomenon called metastasis. Cancer cells that metastasize can become the focal point of new tumour formation in many different tissues. Because cancer cells continue to cycle and replicate their DNA, they can undergo yet more somatic mutations. These further changes can facilitate additional metastasis and cancer cell growth in different locations in the body.

Different cancer cell types have different growth and other behavioural properties. This is what slow-growing and fast-growing cancers refer to. Colon cancers are typically slow-growing, tending to remain in the benign stage longer than other cancers, until an accumulation of mutations results in cancer progression. Periodic colonoscopies that detect and remove colorectal tumours in middle-aged or older people can prevent the disease; however, the patient and doctor must balance the risks of the disease with the procedure. Pancreatic and glial cancers are fast-growing and usually go undetected until they reach an advanced stage. The twin goals of medical research are to detect the different cancers early enough for successful intervention and, of course, to find effective treatments.

Cell Cycle Regulators and Cancer

Cancers accumulate mutations as they mature. Early-stage tumours (benign) can begin with a single mutation, while late-stage tumours (malignant) can have dozens of mutations. Different types of cancer involve different mutations, and each individual tumour has a unique set of genetic alterations. In general, however, mutations of the following two types of cell-cycle regulators may promote the development of cancer:

• Positive regulators may be overactivated (become oncogenic).
• Negative regulators, also called tumour suppressors, may be inactivated.

Proto-Oncogenes

Positive cell-cycle regulators may be overactive in cancer. For instance, a growth factor receptor may send signals without growth factors, or a cyclin may become expressed at abnormally high levels. The overactive (cancer-promoting) forms of these genes are known as 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 its mutation increases its activity.

Mutations that convert proto-oncogenes to oncogenes are activating mutations, which increase rather than decrease the activity of a regulator. Thus, these mutations typically have dominant behaviour at the cellular level, producing an effect (in this case, excessive cell division) when just one of a cell’s two gene copies is mutated.

Mutations that turn proto-oncogenes into oncogenes can take different forms. An oncogene is any gene that, when altered, leads to an increase in the rate of cell cycle progression. Some change the protein’s amino acid sequence, 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 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.⁵

Example 1: Cell Cycle Regulatory Proteins

Consider what might happen to the cell cycle in a cell with a recently acquired oncogene. In some or most instances, altering the DNA sequence results in a less functional (or non-functional) protein. This change is detrimental to the cell and likely prevents it from completing the cell cycle; however, it does not harm the organism because the mutation does not carry forward. If a cell cannot reproduce, the mutation does not propagate, and the damage is minimal. Occasionally, however, a gene mutation causes a change that increases the activity of a positive regulator. For example, a mutation that allows Cdk to activate without being partnered with cyclin (see Unit 4, Topic 3) can push the cell cycle past a checkpoint before meeting all required conditions. If the resulting daughter cells are too damaged to undergo further cell divisions, the mutation does not propagate, and no harm comes to the organism. However, if the atypical daughter cells can undergo further cell divisions, subsequent generations of cells may accumulate even more mutations, some possibly in additional genes that regulate the cell cycle.

Example 2: Growth Factors

In addition to the cell cycle regulatory proteins, any protein that influences the cycle can be altered in such a way as to override cell cycle checkpoints. Unsurprisingly, many genes that help initiate the pro-growth MAPK signalling pathway are proto-oncogenes. Examples include the Ras GTPase, EGFR (epithelial growth factor receptor, a receptor tyrosine kinase), and Her2 (another receptor kinase frequently mutated in breast cancers) (see Unit 4, Topic 2).

Proto-oncogenes encode many proteins that transmit growth factor signals (Figure 5). These proteins usually drive cell cycle progression only when growth factors are available. However, if one of the proteins becomes overactive due to mutation, it may transmit signals even with no growth factor around.⁶

Mutations in genes that promote apoptosis in Drosophila embryos result in the prolonged survival of cells that would die as a normal process of central nervous system (CNS) development.⁷ Conversely, overexpression of such genes can induce inappropriate cell death.⁸ In contrast, increasing and/or prolonging the exposure of CNS cells to EGFR signalling can promote cell survival in the developing CNS of Drosophila embryos.^7,9 Overactive forms of these proteins are often found in cancer cells. For instance, oncogenic Ras mutations are found in approximately 90% of pancreatic cancers. Ras is a G protein, meaning that it switches back and forth between an inactive form (bound to GDP) and an active form (bound to GTP) (see Unit 4, Topic 2). Cancer-causing mutations often change Ras’s structure so that it can no longer switch to its inactive form or do so only very slowly, leaving the protein stuck in the “on” state (Figure 5).¹⁰

Tumour Suppressors

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 usually block cell cycle progression are known as tumour suppressors. Tumour suppressors prevent cancerous tumours from forming when they are working correctly; because of this, tumours may form when they mutate, so they no longer work.

p53 is one of the most important tumour suppressors that plays a key role in the cellular response to DNA damage (Figure 6). p53 acts primarily at the G₁ checkpoint (controlling the G₁ to S transition), where it blocks cell cycle progression in response to damaged DNA and other unfavourable conditions.¹¹

As discussed in Unit 4, Topic 3, when a cell’s DNA is damaged, a sensor protein activates p53, triggering the production of a cell cycle inhibitor to halt the cell cycle at the G₁ checkpoint. This pause provides time for DNA repair, which also depends on p53, whose second job is to activate DNA repair enzymes. If these enzymes fix the damage, p53 releases the cell, allowing it to continue through the cell cycle. If these enzymes cannot fix the damage, p53 plays its third and final role: triggering apoptosis (programmed cell death) so that damaged DNA does not pass on.

In cancer cells, p53 is often missing, nonfunctional, or less active than normal. For example, many cancerous tumours 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 (Figure 7).¹²

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 in 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 tumour suppressors.

Key Concepts and Summary

Cancer is the result of unchecked cell division caused by a breakdown of the mechanisms that regulate the cell cycle. The loss of control begins with a change in the DNA sequence of a gene that codes for one of the regulatory molecules. Faulty instructions lead to a protein that does not function as it should. Any disruption of the monitoring system can allow other mistakes to pass on to the daughter cells. Each successive cell division will give rise to daughter cells with even more accumulated damage. Eventually, all checkpoints become nonfunctional, and rapidly reproducing cells crowd out normal cells, resulting in a tumour or leukemia (blood cancer). 

 Proto-oncogenes: 

• Proto-oncogenes positively regulate the cell cycle.
• Mutations may cause proto-oncogenes to become oncogenes, disrupting normal cell division and causing cancers to form.
• Some mutations prevent the cell from reproducing, which keeps the mutations from being passed on.
• If a mutated cell is able to reproduce because the cell division regulators are damaged, then the mutation will be passed on, possibly accumulating more mutations with successive divisions. 

 Tumour suppressor genes: 

• Tumor suppressor genes are segments of DNA that code for negative regulator proteins, which keep the cell from undergoing uncontrolled division.
• Mutated p53 genes are believed to be responsible for causing tumour growth because they turn off the regulatory mechanisms that keep cells from dividing out of control.
• Sometimes cells with negative regulators can halt their transmission by inducing pre-programmed cell death called apoptosis.
• Without a fully functional p53, the G₁ checkpoint of interphase is severely compromised, and the cell proceeds directly from G₁ to S; this creates two daughter cells that have inherited the mutated p53 gene. 

Key Terms

acute lymphocytic leukemia

a type of leukemia (blood cancer) that comes on quickly and is fast growing. In acute lymphocytic leukemia, there are too many lymphoblasts (immature white blood cells) in the blood and bone marrow. Also called acute lymphoblastic leukemia and ALL

benign

not cancer. Benign tumours may grow larger but do not spread to other parts of the body; also called nonmalignant

cancer

a population of cells that grows uncontrollably and can invade neighbouring tissues

chronic myelogenous leukemia

an indolent (slow-growing) cancer in which too many myeloblasts are found in the blood and bone marrow. Myeloblasts are a type of immature blood cell that makes white blood cells called myeloid cells. Chronic myelogenous leukemia may get worse over time as the number of myeloblasts increases in the blood and bone marrow. This may cause fever, fatigue, easy bleeding, anemia, infection, a swollen spleen, bone pain, or other signs and symptoms. Chronic myelogenous leukemia is usually marked by a chromosome change called the Philadelphia chromosome, in which a piece of chromosome 9 and a piece of chromosome 22 break off and trade places with each other. It usually occurs in older adults and rarely occurs in children. Also called chronic granulocytic leukemia, chronic myeloid leukemia, and CML

coactivator

proteins that connect activators with the gene targets they regulate

DNA-binding domain

a protein sequence in a transcription factor that binds to a target DNA sequence

epidermal growth factor receptor

a tyrosine kinase transmembrane receptor that stimulates growth and division of cells once bound by the epidermal growth factor

gatekeeper gene

tumour suppressor gene that halts cell proliferation; loss-of-function mutations are associated with excessive cell proliferation and tumour formation

genetic instability

the accumulation of multiple mutations in cancer cells caused by defects in DNA repair genes or chromosome sorting processes

Janus kinase

a cytoplasmic protein kinase that is activated by receptor binding and catalyzes the phosphorylation of STAT transcription factors

leukemia

cancer that starts in blood-forming tissue, such as the bone marrow, and causes large numbers of abnormal blood cells to be produced and enter the bloodstream

metastasis

the spread of cancer cells through the blood or lymph system from their origin to a secondary site in an organism

mutation

any heritable change of the base-pair sequence of genetic material

oncogene

a mutated version of a proto-oncogene, which allows for uncontrolled progression of the cell cycle, or uncontrolled cell reproduction

proto-oncogene

a normal gene that controls cell division by regulating the cell cycle that becomes an oncogene if it is mutated

tumour suppressor gene

a gene that codes for regulator proteins that prevent the cell from undergoing uncontrolled division

Long Descriptions

Figure 3 Image Description: The initial cell mutation inactivates a negative cell cycle regulator. The next mutation overactivates a positive cell cycle regulator. The third mutation inactivates a genome stability factor. Additional mutations accumulate rapidly, leading to a cancer cell. [Return to Figure 3]

Figure 7 Image Description: In normal p53, DNA damage activates p53 that binds to the DNA. This binding halts the cell cycle at the G1 checkpoint, activates DNA repair, and activates apoptosis if repair is impossible. Normal p53 ensures cells do not pass on damaged DNA. In nonfunctional p53, p53 cannot bind to damaged DNA. This means that p53 cannot repair the DNA damage, and this damaged DNA (mutations) passes on. [Return to Figure 7]

Media Attributions

• Figure 1: What’s wrong with cancer cells? [Image 1] by Khan Academy ([date unknown]) is used under a CC BY-NC-SA 4.0 license.
• Figure 2: What’s wrong with cancer cells? [Image 2] by Khan Academy ([date unknown]) is used under a CC BY-NC-SA 4.0 license.
• Figure 3: How cancer develops by Khan Academy ([date unknown]) is used under a CC BY-NC-SA 4.0 license.
• Figure 4: Figure 15-8 from Fundamentals of Cell Biology (Katzman et al. 2020) is used under a CC BY-NC-SA 4.0 license.
• Figure 5: Oncogenes by Khan Academy ([date unknown]) is used under a CC BY-NC-SA 4.0 license.
• Figure 6: Figure 10.14 from OpenStax Biology (Rye et al. 2016) is used under a CC BY 4.0 license.
• Figure 7: Tumor suppressors by Khan Academy ([date unknown]) is used under a CC BY-NC-SA 4.0 license.

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