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, the activators that tell the cell to move from G1 to S to G2 to M phases. 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 [1].

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 [2].

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 [3].

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 [4].

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 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) [7].

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 [7].

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) [8].

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 [9]. 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.

Tumor suppressors

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 G1 checkpoint (controlling the G1 to S transition), where it blocks cell cycle progression in response to damaged DNA and other unfavorable conditions [13].

When a cell’s DNA is damaged, a sensor protein activates p53, which halts the cell cycle at the G1 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 [14].

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) [14,15].