Cancer and the cell cycle
AP.BIO:
IST-1 (EU)
,
IST-1.D (LO)
,
IST-1.D.1 (EK)
,
IST-1.E (LO)
,
IST-1.E.1 (EK)
How cancer can be linked to overactive positive cell cycle regulators (oncogenes) or inactive negative
regulators (tumor suppressors).
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Introduction
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^11start superscript, 1, end
superscript.
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^22squared.
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^33cubed.
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^44start superscript, 4, end superscript.
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^55start superscript, 5, end superscript.
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^66start superscript, 6, end superscript.
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)^77start superscript, 7, end superscript.
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^77start superscript, 7, end superscript.
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)^88start superscript, 8, end superscript.
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^99start superscript, 9, end superscript. 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.
Oncogenes
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.
[How many gene copies must mutate?]
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^{10}10start superscript, 10, end superscript.
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^{11}11start superscript, 11, end superscript.
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)^{12}12start superscript, 12, end superscript.
Tumor 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 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.
[How many gene copies must mutate?]
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_11start
subscript, 1, end subscript checkpoint (controlling the G_11start subscript, 1, end
subscript to S transition), where it blocks cell cycle progression in response to
damaged DNA and other unfavorable conditions^{13}13start superscript, 13, end
superscript.
When a cell’s DNA is damaged, a sensor protein activates p53, which halts the cell
cycle at the G_11start subscript, 1, end subscript 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}14start superscript, 14, end
superscript.
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}14,15start superscript, 14,
comma, 15, end superscript.
