Cell cycle and cancer Cancer can develop in any of the body’s

tissues and at any age.

The clinical presentation is variable; however, cancers share a common developmental principle:

A gradual acquisition of errors in genes that are important for cell division.

In this episode, we will cover the basics of the cell cycle, important features of cancer

cells, and their stepwise transformation.

Let’s start with a general reflection of the human body and its cells:

The cells of the human body are very small and not visible to the naked eye.

Therefore, it is difficult to comprehend the total number of cells in the human body.

The current accurate estimate is thirty trillion cells in the body.

If the cells were lined up, they would stretch over approximately 1 million kilometers.

In other words, the cells would circle the earth approximately thirty times.

  However, this amount represents the number

of cells present at any given time.

As cells age, they are continually replaced.

Within the average human lifespan, the body produces approximately 1,000 times more cells

than the number of cells at any given time.

  All of these cells are derived from preexisting

cells by division, which is tightly regulated by the cell cycle and its control mechanisms.

Loss of cell cycle control leads to uninhibited cell division and cancer development.

Let’s start by having a closer look at the cell cycle and its phases:

Cell division results in the formation of two daughter cells from a single parent cell

over several phases.

The cell cycle is composed of four phases: the G1 phase, the S phase, the G2 phase, and

the M phase.

The two most important phases are the S phase and the M phase.

During the S phase, or synthesis, DNA is replicated.

During the M phase, or mitosis, the cell divides into two daughter cells.

The G in the G1 and G2 phases stands for Gap, because these phases correspond to intervals

between the M and the S phases.

Let’s go through the normal sequence of events in the cell cycle.

In the first phase, the G1 phase, the cell grows and synthesizes the proteins required

for DNA replication.

In the S phase, the amount of DNA in the cells is duplicated.

In the G2 phase, the cell prepares for mitosis.

During this phase, additional proteins are synthesized.

The final phase is the M phase, in which cell division occurs.

The chromatids are separated evenly between two daughter cells.

Depending on the nature of the cell, there are three options after mitosis.

If further cell division is required, the cells re-enter the G1 phase and prepare for

the S phase.

If further cell division is not required, but potentially at a later stage, the cell

may enter a resting phase, the G0 phase.

Once in the G0 phase, the cells can exit and re-enter the G1 phase.

This is regulated by external signals such as growth factors, which bind to receptors

and initiate an array of signals that trigger cell division.

However, in most cases, the daughter cells make an irreversible exit from the cell cycle

and differentiate.

The process of cell division is prone to errors and it is important that no genetic errors

are passed on to the daughter cells.

To deal with such errors, the cell cycle has checkpoints at certain stages.

These checkpoints ensure that the requirements for the next phase are fulfilled.

At the end of the G1 phase, the cell is examined for any DNA damage and whether necessary substrates

are available for DNA replication.

If necessary, the cell cycle is stopped to repair any damage.

In the G2 checkpoint, the cell is examined for incomplete DNA replication.

If this is the case, the cell can initiate programmed cell death, also termed apoptosis,

to prevent damaged genes from being passed on.

The M checkpoint, which occurs during mitosis, determines whether the chromosomes are about

to be correctly distributed.

All of these checkpoints are necessary, because errors are frequent and the checkpoints ensure

the integrity of the cell's genome.

The cell cycle is internally regulated by proteins called cyclins.

They determine whether a cell transitions into the next phase.

Cyclin activity is influenced by proteins such as p53 and retinoblastoma protein, which

can halt cell cycle progression.

In cancer cells, the function of cell cycle checkpoints is usually limited.

This leads to uncontrolled cycling, even in the presence of DNA damage.

Cancer cells are also independent of growth signals and initiate the cell cycle, even

though cell division is not required.

In the next slide, we will take a closer look at the development of cancer cells.

The uncontrolled division of cancer cells may develop after several characteristics

are acquired, allowing the cell to become neoplastic.

Ten hallmarks of cancer have been postulated to describe these changes and are shared by

most cancers.

We would like to highlight five of these hallmarks in this episode: First: Cancer cells are capable

of sustaining proliferative signaling in the absence of growth factors.

In other words, they are able to enter the cell cycle without requiring positive external

signals.

Second: Cancer cells are able to evade growth suppressors.

Let’s use an example here.

Non-tumorous cells grown in a petri dish would proliferate until a single layer is formed

that covers the bottom of the dish.

A phenomenon known as contact inhibition would then prevent the cells from further proliferation.

In contrast, contact inhibition is lost in cancer cells and results in uncontrolled cell

growth and proliferation, producing a multilayer of cells.

Another example of growth suppressors are the cell cycle checkpoints, whose function

is usually impaired in cancer cells and leads to unchecked growth.

Third: Cancer cells can divide indefinitely; they have limitless replicative potential.

This is in contrast to non-cancerous cells of the body, which are incapable of indefinite

division.

The mechanism behind this lies in the telomeres, which shorten with each cell division.

However in germline cells, where repeated division is required, the enzyme telomerase

is able to elongate these ends, thereby enabling indefinite cell division.

The interesting part: Telomerase is often re-activated in cancer cells, allowing them

to divide indefinitely.

Fourth: Cancer cells also show increased genetic instability and therefore have a higher frequency

of mutations.

This occurs as a result of the inefficient repair of DNA damage during the cell cycle

and does not induce programmed cell death.

Fifth: Another hallmark is the disabling of apoptosis; as a consequence, damaged cells

are not neutralized.

In other words, cancer cells evade programmed cell death.

The acquisition of these hallmarks and other cells characteristics are not the result of

a single event, but the accumulation of DNA damage over time.

Let’s take a closer look at the relevant genes.

It is important to note that mutations can occur in all genes.

However, in several genes, mutations will lead to tumor formation.

These genes can be differentiated into two groups: proto-oncogenes and tumor suppressor

genes.

Proto-oncogenes are genes whose uncontrolled activation contributes to tumor formation.

If the gene is mutated, it is called an oncogene and cell division is facilitated.

Oncogenes are, for example, involved in transmitting growth signals such as the receptor for the

human epidermal growth factor, HER2/neu.

In contrast, tumor suppressor genes require deactivation to contribute to tumor formation.

The most important tumor suppressor genes control the cell cycle and, when functional,

inhibit uncontrolled cell division.

One example is p53.

It has been nicknamed the guardian of the genome due to its importance.

Regarding the terminology, you might want to keep in mind that anti-oncogene is sometimes

used synonymously with tumor suppressor gene.

Mutations in these genes usually occur over time and will be discussed in the next slide.

Tumor development is the result of DNA damage in the cell.

The cell’s own repair mechanisms usually remove any defects.

If the defect can not be repaired, it is inherited by the daughter cells.

In the latency period, further mutations accumulate in the oncogenes and tumor suppressor genes

in the cell line.

Because cancer formation has not yet occurred, this period is termed latency.

Latency can lead to progression, that is, the cell line undergoes malignant transformation

and its division is markedly amplified compared to the cells of origin.

To understand the dynamics of tumor formation, it is important to realize that mutations

are not inherited in a predetermined order from the original cell to the tumor.

There is no sense of direction: instead, cancer formation is the result of random mutations

that can affect all genes.

Some of the mutations affect cell division and control mechanisms.

Such cells divide more frequently and have a growth advantage compared to other cells.

In these cells, the probability of a new mutation is elevated because of its increased rate

of cell division and absent control mechanisms.

On the one hand, mutations in cancer genes are a random event; however, the risk of further

mutations increases over time and malignancy is more likely after acquisition of certain

hallmarks.

The image shown here illustrates a further feature of tumors.

Tumors are not composed of a large number of one exact type of cancer cell, but are

a diverse population of cancer cells.

This is sometimes referred to as tumor heterogeneity.

So in this episode, we have introduced some of the main concepts of cancer cell formation.

Some of these concepts will be repeated in the next slide in the form of a quiz.

Which of the following statements are true and which are false?

1.

The cell cycle has four checkpoints, one in each phase.

2.

Because oncogenes are mainly dominant, activation of a single gene copy is sufficient.

3.

Tumor formation is a linear process and cells from a single cancer type share the same genotype

or phenotype. 4.

Cancer cells require many growth factors to maintain their high rate of cell division.

5.

Genomic instability of cancer cells favours the accumulation of further mutations.