Topic 2: How cancer form and spread

Cell changes and cancer

All cancers begin in cells. Our bodies are made up of more than a hundred million million
(100,000,000,000,000) cells. Cancer starts with changes in one cell or a small group of cells.

Usually we have just the right number of each type of cell. This is because cells produce signals
to control how much and how often the cells divide. If any of these signals are faulty or missing,
cells may start to grow and multiply too much and form a lump called a tumour. Where the
cancer starts is called the primary tumour.

Some types of cancer, called leukaemia, start from blood cells. They don't form solid tumours.
Instead, the cancer cells build up in the blood and sometimes the bone marrow.

For a cancer to start, certain changes take place within the genes of a cell or a group of cells.

Genes and cell division

Different types of cells in the body do different jobs, but they are basically similar. They all have
a control centre called a nucleus. Inside the nucleus are chromosomes made up of long strings of
DNA (deoxyribonucleic acid). DNA contains thousands of genes, which are coded messages that
tell the cell how to behave.

Each gene is an instruction that tells the cell to make something. This could be a protein, or a
different type of molecule called RNA. Together, proteins and RNA control the cell. They decide
what sort of cell it will be, what it does, when it will divide, and when it will die.

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Gene changes within cells (mutations)
Normally genes make sure that cells grow and reproduce in an orderly and controlled way. They
make sure that more cells are produced as they are needed to keep the body healthy.

Sometimes a change happens in the genes when a cell divides. The change is called a mutation.
It means that a gene has been damaged or lost or copied twice. Mutations can happen by chance
when a cell is dividing. Some mutations mean that the cell no longer understands its instructions
and starts to grow out of control. There have to be about half a dozen different mutations before
a normal cell turns into a cancer cell.

Mutations in particular genes may mean that too many proteins are produced that trigger a cell to
divide. Or proteins that normally tell a cell to stop dividing may not be produced. Abnormal
proteins may be produced that work differently to normal.

Features of normal cells

Normal body cells have a number of important features. They can

 Reproduce themselves only when and where they are needed

 Stick together in the right place in the body
 Self-destruct if they are damaged or too old
 Become specialised (mature)

Cancer cells are different to normal cells in various ways.

Genes, DNA and Cancer

How faulty genes lead to cancer

Our genes pick up mistakes that occur when cells divide. These mistakes are called faults or
mutations and happen throughout our lives. They are caused by the natural processes in our cells,
and by various other factors. These include

 Tobacco smoke
 Radiation
 Ultraviolet radiation from the sun
 Some substances in food
 Chemicals in our environment

Sometimes people inherit certain faulty genes from their parents that mean they have an
increased risk of cancer.

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Usually, cells can repair faults in their genes. If the damage is very bad, they may self- destruct
instead. Or the immune system may recognise them as abnormal and kill them. This helps to
protect us from cancer.

But sometimes mutations in important genes mean that a cell no longer understands its
instructions, and starts to multiply out of control. It doesn't repair itself properly, and it doesn't
die when it should. This can lead to cancer.

There are four main types of gene involved in cell division. Most tumours have faulty copies of
more than one of these types.

1.Genes that encourage the cell to multiply (Proto-

oncogenes)
Proto-oncogene: A normal gene which, when altered by mutation, becomes an oncogene that
can contribute to cancer. Proto-oncogenes may have many different functions in the cell. Some
proto-oncogenes provide signals that lead to cell division. Other proto-oncogenes regulate
programmed cell death (apoptosis).

The defective versions of proto-oncogenes, known as oncogenes, can cause a cell to divide in an
unregulated manner. This growth can occur in the absence of normal growth signals such as
those provided by growth factors. A key feature of oncogene activity is that a single altered copy
leads to unregulated growth.

2.Genes that stop the cell multiplying (tumour suppressor

genes)
Usually, cells can repair faults in their genes. If the damage is very bad, genes called tumour
suppressor genes may stop the cell growing and dividing.

Mutations in tumour suppressor genes mean that a cell no longer understands the instruction to
stop growing and starts to multiply out of control. This can lead to cancer.

The best known tumour suppressor gene is p53. The p53 gene is damaged or missing in most
human cancers.

3.Genes that repair other damaged genes (DNA repair

genes)
The DNA in every cell in our body is constantly in danger of being damaged. But cells contain
many different proteins whose job is to repair damaged DNA. Thanks to these, most DNA

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damage is repaired immediately, with no ill effects. But if the DNA damage occurs to a gene that
makes a DNA repair protein, a cell has less ability to repair itself. So errors will build up in other
genes over time and allow a cancer to form.

Scientists have found these genes to be damaged in some human cancers, including bowel
cancer.

4. Genes that tell a cell to die (self-destruction genes)

Some genes normally tell a cell to self-destruct if it has become too old or damaged. This is
called apoptosis or programmed cell death. It is a highly complex and very important process.
Cells usually die whenever something goes wrong, to prevent a cancer forming.

There are many different genes and proteins involved in apoptosis. If these genes get damaged, a
faulty cell can survive rather than die and it becomes cancerous.

Showing Genes frequently mutated in cancer and cancer

formation
The genes that have been implicated in carcinogenesis are divided into two broad categories
oncogenes (‘cell accelerators’) and tumour suppressor genes (‘cell brakes’) but also include
DNA repair genes

Cellular oncogenes

Genes that promote autonomous cell growth in cancer cells are called oncogenes, and their
normal cellular counterparts are called proto-oncogenes. Proto-oncogenes are physiologic
regulators of cell proliferation and differentiation while oncogenes are characterised by the
ability to promote cell growth in the absence of normal mitogenic signals. Their products,
oncoproteins, resemble the normal products of proto-oncogenes with the exception that
oncoproteins are devoid of important regulatory elements. Their production in the transformed
cells becomes constitutive, that is, not dependent on growth factors or other external signals.
Proto-oncogenes can be converted to oncogenes by several mechanisms including point mutation
and gene amplification resulting in:

 Overproduction of growth factors

 Flooding of the cell with replication signals
 Uncontrolled stimulation in the intermediary pathways
 Cell growth by elevated levels of transcription factors

Tumour suppressor genes

Tumour suppressor genes encode proteins that are:

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  receptors for secreted hormones that function to inhibit cell proliferation
 negative regulators of cell cycle entry or progression
 negative regulators of growth signalling pathways
 checkpoint-control proteins that arrest the cell cycle if DNA is damaged or chromosomes
are abnormal
 Proteins that promote apoptosis and DNA repair enzymes.

The transformation of a normal cell to a cancer cell is accompanied by the loss of function of one
or more tumour suppressor genes and both gene copies must be defective in order to promote
tumour development.

Table 1. Examples of tumour suppressor genes

Spontaneous
Gene Protein function Inherited Disease
Tumours
APC Negative regulator of the Adenomatous polyposis Most colon cancers
signalling pathway coli
BRCA1 Components of DNA repair Familial breast and Spontaneous breast
BRCA2 systems ovarian cancer cancers
E-cadherin, a cell adhesion Hereditary diffuse gastric Many epithelial
CDH1
molecule cancer cancers

Note:

APC- Anaphase-promoting complex

BRCA 1- Breast cancer 1 is also known as the BRCA 1 gene. The protein encoded by this gene plays a
crucial role in DNA repair and tumour suppression.

CDH1-Cadherin

The diagram below shows how cancer forms from mutations. Cancers are caused by a series of
mutations. Each mutation alters the behavior of the cell somewhat.

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Showing how cancer cells don't stop growing and dividing
Unlike normal cells, cancer cells don't stop growing and dividing when there are enough of them.
So the cells keep doubling, forming a lump (tumour) that grows in size.

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Eventually a tumour forms that is made up of billions of copies of the original cancerous cell.

Cancers of blood cells (leukaemias) don't form tumours but they make many abnormal blood
cells build up in the blood.

Cancer cells ignore signals from other cells

Cells send chemical signals to each other all the time. Normal cells obey signals that tell them
when they have reached their limit and will cause damage if they grow any further. But
something in cancer cells overrides the normal signalling system.

Benign and cancerous (malignant) tumours

Tumours (lumps) can be benign or cancerous (malignant). Benign means it is not cancer.

Benign tumours

 Usually grow quite slowly

 Don't spread to other parts of the body
 Usually have a covering made up of normal cells

Benign tumours are made up of cells that are quite similar to normal cells. They will only cause a
problem if they

 Grow very large

 Become uncomfortable or unsightly
 Press on other body organs
 Take up space inside the skull (such as a brain tumour)

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  Release hormones that affect how the body works

Malignant tumours are made up of cancer cells. They

 Usually grow faster than benign tumours

 Spread into and damage surrounding tissues
 May spread to other parts of the body in the bloodstream or though the lymph system to
form secondary tumours. Spreading to other parts of the body is called metastasis

How cancers get bigger

To start with, cancer cells are contained within the body tissue from which they have developed
– for example, the lining of the bladder or the breast ducts. Doctors call this superficial cancer
growth. It may also be called carcinoma in situ.

The cancer cells grow and divide to create more cells and will eventually form a tumour. A
tumour may contain millions of cells. All body tissues have a layer keeping the cells of that
tissue inside called the basement membrane. Once the cancer cells have broken through the
basement membrane it is called an invasive cancer.

Blood supply and cancer

As the tumour gets bigger, the centre of it gets further and further away from the blood vessels in
the area where it is growing. So the centre of the tumour gets less and less of the oxygen and the
other nutrients all cells need to survive.

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Like healthy cells, cancer cells cannot live without oxygen and nutrients. So they send out
signals, called angiogenic factors that encourage new blood vessels to grow into the tumour. This
is called angiogenesis. Without a blood supply, a tumour can't grow much bigger than a pin head.

Once a cancer can stimulate blood vessel growth, it can grow bigger and grow more quickly. It
will stimulate the growth of hundreds of new capillaries from the nearby blood vessels to bring it
nutrients and oxygen.

How cancer spreads into surrounding tissues

As a tumour gets bigger, it takes up more room in the body. The cancer can then cause pressure
on surrounding structures. It can also grow directly into body structures nearby. This is called
local invasion. How a cancer actually grows into surrounding normal body tissues is not fully
understood.

A cancer may just grow out in a random direction from the place where it started. However,
tumours can spread into some tissues more easily than others. For example, large blood vessels
that have very strong walls and dense tissues such as cartilage are hard for tumours to grow into.
So locally, tumours may grow along the 'path of least resistance'. This means that they probably
just take the easiest route.

Research has pointed to 3 different ways that tumours may grow into surrounding tissues and
they are outlined here. A particular tumour will probably use all 3 of these ways of spreading.
Which way is used most will depend partly on the type of tumour, and partly on where in the
body it is growing.

Pressure from the growing tumour

As the tumour grows and takes up more space, it begins to press on the normal body tissue
nearby. The tumour growth will force itself through the normal tissue, as in the diagram below.

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The finger like appearance of the growth happens because it is easier for the growing cancer to
force its way through some paths than others. For example, cancers may grow between sheets of
muscle tissue rather than straight through one particular muscle.

As the cancer grows, it will squeeze and block small blood vessels in the area. Due to low blood
and oxygen levels, some of the normal tissue will begin to die off. This makes it easier for the
cancer to continue to push its way through.

Using enzymes

Some normal cells produce chemicals called enzymes that break down cells and tissues. The
cells use the enzymes to attack invading bacteria and viruses. They also use them to break down
and clear up damaged areas in the body. The damaged cells have to be cleared away so that the
body can replace them with new ones. This is all part of the natural healing process.

Many cancers contain larger amounts of these enzymes than normal tissues. Some cancers also
contain a lot of normal white blood cells, which produce the enzymes. They are part of the
body's immune response to the cancer. Unknown where the enzymes come from, but they are
likely to make it easier for the cancer to make a pathway for itself through the healthy tissue.

As the cancer pushes through and breaks down normal tissues, it may cause bleeding due to
damage to nearby blood vessels.

Cancer cells moving through the tissue

One of the things that make cancer cells different to normal cells is that they can move about
more easily. So it seems likely that one of the ways that cancers spread through nearby tissues is
by the cells directly moving.

Scientists have discovered a substance made by cancer cells which stimulates them to move.
They don't know for sure yet, but it seems likely that this substance plays a big part in the local
spread of cancers.

This research is interesting because, if a substance has been found that helps cancer cells move,
then researchers can start to find ways to stop the substance working. They may also be able to
find ways to stop the cancer cells making the substance in the first place. If cancers can be
stopped from spreading, it may be easier to cure them.

Researchers are also trying to understand how cancer cells change shape as they move and
spread to other parts of the body.

Primary and secondary cancer

The place where a cancer starts in the body is called the primary cancer or primary site. If cancer
cells spread to another part of the body the new area of cancer is called a secondary cancer or
a metastasis.
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Some cancers may spread to more than one area of the body to form multiple secondary or
metastases.

How cancer can spread to other areas of the body

Cancer cells can be carried in the bloodstream or lymphatic system to other parts of the body.
There they can start to grow into new tumours. The diagram shows a primary bowel cancer that
has spread to the liver.

In order to spread, some cells from the primary cancer must break away, travel to another part of
the body and start growing there. Cancer cells don't stick together as well as normal cells do.
They may also produce substances that stimulate them to move.

The diagram shows a tumour appearing in cells lining a body structure such as the bowel wall.
The tumour grows through the layer holding the cells in place (the basement membrane).

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Some cells can then go into small lymph vessels or blood vessels called capillaries in the area.

Spread through the blood circulation

If the cancer cells go into small blood vessels they can then get into the bloodstream. They are
called circulating tumour cells.

Researchers are currently looking at using blood tests to find circulating tumour cells to diagnose
cancer and avoid the need for tests such as biopsies. They are also looking at whether they can
test circulating cancer cells to predict which treatments will work best for each patient.

The circulating blood sweeps the cancer cells along until they get stuck somewhere. Usually they
get stuck in a very small blood vessel called a capillary.

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Then the cell must move through the wall of the capillary and into the tissue of the organ close
by. The cell can multiply to form a new tumour if the conditions are right for it to grow and it has
the nutrients that it needs.

This is quite a complicated journey and most cancer cells don't survive it. Probably, out of many
thousands of cancer cells that reach the blood circulation only a few will survive to form a
secondary cancer (metastasis).

Some cancer cells are probably killed off by the white blood cells in our immune system. Others
cancer cells may die because they are battered around by the fast flowing blood.

Cancer cells in the circulation may try to stick to platelets to form clumps to give themselves
some protection. Platelets are blood cells that help the blood to clot. This may also help the

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cancer cells to be filtered out in the next capillary network they come across so they can then
move into the surrounding tissues.

Spread through the lymphatic system

The lymphatic system is a network of tubes and glands in the body that filters body fluid and
fights infection. It also traps damaged or harmful cells such as cancer cells.

If cancer cells go into the small lymph vessels close to the primary tumour they can be carried
into nearby lymph glands. The cancer cells may get stuck there. In the lymph glands they may be
destroyed but some may survive and grow to form tumours in one or more lymph nodes. Doctors
call this lymph node spread.

Micrometastases
Micrometastases are areas of cancer spread (metastases) that are too small to see. Some areas of
cancer cells are too small to show up on any type of scan.

For a few types of cancer, blood tests can detect certain proteins released by the cancer cells.
These may give a sign that there are metastases in the body that are too small to show up on a
scan. For most cancers, there is no blood test that can indicate whether a cancer has spread or
not.

For most cancers the doctor can only say whether it is likely or not that a patient has
micrometastases. This may be based on the following factors.

 Previous experience of many other patients treated in the same way. Doctors collect and
publish this information to help each other
 Whether cancer cells are found in the blood vessels in the tumour removed during
surgery (for example in testicular cancer). If cancer cells are found then cancer cells are
more likely to have reached the bloodstream and spread to somewhere else in the body
 The grade of the cancer (how abnormal the cells are) – the higher the grade, the more
quickly the cancer is growing and the more likely that cells have spread
 Whether lymph nodes removed during an operation contained cancer cells (for example
in breast cancer or bowel cancer). If the lymph nodes contained cancer cells this shows
that cancer cells have broken away from the original cancer. But there is no way of
knowing whether the cells have spread to any other areas of the body

This information is important in treating cancer. If the doctor thinks it is likely that
micrometastases are present, they may offer extra treatment, such as chemotherapy, radiotherapy
or hormone therapy. The aim is to kill any areas of cancer cells before they grow big enough to
be seen on a scan. So the extra treatments may increase the chance of curing the cancer.

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Places cancers can spread to
Cells can break away from a cancer and spread in the blood or lymph systems to almost
anywhere in the body. But most types of cancer tend to spread most often to one or two places.

The lungs
The lungs are the most common organ for cancers to spread to. This is because the blood from
most parts of the body flows back to the heart and then to the lungs before it goes to any other
organ. Cancer cells that have found their way into the bloodstream can get stuck in the tiny blood
capillaries of the lungs.

Cancer that has spread to the lungs may not cause any symptoms or it may cause

 A cough that doesn't go away

 Shortness of breath
 Chest infections
 A build -up of fluid between the chest wall and the lung called a pleural effusion – this in
turn causes shortness of breath, chest aching, discomfort and heaviness

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Fluid builds up because cancer cells cause inflammation of the pleura (also called the pleural
membrane). The pleura are the two sheets of tissue that cover the lungs. The inflamed tissues
make extra fluid and the fluid collects between them. There may also be cancer cells in the
pleural space that stop the extra fluid draining away. The lungs expand (inflate) as we breathe in.
This fluid build- up gets in their way and presses on the lungs, stopping them from expanding
fully.

The treatment for cancer that has spread (secondary cancer) depends on where the cancer started
in the body (the primary cancer). So breast cancer that has spread to the lungs will be treated like
a breast cancer, not like lung cancer.

The liver
Many types of cancer can spread to the liver. It is most likely to occur with cancers of the
digestive system because the blood from the digestive system circulates through the liver before
it goes back to the heart. The cancer cells get stuck in tiny capillaries of the liver.

Cancer that has spread to the liver may not cause any symptoms. But it may cause

 A lack of energy
 Feeling generally unwell
 Feeling sick
 Lack of appetite
 Discomfort on the right side of the body under the rib cage
 Jaundice
 A build- up of fluid in the abdomen

Jaundice is the medical name for a build- up of bile salts in the blood. This usually happens
when the bile ducts in the liver are blocked. The build -up of bile salts makes the skin and whites

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of the eyes turn yellow. It can also make the skin become itchy. The urine often looks very dark
and bowel motions can look pale.

Ascites is the name for a build up of fluid in the abdomen. It forms if the cancer blocks the
normal blood flow through the liver and causes a back pressure of fluid. The healthy liver also
makes proteins that circulate in the blood. The proteins help to keep fluid in the blood and stop it
from leaking out into the tissues. If the liver is damaged, it may not make enough of these
proteins and so fluid can leak out and collect in the abdomen or in other parts of the body, such
as the feet and ankles.

The lymph nodes

It is very common for cancer cells to travel from the area of the original cancer to nearby lymph
nodes. This is because there is a natural circulation of tissue fluid from the organs into the
lymphatic system. This is not the same as having a cancer of the lymphatic system, such
as lymphoma.

If cancer spreads to the lymph nodes it may make them swell up. The swollen lymph nodes are
easy to see if they are near the surface of the body – for example, in the neck or under the arm.
But if the nodes are deeper in the body, they can only be seen on a scan.

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Cancer in the lymph nodes may not cause any symptoms. But sometimes, the swollen lymph
nodes can block the circulation of tissue fluid. This can cause swelling in the affected part of the
body. For example, swollen lymph nodes in the armpit or groin can cause swelling in the arm or
leg on the same side of the body. This swelling is called lymphoedema.

The bones
Some cancers are quite likely to spread to the bones – for example, prostate cancer, breast cancer
and lung cancer.

The most common effects of secondary cancer in the bones are

 Pain in the affected bones

 Weakness in the affected bones
 Raised calcium levels in the blood

Pain occurs because the cancer cells multiply in the bone and press on nerves. The growing
cancer can weaken the bone by damaging its normal structure. This may mean that it is more
likely to break. If this happens it is called a pathological fracture.

Damaged bone cells can release calcium into the blood. If high calcium levels build up in the
blood you may

 Feel sick
 Feel tired, drowsy or muddled
 Become constipated
 Feel very thirsty

If the calcium levels become very high they can cause irritability and confusion and eventually
unconsciousness.

The brain
Some types of cancer can spread to the brain, such as lung cancer and breast cancer. More
rarely colon (bowel) cancer, kidney cancer and melanoma can spread to the brain.

The most common symptoms are headaches and feeling sick. These symptoms are caused by the
growing cancer taking up space. The space for the brain is limited by the skull so the growing
cancer causes an increase in pressure inside the skull. This is called raised intracranial pressure.

Other symptoms depend on which part of the brain the cancer is growing in. They also depend
on the size of the tumour (or tumours). Small secondary brain tumours may not cause symptoms.
If symptoms occur they may include any of the following

 Weakness in an arm, leg, or on one side of the body

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  Moodiness or changes in behaviour
 Fits (seizures)
 Confusion
 Drowsiness
 A feeling of the room spinning (vertigo)
 Feeling dizzy or unsteady

The skin
Sometimes cancer cells can start growing in the skin. The secondary skin cancer may start to
grow on or near an operation scar where the primary cancer was removed. Or sometimes
secondary skin cancers can grow in other parts of the body.

A secondary skin cancer may look like a pink or red raised lump (a bit like a boil). Doctors may
call these areas plaques or nodules. Secondary skin cancers can be treated. It is important to tell
your doctor if you think you have one. Without treatment the area may become bigger and may
bleed or ooze fluid. This is called an ulcerating cancer.

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