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Cancer cell, horrifying but intriguing
Magdalena CHECHLIŃSKA
Department of Immunology
Maria Skłodowska-Curie Memorial Cancer Centre
and Institute of Oncology
Warszawa
Cells
Your body is made up of approx.
1013-1014 cells that can only be
seen under a microscope.
These cells are grouped together
to make up the tissues and
organs of our bodies.
Cells are basically similar. They all
have a centre called
a nucleus. Inside the nucleus are
the genes.
Genes are really bits of code. The
information they carry can be
switched on or off. The genes
control the cell. They decide
when it will reproduce, what it
does and even when it will die.
Body tissues
• Body tissues grow by
increasing the number of cells
that make them up. The cells
reproduce themselves exactly.
• But once we are grown up,
most cells mature, become
specialised for their particular
job in the body and lose the
ability to reproduce.
• There are always immature
cells around (called stem cells)
to replace cells that are
damaged or killed.
• Some cells carry on
reproducing. These include
sperm cells, hair cells, cells in
the gut and cells that make
blood in the bone marrow.
How do the cells know
when to stop
growing?
Normal growth and
healing is very orderly
and precise. The
cells send chemical
messages to each
other. The messages
come from the genes
inside the cells.
How do new cells end up
in the right place?
The cells have a natural
ability to stick
together in the right
place. Scientists call
this cell adhesion.
If the cell does find itself
in a place where its
surface molecules are
different from its
neighbours, it will die.
How cells reproduce
• Cells double up very
precisely so that the
new cells are exactly
the same as the old
ones. Each cell
makes copies of all its
genes. Then it splits
into two with one set
of genes in each new
cell.
• This is called mitosis
Can cells carry on doubling for ever?
No they can't!
It seems human cells are pre-programmed
to reproduce up to 50 or 60 times maximum.
Then they will become senescent
and eventually die.
40 population doublings = 1 cell gives rise to 1012 cells
What cancer is
Cancer is a disease caused by normal cells
changing so that they grow in an uncontrolled
way. The uncontrolled growth causes a lump
called a tumour to form.
There are over 200 different types of cancer
because there are over 200 different types of
body cells. For example, cells that make up the
lungs can cause a lung cancer. There are
different cells in the lungs, so these may cause
different types of lung cancer.
How cancer starts - MUTATIONS
One cell (?) that has lost a number of vital control systems due to
mutations. Mutation means a gene has been damaged or lost.
One gene 'codes' for one protein.
Mutation  too much protein is made
 a protein is not made at all.
 the properties of a protein are changed
3 types of genes that are important in making a cell cancerous:
» Genes that encourage the cell to multiply
» Genes that stop the cell multiplying
» Genes that repair the other damaged genes
How cancer starts
Oncogenes
Some genes encourage cells to multiply (proliferate). If these genes become
abnormal, they tell the cell to multiply all the time.
Tumour suppressor genes (anti-oncogenes)
Some genes specifically to stop the cell multiplying - they act as the brake to the
oncogene's accelerator.
If one of these 'tumour suppressor genes' becomes damaged and stops working, then the
cell may carry on and on multiplying and it becomes immortal, which is one of the
properties of a cancer cell.
p53 normally stops cells with other damaged genes from reproducing and encourages
them to commit suicide (apoptosis). p53 is damaged or missing in most human cancers.
Genes that repair other damaged genes
These genes normally repair any damage to the DNA that the cell's genes are
made of. If these genes are damaged, then other mutations are not repaired and
the cell can reproduce the mutations in its daughter cells. These genes have
been found to be damaged in some human cancers, including bowel cancer.
How cancer starts
How do mutations happen?
By chance when a cell is reproducing. It is not easy for a
normal cell to turn into a cancer cell. There have to be about
half a dozen different mutations before this happens. Cells
often self destruct if they carry a mutation. Or they might be
recognised by the immune system as abnormal and
killed. This means most pre-cancerous cells die before they
can cause disease. Only a few can turn into a cancer.
•
It can take a long time before enough mutations happen for a
cell to become cancerous. This is why many cancers are
more common in older people. There has been more time to
be exposed to carcinogens. And more time for accidents
when cells reproduce.
How cancer starts
Genetic make up
• There have to be a number of genetic mutations within a cell before it
becomes cancerous.
Sometimes we are born with one of these mutations already. This does
not mean we will get cancer. But with one mutation from the outset, it
makes it more likely statistically that we will ( 'genetic predisposition‘).
Examples: the BRCA1 and BRCA2 breast cancer genes. Women who
carry one of these faulty genes have a higher chance of developing
breast cancer than women who do not.
BUT: Most women with breast cancer do not have a mutated BRCA1 or
BRCA 2 gene. Less than 5% of all breast cancer is due to these
genes. So most breast cancer is not caused by a high risk inherited gene
fault.
How
starts
Howcancer
cancer starts
Genetic make up
Genetic
make up
• There have to be a number of genetic mutations within a cell before it
becomes
• There have
to becancerous.
a number of genetic mutations within a cell before it
Sometimes we are born with one of these mutations already. This does
becomesnot
cancerous.
mean we will get cancer. But with one mutation from the outset, it
Sometimes
weit more
are born
with onethat
of these
already. This does
makes
likely statistically
we will (mutations
'genetic predisposition‘).
not mean we will get cancer. But with one mutation from the outset, it
Examples: the BRCA1 and BRCA2 breast cancer genes. Women who
makes it more
likely statistically that we will ( 'genetic predisposition‘).
carry one of these faulty genes have a higher chance of developing
breast cancer than women who do not.
Examples: the BRCA1 and BRCA2 breast cancer genes. Women who
Most women with breast cancer do not have a mutated BRCA1 or
carry oneBUT:
of these
faulty genes have a higher chance of developing
BRCA 2 gene. Less than 5% of all breast cancer is due to these
breast cancer
women
who do
not.
genes. than
So most
breast cancer
is not
caused by a high risk inherited gene
fault.
BUT: Most women with breast cancer do not have a mutated BRCA1 or
BRCA 2 gene. Less than 5% of all breast cancer is due to these
genes. So most breast cancer is not caused by a high risk inherited gene
fault.
Progression of epithelial cancer (carcinoma)
Thiery, 2002
Normal cells
Cancer cells
• Reproduce themselves
exactly (FIDELITY)
• Stop reproducing at the
right time (CONTACT
INHIBITION)
• Stick together in the right
place
• Self destruct if they are
damaged (APOPTOSIS)
• Become specialised or
'mature‘
(DIFFERENTIATION)
• Carry on reproducing
• Don't obey signals from
other neighbouring cells
• Don't stick together
• Don't become
specialised, but stay
immature
• Don't die if they move to
another part of the body
Cancer cell – acquired capabilities
Hanahan, 2000
Self-sufficiency in growth signals
•
Synthesis of
growth factors
•
Expression of
growth factor
receptors
•
Receptor
structure
changes
resulting in
signal
transmission in
spite of the lack
of a growth
factor
Membrane
Intracellular
signals
EGFR
Normal cells:
Dysplasia
• Tightly packed
• Autocrine interactions blocked
• Cells do not stick together
• Autocrine activation and
further detachment of cells
Kassis, 2001
Tumour
ECM
Kunz-Schugart, 2002
„successful neoplastic cells are those able
to engage other cells to promote their
growth ”. Skobe i Fusenig
HaCaT
(immortalised human keratinocytes)
i
n
v
i
t
r
o
i
n
v
i
v
o
Tumour microenvironment
influence
cancer cell growth
Tranfected with H-ras
oncogene
Benign cells
No malignant
transformation,
Malignant cells
Reduced
malignant
tumour
development
potential
Wounding stimulates the growth
of primary and secondary
tumours. (Experimental
models of human cancers)
Hofer, 1999
Malignant
transformation
Increased growth
potential
INCREASED POTENTIAL TO
PRODUCE DISTANT METASTASES
dośw.Mueller i wsp. 2001
TGFRII- mice, selectively on fibroblasts,
excessive fibroblasts in prostate, followed by
prostate cancer.
Conclusion: defective stromal fibroblasts
stimulate epithelial tumour growth due to the
lack of TGFb inhibitory activity
Bhowmick i wsp., Science, 2004
Insensitivity to anti-growth signals
IL-6
Inhibits:
● nomal melanocytes,
● melanoma cells –
early stages czerniaka
● lung and liver
epithelial cells
stimulates:
● advanced
melanoma cells
Does not inhibit
cell lines in
vitro:
● lung cancer
● liver cancer
Apoptosis = programmed cell death =
= gene-directed cellular self-destruction
Cells are programmed to die at a particular point.
This cell suicide mechanism enables metazoans (multicellular
organisms) to control cell number.
„Apoptosis” is of greek origin, meaning "falling off or dropping
off", in analogy to leaves falling off trees.
This analogy emphasizes that the death of living matter is
an integral and necessary part of the life cycle of
organisms.
Apoptosis
Functions of apoptosis
– Development
– Homeostasis:
• Immune cell regulation
• Cell damage or infection
• Response to stress or DNA damage
• In the human body 100.000 cells are produced every
second by mitosis and a similar number die by apoptosis,
i.e. 50 to 70 billion cells die each day due to apoptosis in
the average human adult. In a year, this amounts to the
proliferation and subsequent destruction of a mass of
cells equal to an individual's body weight.
Evading apoptosis :
example: TNF – pro- and anti-apoptotic
Apoptosis
• Cell damage or infection
• Response to stress or DNA damage
Repair
DNA damage
Damage response
Arrest
p53
Apoptosis
Evading apoptosis – ineffective effectors
Cytotoxic/effector cell
Tumour cell
IL-10
FasL
Fas
Fas
FasL
No
apoptosis
TNFR
mTNF
sTNF
TGF-b
IL-6
Apoptosis
Limitless proliferative potential –
cancer cells are immortal
Avoiding the progressive erosion of chromosomes (all
cancer cells) by telomerase expression (85-90%) and
other mechanism.
What telomeres are
• Telomeres are extensions of the linear, doublestranded DNA molecules of which chromosomes
are composed, and are found at each end of both
of the chromosomal strands.
• Telomeres are essential for chromosome stability
• Telomeres shorten with each cell division
each round of DNA replication leaves 50-200 bp
DNA unreplicated
Telomeres,
normal
metaphase
Telomere shortening as a mitotic counter
Telomere lenght
Sperm, eggs
Foetal cells
Adult cells
Senescent cells
20 kilobases
~15 kilobases
~10 kilobases
~5 kilobases
Each round of DNA replication leaves 50-200 base pairs
DNA unreplicated
Cells with telomeres that are 10-12 kb in length (average)
divide 50-60 times
Telomere maintenance is evident in all types of malignant
cells.
The main mechanism: upregulation of telomerase
(85-90% of malignant cells).
Telomerase is an enzyme, which is able to extend
telomeres.
Progression of epithelial cancer (carcinoma)
Thiery, 2002
Cancer cells stimulate angiogenesis, i.e. new vessels’ development
Angiogenesis – the growth of new blood vessels
< 100mm from capillaries
Pro-and anti-angiogenic factors
There are at least:
• 20 angiogenic growth factors
• 30 known natural angiogenesis inhibitors found in the
body.
Tumours present „proangiogenic” profile,
i.e the balance between angiogenic inducers and inhibitors
is disturbed in favour of the inducers.
Proangiogenic factors
• Hypoxia
• VEGF increased expression: breast, ovarian,
pancreatic,prostate cancer
High serum levels correlate with adverse
prognosis.
Progression of epithelial cancer (carcinoma)
Thiery, 2002
Cancer cells invade and colonise other sites
•
Adhesion to extracellular matrix components
and basement membrane
•
Basement membrane degradation
•
Extracellular matrix modification and
degradation
•
Active migration in extracellular matrix
•
Penetration thorough: blood vessel walls,
 lymphatic vessel walls,  body cavities walls
•
Implantation, survival and growth at distant
sites
Carcinoma cells in primary mammary tumour move along ECM fibres
Scale bar 25mm
Intravasation in primary mammary tumour
Condeelis and Segal, 2003
Adhesion molecules
• Growth factors released in tumour
microenvironment induce changes of
adhesion molecules on:
• Cancer cells
• Fibroblasts
• Endothelial cells
Proteases - enzymes
• Released not only by
cancer cells but also by
other cells in the
microenvoronment
• Role: extracellular matrix
degradation
• Activation and release of
matrix-associated growth
factors
• Protease activity correlates
with the ability to form
distant metstases.
• Protease inhibitors inhibit
cell migration
Active migration
Distant metastases
Organ-specific pattern of metastasis
Site
10%
Breast
10-30%
30-50%
50-70%
70%
Kidney, skin,
brain
Adrenal
Liver, bone,
lung
Lymph nodes
Bladder
Brain, skin
Kidney, bone
Adrenal, lung
Cervix
Brain, skin
Kidney, bone
Adrenal, lung
Colorectum
Skin
Brain, kidney,
lung
Bone, adrenal, Lymph
liver
nodes
Kidney
Skin, bone
Brain, kidney
Liver
Lung
Lung
Lung
Kidney, distant
nodes
Adrenal, brain
Bone
Kidney
Adrenal, brain, Lung. Liver
bone, skin
nodes
Melanoma
Ovary
Brain, skin,
kidney
Bone, adrenal
Lung, liver
nodes
Prostate
Brain, skin
Kidney, adrenal,
liver, lung
Bone, nodes
Liver, local
lymph nodes
„What is that decides which organs shall suffer in a
case of disseminated cancer?” (S. Paget, The Lancet, 1889)
• „When a plant goes to seed, its seeds are carried in all
directions, but they can only live and grow if they fall in
congenial soil.”
• Cancer cell dissemination – an ineffective process
• New microenvironment may be favourable to cancer cells,
e.g. in the bone marrow breast cancer cells are
stimulated by IGF 1, prostate cancer cells - by TGFb;  in
the liver, colorectal cancer cells have an increased ability
to grow due to TGFa presence.
Molecules determining cancer dissemination
• Constitutively expressed in the metastasis
development site
• Promote cancer cell adhesion to endothelium
and migration in and out the vessels
• Induce invasion into the new, favourable
environment
• Cells colonising new sites must express the
receptors relevant to the growth factors present
in the secondary sites.
Cancer cells express patterns of chemokine receptors that match
chemokines specifically expressed in organs
to which they commonly metastasise.
Muller, 2001
Immunosuppression
• Impairment of immune reponse, local and
systemic
Immunosupresja
FasL
The relative rarity of the cancer cell
Mutation rate: 2.2 x 10-9 per base pair per year X 3 billion (3x109) chemical base
pairs that make up human DNA X 5% of genome encoding X 1014 cells in
the average human = 3.3 x 1013 mutations per person per year.
Still, cancer arises in only 1 in 3 lifetimes.
The rarity of cancer highlights the efficacy of potent anti-tumorigenic
mechanisms presiding over somatic cells. Cancers prevail only when these
mechanisms have failed.
We perceive only the rare surviving clones that beat all the odds and appear as
clinical disease. We see only successes of cancer cells, not the failures.
Cancer progression and clinical appearance
Liotta, 2001
„Biology and Cancer Research have developed together.
Invariably, at each stage, the characteristics of the
cancer cell have been ascribed to some defect in
whatever branch of biology happens at the time to be
fashionable and exciting ”
John Cairns