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Cancer cell, horrifying but intriguing
Magdalena CHECHLIŃSKAMagdalena CHECHLIŃSKADepartment of Immunology
Maria Skłodowska-Curie Memorial Cancer Centre and Institute of Oncology
Warszawa
CellsYour 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 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 genefault.
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 genefault.
Progression of epithelial cancer (carcinoma)
Thiery, 2002
Normal 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)
Cancer cells
• 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
Intracellular signals
Membrane
Kassis, 2001
Normal cells:• Tightly packed• Autocrine interactions -
blocked
Dysplasia• Cells do not stick together
• Autocrine activation and further detachment of cells
EGFR
Tumour
Kunz-Schugart, 2002
ECM
„successful neoplastic cells are those able
to engage other cells to promote their
growth ”. Skobe i Fusenig
Tumour microenvironment influence
cancer cell growth
HaCaT (immortalised human keratinocytes)
Tranfected with H-ras oncogene
Benign cells Malignant cells
Increased growth potential
Malignant transformation
INCREASED POTENTIAL TO PRODUCE DISTANT METASTASES
in v i v o
i n v i t r o
No malignant transformation,
Reduced malignant
tumour development
potential
dośw.Mueller i wsp. 2001
Wounding stimulates the growth of primary and secondary tumours. (Experimental models of human cancers)
Hofer, 1999
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 TGFinhibitory activity
Bhowmick i wsp., Science, 2004
Inhibits:● nomal melanocytes, ● melanoma cells – early stages czerniaka
● lung and liver epithelial cells
Insensitivity to anti-growth signals
stimulates:● advanced melanoma cells
Does not inhibit cell lines in vitro:
● lung cancer
● liver cancer
IL-6
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
DNA damage Damage response
p53
Repair
Arrest
Apoptosis
Evading apoptosis – ineffective effectors
IL-10
TGF-
mTNF
sTNF
TNFR
FasL
Fas
Fas
FasL
Cytotoxic/effector cellTumour cell
IL-6
No apoptosis 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, double-stranded 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 lenghtSperm, eggs 20 kilobasesFoetal cells ~15 kilobasesAdult cells ~10 kilobasesSenescent cells ~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
< 100m from capillaries
Pro-and anti-angiogenic factorsThere 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 25m
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% 10-30% 30-50% 50-70% 70%
Breast 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, liver
Lymph nodes
Kidney Skin, bone Brain, kidney Liver Lung
Lung Lung Kidney, distant nodes
Adrenal, brain Bone Liver, local lymph nodes
Melanoma Kidney Adrenal, brain, bone, skin
Lung. Liver nodes
Ovary Brain, skin, kidney
Bone, adrenal Lung, liver nodes
Prostate Brain, skin Kidney, adrenal, liver, lung
Bone, 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 TGF; in the liver, colorectal cancer cells have an increased ability to grow due to TGF 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
FasLImmunosupresja
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.
The relative rarity of the cancer cell
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