imunology of cancer 2012
TRANSCRIPT
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Cancer
Cancer is one of the most common diseases inthe developed world:
1 in 4 deaths are due to cancer 1 in 17 deaths are due to lung cancer
Lung cancer is the most common cancer in men
Breast cancer is the most common cancer inwomen
There are over 100 different forms of cancer
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Cancer
The division of normal cells is preciselycontrolled. New cells are only formed for growth
or to replace dead ones. Cancerous cells divide repeatedly out of control
even though they are not needed, they crowdout other normal cells and function abnormally.
They can also destroy the correct functioning ofmajor organs.
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What causes cancer?
Cancer arises from the mutationof a normal
gene. Mutated genes that cause cancer are called
oncogenes.
Cells that are old or not functioning properlynormally self destruct and are replaced bynew cells.
However, cancerous cells do not self destruct
and continue to divide rapidly producingmillions of new cancerous cells.
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A factor which brings about a mutation iscalled a mutagen.
A mutagen is mutagenic.
Any agent that causes cancer is called acarcinogenand is described ascarcinogenic.
So some mutagens are carcinogenic.
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Carcinogens Ionising radiation
X Rays, UV light
Chemicalstar from cigarettes
Virus infectionpapilloma virus can beresponsible for cervical cancer.
Hereditary predispositionSome families aremore susceptible to getting certain cancers.Remember you cant inherit cancerits just thatyou maybe more susceptible to getting it.
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Benign or malignant?
Benign tumoursdo not spread from their site of origin,but can crowd out (squash) surrounding cells eg braintumour, warts.
Malignant tumourscan spread from the original site
and cause secondary tumours. This is calledmetastasis. They interfere with neighbouring cells andcan block blood vessels, the gut, glands, lungs etc.
Why are secondary tumours so bad?
Both types of tumour can tire the body out as theyboth need a huge amount of nutrients to sustain the
rapid growth and division of the cells.
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The Development of Cancer
Within every nucleus of every one of thehuman body's 30 trillion cells exists DNA,
the substance that contains theinformation needed to make and controlevery cell within the body. Here is a close-
up view of a tiny fragment of DNA.
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1. DNA of a normal cell
This piece of DNA is an exact copy of the DNA from
which it came. When the parent cell divided to createtwo cells, the cell's DNA also divided, creating twoidentical copies of the original DNA.
2 f
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2. Mutation of DNA
Here is the same section of DNA but from another cell. If youcan imagine that DNA is a twisted ladder, then each rung of theladder is a pair of joined molecules, or a base pair. With thissection of DNA, one of the base pairs is different from the
original.
This DNA has suffered a mutation, either through mis-copying(when its parent cell divided), or through the damaging effectsof exposure to radiation or a chemical carcinogen.
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3. Genetically altered cell
Body cells replicate through mitosis, they respond totheir surrounding cells and replicate only to replaceother cells. Sometimes a genetic mutationwill cause acell and its descendants to reproduce even thoughreplacement cells are not needed.
The DNA of the cell highlighted above has a mutationthat causes the cell to replicate even though thistissue doesn't need replacement cells at this time or at
this place.
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4. Spread and second mutation
The genetically altered cells have, over time, reproducedunchecked, crowding out the surrounding normal cells. Thegrowth may contain one million cells and be the size of apinhead. At this point the cells continue to look the same as the
surrounding healthy cells.
After about a million divisions, there's a good chance that oneof the new cells will have mutated further. This cell, nowcarrying two mutant genes, could have an altered appearanceand be even more prone to reproduce unchecked.
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5. Third mutation
Not all mutations that lead to cancerous cells result in the cellsreproducing at a faster, more uncontrolled rate. For example, amutation may simply cause a cell to keep from self-destructing.All normal cells have surveillance mechanisms that look fordamage or for problems with their own control systems. If such
problems are found, the cell destroys itself.Over time and after many cell divisions, a third mutationmayarise. If the mutation gives the cell some further advantage,that cell will grow more vigorously than its predecessors andthus speed up the growth of the tumour.
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6. Fourth mutation
The new type of cells grow rapidly, allowing formore opportunities for mutations. The nextmutation paves the way for the development of
an even more aggressive cancer.
At this point the tumour is still contained.
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7. Breaking through the membrane
The newer, wilder cells created by another mutation areable to push their way through the epithelial tissue'sbasement membrane, which is a meshwork of proteinthat normally creates a barrier. The invasive cells in thistumour are no longer contained.
At this point the cancer is still too small to be detected.
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8. Angiogenesis
Often during the development of earlier stages of the tumour,or perhaps by the time the tumour has broken through thebasement membrane (as pictured above), angiogenesis takesplace.Angiogenesis is the recruitment of blood vessels fromthe network of neighbouring vessels.
Without blood and the nutrients it carries, a tumour would beunable to continue growing. With the new blood supply,however, the growth of the tumour accelerates; it sooncontains thousand million cellsand, now the size of a smallgrape, is large enough to be detected as a lump
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9.Invasion and dispersal
The tumour has now invaded the tissuebeyond thebasement membrane.
Individual cells from the tumour enter into the networkof newly formed blood vessels, using these vessels ashighways by which they can move to other parts of thebody. A tumour as small as a gram can send out amillion tumour cells into blood vessels a day.
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10. Tumour cellstravel -
metastasis
What makes mosttumours so lethal istheir ability tometastasize -- that is,establish new tumoursites at other locationsthroughout the body.Secondary tumours.
Metastasis is nowunderway, as tumourcells from the originalcancer growth travelthroughout the body.Most of these cells willdie soon after enteringthe blood or lymph
circulation.
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11. Metastasis
To form a secondary tumour, a tumour cell needs toleave the vessel system and invade tissue. The cell must
attach itselfto a vessel's wall. Once this is done, it canwork its way through the vessel and enter the tissue.
Although perhaps less than one in 10,000 tumour cellswill survive long enough to establish a new tumour site,a few survivors can escape and initiate new coloniesofthe cancer.
C G l Eti l d
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Cancer: General Etiology andPathogenesis
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Hallmarks of Cancer Cells
Self-maintainedreplication
Longer survival Genetic instability
Capable of inducingneoangiogenesis
Capable of invasionand metastasis
Apoptosis down-regulation
Lack of responseto inhibitoryfactors
Self-sustained
proliferation
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Hallmarks of Cancer Cells
Self-maintainedreplication
Longer survival Genetic instability
Capable of inducingneoangiogenesis
Capable of invasionand metastasis
Apoptosisdown-
regulation Telomerase
reactivation
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Hallmarks of Cancer Cells
Self-maintainedreplication
Longer survival Genetic instability
Capable of inducingneoangiogenesis
Capable of invasionand metastasis
Cooperativegenetic damage
Mutagenicagents
Defective repairsystems
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Hallmarks of Cancer Cells
Self-maintainedreplication
Longer survival Genetic instability
Capable of inducingneoangiogenesis
Capable of invasionand metastasis
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So, you have a tumor cell.
Now what? You need three things:
1. See the cancer
Ternary complex and costimulation by B7
2. Activate lymphocytes
Release IL-2, IFN-gamma, and TNF-alpha
3. Cancer cells must be susceptible to killing CTL lysis, macrophages, NK cells
Info From:http://www.brown.edu/Courses/Bio_160/Projects1999/cancer/imevstca.html#Introduction
http://www.brown.edu/Courses/Bio_160/Projects1999/cancer/imevstca.htmlhttp://www.brown.edu/Courses/Bio_160/Projects1999/cancer/imevstca.html -
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Anti-tumour immunity:
basic mechanisms
Immunology 7thEd( D. Male et al)
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Antigen presenting cells (APC)
Dendritic Cells (DC)
DCs are the interface between innate andadaptive immunity
DCs are immature as they circulate waitingto encounter pathogens. At this point, they
are highly phagocytic, but not goodstimulators of adaptive T cell responses
Once they are activated, they secretecytokines to initiate inflammation and then
they migrate to lymph nodes and mature As mature DCs they are very efficient APCs
for T cell stimulation
Other APCs: macrophages, neutrophils, B-
lymphocytes, monocytes.
A ti t o i it b i
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Anti-tumour immunity: basicmechanisms
Smyth, M. J. et al. Nature Immunology 2, 293 - 299 (2001)
Presence of tumour cells
and tumour antigens may
initiate the release ofdanger signals; cytokines,
heat shock proteins (HSP),
uric acid etc.
Activation and maturation
of dendritic cells, which
present tumour antigens to
CD8 and CD4 cells
Clonal expansion of CD8 and
CD4 T cells; migration from
the lymph node
Subsequent T cell mediated
destruction of tumour cells
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The cellular basis of tumour immunology: CTL - tumor cellinteractions
N t l Kill (NK) C ll
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Natural Killer (NK) Cells- First identified by having the ability to lytically
kill certain tumor cell lines without priorsensitization
- Kill target cell by release of cytotoxic granulescontaining granzymes and perforin whichpenetrate target cell membrane and induceprogrammed cell death
- Can mediate Antibody-Dependent CellularCytotoxicity (ADCC); (mechanism of immunologiclysis in which cellular targets sensitized by specificantibodies are efficiently and selectively lysed bynonspecific effectors)
- Kill virally-infected cells with missing MHC classI
- Activated by IFN-a bor IL-12 (produced rapidlyby activated macrophages)
Fig 8-3
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4. Tumours antigens: novel or over-expressed proteins produced by
tumours that may be recognized bythe immune system.
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Major Histocompatability Complex antigens
TSTA
TATA
TSTA: unique to a tumourPlay an important role in tumor rejection.
TATA: shared by normal and tumour cells
Tumour-associated developmental Ag (TADA)
Tumour-associated viral Ag (TAVA)
Tumour-specific
transplantation Ag
Tumour-associated
transplantation Ag
Antigens expressed on tumour cells
Tumor-Associated
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Tumor-AssociatedDevelopmental Antigens
Found on cancer cells and onfetal cells.
Do not trigger anti-tumorimmunity.
Used in diagnosis.
Alpha-fetoprotein(AFP)Cancers of liver
Carcinoembryonic Ag (CEA)
colorectal cancer
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5. How do tumour cellsescape from the immune
system?
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Conniving Cancer.
Bad antibodies? Some antibodies do not protect against tumor
growth, but also ENHANCEit. Release of immunosuppressive cytokines
transforming growth factor-beta (TGF-beta), interleukin-10(IL-10) and vascular endothelial growth factor (VEGF)
Hide and go Seeking Antigen Antigens actually seem to hide in the presence of
antibody
Also, some cancer cells completely shed themselvesof the antigen