imunology of cancer 2012

8/10/2019 Imunology of Cancer 2012

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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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Apoptosisdown-

regulation Telomerase

reactivation


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Cooperativegenetic damage

Mutagenicagents

Defective repairsystems


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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

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