Block 9 week 5 Flashcards
Two types of genes cause cancer:
- Tumor suppressor gene
- Oncogene
Apoptotic pathways
Apoptotic pathways: programmed cell death pathways. Typically doesn’t cause inflammation .
There are two apoptotic pathways:
- Extrinsic pathway (death receptor pathway)
- Intrinsic pathway ( mitochondrial pathway)
Extrinsic (death receptor) pathway
- External signal tells the cell to undergo apoptosis, eg. virus or cancer cell
- Signal comes from the outside, cell presents MHC1 ( damaged antigen or foreign antigen). CD8+ binds and tells the cell to undergo apoptosis.
- Cell will downstream MHC1 ( so less MHC1 receptors) which will attract NKCs to destroy the cell.
- Common signals are TNF-a which binds to TNFR.
- And FastL which binds to FastR.
- This activates caspases.
Intrinsic pathway (mitochondrial pathway)
- damage in cell due to mutation or dna damage …
- activation of p53
- stimulates Bax, Bad and Bak
- release of cytochrome c from the mitochondria activates caspases.
- Bax, Bad and Bak = Pro-apoptotic (mitochondrial permeability -> so cytochrome c can leak)
- Bcl-2, Bcl-xl = Anti-apoptotic ( maintains mitochondrial membrane -> cytochrome c kept in mitochondria)
- Bcl-2 overexpression can happen when you have t(14:18). This stops cell apoptosis so you keep and producing damages cells. This is the basis of a lot of cancers particularly follicular lymphoma
- HPV mutation -> E6 causes the inactivation of p53 - so we have no supression of dna damage cells -> we continue to produce abnormal cervical tissue.
Which pathogen can directly inactivate the p53 protein?
- HPV
Which translocation leads to excessive activation of c-myc?
t(8;14)
CELL CYCLE
G1 and G2 checkpoint:
- cells checks to see if there is any DNA damage
- The main checkpoint is the G1 checkpoint
- If there is DNA damage the cell will enter a G0 phase. It will try to repair the DNA or undergo apoptosis
- If the cell manages to get past the G1 and G2 checkpoint it will undergo mitosis to produce two identical daughter cells
However once cells differentiate and become mature cells - like liver cells - they dont go thorough the cell cycle over and over again.
- Actually cells tend to stay in the G0 phase (cell is neither dividing or preparing for division). Some cells like neurons stay in the G0 phase their whole life.
- Other cells stay in the G0 phase until they get an external signal like a growth factor
- The growth factors are secreted by other cells or by the cell itself like when theres a tissue injury and the remaining cells need to divide to replace the lost cells
- Growth factors bind to growth factor receptors in the cell’s membrane, which activates signal transduction proteins.
-Ultimately that leads to increased transcription of genes that code for special proteins - like cyclins and cyclin dependent kinases - so more of these proteins are being made.
-This is important because whether or not a cell gets cleared at G1 and G2, depends largely on the activity of cyclin dependent kinases, which add phosphate groups to various proteins within the cell.
- when there’s DNA damage, the cell doesn’t produce cyclins
- ## the cyclin dependent kinases can’t phosphorylate proteins within the cell and that’s the signal for the cell to halt the cell cycle.
G1 phase regulation
- Cell gets a growth signal which binds to the tyrosine kinase receptor on the cell
- Tyrosine kinase receptor activates cyclin D, which go on to activate cyclin dependent kinases. These together form a complex cyclin/cdk complex
- We have RB protein and E2F transcription factor. Job of RB is to hold onto E2F.
- If RB lets go on E2F, then E2F can push itself into G1-S phase progression, so past the checkpoint.
- So E2F release will ultimately help DNA replication
- function of Rb is to hang onto E2F (active). If you phosphorylate Rb it becomes inactive. The cyclin/CDK complex is what phosphorylates Rb.
(hyperphosphorylation of Rb is gonna release E2F)
hypophosphorylation = decrease in DNA replication
hyperphosphorylation = increase in DNA replication
P53: in some situations we dont want DNA replication.
- damaged cells we dont want to replicate
- DNA damage p53 becomes active by phosphorylation
- p53 will activate p21 and will inactivate CDK (enzyme).
- therefore no hyperphosphorylation of RB so E2F not freed, so cell cant get past checkpoint.
Protooncogenes
- stimulate cell cycle and division
- Examples of proto-oncogenes include genes that code for growth factors or growth factor receptors
- Eg. like the receptor tyrosine kinase or RTK which adds phosphate groups to other proteins
RAS genes
-Another example are genes that code for signal transduction proteins - like Ras genes, that code for Ras proteins.
-Ras proteins are GTP-ases, meaning that they bind an intracellular GTP molecule, and break it down into GDP and a free phosphate group.
-This further activates various cellular pathways, which ultimately result in cell growth, differentiation, and survival.
MYC proto-oncogene
Another example is the MYC proto-oncogene which codes for a transcription factor that increases expression of cyclins and cyclin dependent kinases.
Proto-oncogenes that inhibit cell apoptosis
An example is bcl-2 which prevents the activation of caspases - the enzymes that actually carries out apoptosis.
Protooncogene to oncogene
-Now, proto-oncogenes are normally only active when a cell needs to grow and divide - like you only push the accelerator pedal in a car when you want to speed up.
-However, some genetic mutations like translocations, amplifications, or point mutations turn proto-oncogenes into oncogenes.
- When a gene is an oncogene it gets overexpressed - meaning, it results in too many proteins, or it means that it codes for hyperactive proteins - which would be kinda like leaving a brick on the gas pedal and going to take a nap in the backseat as the car speeds down the highway.
-Cells have two copies of proto-oncogenes; however, if there’s a dominant mutation, that means that just one mutant oncogene copy is enough for the cell to avoid apoptosis and keep growing and dividing uncontrollably.
Tumor suppressor genes
- code for proteins that stop cell cycle or promote apoptosis
- normally active throughout cell cycle
- Some genetic mutations - mainly deletions - turn off the expression of tumor suppressor genes - which leads to a reduction in the number or function of the protein that they encode.
- This is a recessive kind of mutation, because it takes two damaged copies for tumor suppressor genes to have no functioning proteins.
When that happens, it’s relatively easy for genetic mutations to accumulate, ultimately allowing the cell to keep growing and dividing uncontrollably.
That’s why a wide variety of cancers feature mutated tumor suppressor genes.
p53
- p53 is a mutation found in over 50% of all cancers. Involved in the DNA damage checkpoint
- RB mutated in retinoblastoma. Controls G1-> S restriction checkpoint
if p53 is absent it cannot arrest the cell at G1. The cell will divide without control.
Rb
- cancer which features a mutated tumor suprresor gene
-For example, the Rb protein is considered a “governor” protein, because it normally inhibits cell proliferation by binding and inactivating a transcription factor called E2F.
-Normally, E2F promotes transcription of cyclin E, and cyclin dependent kinase-2, but it can’t do that with Rb holding on to it for dear life.
-But, here’s the catch - the Rb protein is only active and clinging to E2F when it isn’t bound to a phosphate.
-So when a growth factor stimulates a growth signaling pathway, that activates the cyclin dependent kinases which add a phosphate group to Rb, inhibiting it.
- Phosphorylated Rb releases E2F, allowing the cell cycle to progress.
- It’s like bribing the inspector with a phosphate to let the cell keep moving ahead with it’s plans.
Retinoblastoma
-In many types of cancer, including retinoblastoma - which gives Rb its name, Rb is inactivated and the loss of the brakes increases the rate of cell division.
-Typically, Rb is inactivated by a gene mutation, or by other proteins that specifically inactivate the Rb protein - like protein E7 made by human papillomavirus.
-
p53 - guardian protein
- another example, is the p53 “guardian” protein. P53 is a transcription factor that checks for DNA damage before a cell enters the S phase.
- And if there is DNA damage, then specific protein kinases add phosphate groups to p53 - prolonging its life.
-P53 binds to DNA and promotes transcription of a gene encoding protein called p21. p21 binds and inhibits the cyclin E-cyclin dependent kinase-2 protein complex, thus preventing passage from the G1 phase to S phase
-This buys a bit of time for DNA repair proteins, which are also expressed thanks to p53 - to get to work.
- In fact, studies have found that more than 70% of human cancers are associated with mutations in the p53 gene.
-When mutations inactivate p53, the cell can no longer repair DNA before it enters the S phase, which means mutations build up, and this can lead to uncontrolled cell division
HPV and cervical cancer
Cancer starts with one damaged cell
What causes cancer:
- HPV causes cervical cancer
- smoking can cause lung cancer
-brain cancer we dont know teh cause
Some types ofc cancers are preventable:
- limit UV radiation
- drink less alcohol, better diet, more physical activity,
- dont smoke
Oncogenesis
How cancer presents ?
- organ compression ( due to cancer pressing)
- organ failure
- lumps and bumps
- thrombosis
- endocrine effects
paraneoplastic syndromes:
- unexplained weightloss ( cachexia)
How is cancer treated:
- radiotherapy
- surgery
- cytotoxic chemotherapy
Most of the time once a cancer spread it very difficult to get rid of. Otherwise your largely looking at palliative treatment like chemotherapy and surgery (to prolong life and relieve symptoms)
Theres a new research on cancer treatments that focus on the immune system. People who have a reduced immune response eg have HIV are more likely to get cancer
Benign vs Malignant
How is cancer classified ?
We classify cancer by the organ its evolved from
Tissue Origin
Degree of differentiation
- normal
- beningn cancer
- maliganat cancer
- bad maligant cancer
Classification of hematological cancer
- classification of haemotological cancers more difficult than solid tumors
- 185 blood cancers
- leukemias: cancers circulating in blood
- lymphoma: mainly in the lymph nodes
- there is some cross over
types:
Acute leukemias: fast growing
Chronic leukemias: slow growing
Blood cancers are easier to treat, more aggressive blood cancers are easier to treat which is very different from solid tumors
Different types of names for cancers you might see
Pie chart shows the key genomic thats give rise to lung cancer
- Key message lung cancer is the most common cancer in the UK.
- We understand the genomics that give rise to cancer and this has led to treatements
- 30% of lung cancers have mutation in a gene called EGFR. Understanding this has helped create treatment which blocks this gene.
How is cancer diagnosed ?
CANCER
- cancer accounts for 28% of all deaths in the UK. It is the second highest cause of death with the first being CV diseases.
- 2010/2011 statistics show 50% of people survive cancer for 10 or more years
- 50% of people will be diagnosed with some sort of cancer during their lifetime
Cell Cycle
- Once growth has finished cell divisions are needed to replace cells that die (eg bone marrow, gut epithelium, skin)
Challenges:
1. Replicating the genetic information with high fidelity ( without mutations)
- Distributing chromosomes equally between daughter cells
( each daughter cell gets full copy of genetic information, not a bit more not a bit less)
What controls cell cycle
MAKING SURE THE PROCESS HAPPENS IN THE RIGHT ORDER:
- regulated by cyclin-CDK (syclin dependenet kinase) complexes and regulators (CDK inhibitors, Cdc25 phosphotases)
- cyclin CDK complexes signals stages of cell cycle
DECIDING WHETHER CELLS DIVIDE AT ALL:
- progression is controlled at transition points
-checkpoint pathways monitor conditions and transiently halt the cell cycle if unsuitable
BEING ABLE TO RESPOND TO SIGNALS:
- external (e.g. growth factors) and internal signals (e.g. quality control)
- involves signal transduction pathways (e.g. receptors, G proteins, kinases , DNA binding proteins)
Seborrheic dermatitis
- chronic but more milder type of dermatitis
- usually affects areas with sebaceous glands like scalp and face. Soemtimes even chest and armptis.
- cause not known
Dyshidrosis (acute palmoplantar eczema)
- intensely pruritic, chronic
- recurrent intraepidermal vesicles
Nummular dermatitis (discoid eczema)
Statis dermatitis
- appears on legs on pts with chronic venous insufficiency
Eczema pathophysiology
- Eczema is a type 1 hypersensitivity reaction
- starts with allergen like flower pollen
- immune cell (APC) picks up allergen -> presents to T-cell _> activates and becomes Th2 cell -> stimulates B-cells to produce IgE -> IgE bind to mast cells and basophils (sensitisation)
- second exposure - allergens cross link IgE on sensitised cells -> degranulation -> release histmaine, leukotrines and proteases.
- blood vessels dilate and become leaky and attract even more immune cells - become leaky
- inflammation makes skin barrier more leaky allowing more allergens in and water out. Makings skin dry
- Dry skin is very itchy, and scratching further damages the skin barrier, worsening the process and setting up a vicious cycle of allergy-mediated inflammation, dry skin, and itching which characterizes atopic dermatitis. Occasionally, bacteria can invade the damaged skin causing even more inflammation.
Malignant skin tumors
- break through basement membrane and invade nearby tissues
- can get into nearby blood and lymph vessels and establish a secondary tumor site somewhere else in the body. This is called Metastasis
Basal cell carcinoma
- skin cancer is differentiated based on the type of skin cell involved
- Basal cell carcinoma is the most common
- Basal carcinoma involves cells from the stratum basale. Its SLOW GROWING and RARLEY METASTASIZES
- grow superficially over the epidermis and also invade the dermis forming islands
Squamous cell carcinoma
- 2nd most common skin cancer
- involves squamous keratinocytes
- ACTINIC KERATOSIS is a precancerous legion which can turn into squamous cell carcinoma. in actinic keratsosis keratinocytes are damaged by uv radiation and begin to overproduce keratin.
- early stage scc is called Bowens Disease or squamous cell carcinoma in situ. The tumor is found in the epidermis but has not broken through the basement membrane.
- as scc becomes more invasive it can break through the basement membrane and extend into the dermis and can even reach the hypodermis.
Melanoma
- most aggressive form of skin cancer (metastasis quickly) , involves melanocytes
- moles are because of a type of melanocyte that overproduces melanin. These moles are considered precancerous because there is a increased risk of it becoming a melanoma
- present in epidermis and dermis
Risk factors for melanoma
- fair skin
- excessive uv exposure
- weakened immune system
- family history of melanoma
- ## virus eg. HPV
TNM staging
Tumor, node and metastasis staging. Purpose to see if there is any lymph node involvement or distant metastasis
- carried out using CT of chest, abdomen and pelvis
- PET/CT scan: involves administering a radiotracer which is collected by cells with abnormally high metabolism like cancer and inflammatory cells , which reveals areas of the body which might contain cancer cells.
- CT of neck
- MRI of brain
The TNM staging system stands for Tumour, Node, Metastasis. T describes the size of the tumour. N describes whether there are any cancer cells in the lymph nodes. M describes whether the cancer has spread to a different part of the body.
If melanoma patient has no metastasis
- appropriate treatment to carry out wide local excision and remove tumor.
- Breslow thickness. Less than 8mm and no ulcerations can remove
- Over 8mm and ulcerations requires alternate treatment
- lymph node biopsy: then lymphadenopathy if appropriate, and test for BRAF V600 mutation.
- Adjuvant immunotherapy
Dermatological history
