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Y2S2 > Cancer Biology > Flashcards

Cancer Biology Flashcards

1
Q

What is cancer?

A

An abnormal growth of cells in an uncontrolled way that can spread or metastasise into other tissues

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2
Q

What is a benign tumour?

A

Abnormal growth that are no longer under normal regulation

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3
Q

What is a malignant tumour?

A

Poorly differentiated cells, growing in a rapid, disorganised manner and can invade surround tissue and become metastatic, initiating the growth of similar tumours in distant organs

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4
Q

What are the different classes of cancer based on cell origin?

A

Carcinomas
Sarcomas
Lymphomas
Leukaemias

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5
Q

Describe carcinomas:

A

Most common (85%)
Arise from cells that cover external and internal (epithelial) body surfaces
Lung, breast and colon are the most frequent and includes glandular epithelial tissue adenocarcinoma *+(malignant stage)

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6
Q

Describe sarcomas:

A

Originate from cells found in the supporting tissue of the body (mesenchymal layer) e.g bone, cartilage, fat, connective tissue and muscle
Highly malignant e.g:
-liposarcoma (fat cells)
-osteosarcoma (bone)
-fibrosarcoma (fibrous connective tissue)

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7
Q

Describe lymphomas:

A

Make up 3% with leukaemia
Arise in the lymph nodes and tissue of the body immune system (B,T,NK cells) the can spread to the intestine, spinal cord, bone or brain

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8
Q

Describe leukaemias:

A

Cancers of the immature white blood cells that proliferate in the bone marrow and accumulate in the blood stream

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9
Q

What are the stages of cancer based on?

A

Size of tumour
Site of primary tumour
How far it has invaded into local tissues and structures
Whether it has spread to regional lymph nodes
Whether it has metastaized to other regions of the body

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10
Q

How is cancer graded?

A

Based on differences in microscopic cellular appearance
Doctors assign a numerical ‘grade’ to most cancers
A low number (I or II) refers to cancer with fewer cell abnormalities than those with higher numbers (III or IV)

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11
Q

What is tumour progression?

A

Normal cells evolve into cancer cells through a process called tumour progression
It is driven by a series of random mutations and epigenetic alteration (changes in DNA methylation) of DNA that affects the genes controlling proliferation and survival
This process takes place at several places throughout the human body and advances as we age

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12
Q

Name three ways in how DNA damage/ mutations can occur:

A

Mistakes in DNA replication
Nucloetides within DNA molecules undergo chemical changes spontaneously
Effect of mutagenic agents

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13
Q

Describe how mistakes in DNA replication can cause DNA mutations:

A

Misincorporation of deoxynucleotides during replication- incorrect bases assigned

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14
Q

Describe how chemically changed nucleotides cause DNA mutations:

A

Alter the base sequences of DNA

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15
Q

Describe how mutagenic agents cause DNA mutations:

A

Molecules generated endogenously by normal cell metabolism (Reactive Oxygen Species- ROS)
Mutagenic agents:
-physical agents (X-rays, UV rays)
-chemical agents (vinyl chloride, nitrosamines)

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16
Q

Describe how an incorrect base can have an effect on DNA formation:

A

Removal of altered bases affecting 3’-5’ exonuclease activity
Proof reading of incorrectly incorporated bases

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17
Q

Describe how a missing base can have an effect on DNA formation:

A

Removal of altered bases by DNA glycosylases
Removal of purines by acid or spontaneously

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18
Q

Describe an example of how a 3’ deoxyribose fragments are formed and cause DNA mutations:

A

By free radicals leading to strand breaks

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19
Q

Describe an example of how a bulge due to deletion or insertion of nucleotides are formed and cause DNA mutations:

A

Intercalculating agents that cause addition or loss of a nucleotide during recombinant replication

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20
Q

Describe how a single or double stand of DNA breaks:

A

By ionising radiation or chemical agents

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21
Q

Describe how linked pyrimidines are formed to cause a DNA lesion:

A

From UV radiation

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22
Q

Describe how cross linked strands are formed to cause a DNA lesion:

A

Covalent linkage of two strands by alkylating agents

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23
Q

Which viruses can cause cancer?

A

Human herpes virus, HPV, EBV, HBV

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24
Q

How are smoking and viruses linked to cancer?

A

Viruses are important risk factors for developing cancer after smoking

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25
Q

How do viruses cause cancer?

A

The viral genome can persist in the infected cells as an episome (circular DNA) and promote the expression of proteins that promote proliferation or that inhibit tumour suppressor genes

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26
Q

Describe how RNA viruses can enter the cell for carcinogenesis:

A

Reterotranscribed into DNA and incorporated into the host genome (provirus) and allows it to replicate

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27
Q

Describe two ways how RNA viruses cause carcinogenesis:

A
  1. Providing a gene that alters growth, the RNA viruses can contain an extra gene additional to the sequence needed for viral replication
  2. Insertional mutagenesis, the virus integrates into the host genome close to a host gene that regulates growth (e.g GF) and upregulates its expression
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28
Q

How do viruses cause direct carcinogenesis?

A

Direct-acting carcinogenic agents are generally found in a monoclonal form within the tumour cells, these agents help to keep the tumour phenotype
Viral genomes can form episomes (herpes), or integrate into the host genomic DNA (EBV, reteroviruses) so a viral oncogene expression is switched on all the time
After infecting the target cells tumour viruses are persistently maintained as genetic elements

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29
Q

How do viruses cause indirect carcinogenesis e.g HBV/HCV?

A

The virus is acting from outside the cell the will form the tumour
Chronic inflammation produced by persistent infection associated with any of these viruses is a major risk to develop hepatocellular carcinoma as it releases chemokines, they recruit inflammatory cells for many years so lots of ROS
Free radicals can cause DNA damage and mutations and oxidative stress that persistently damages local tissue

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30
Q

How do viruses cause indirect carcinogenesis e.g HIV?

A

Produces immunosuppression that reduces or eliminates anti-tumour (CD8) immune surveillance mechanisms
Typical of HIV, patients with non controlled infection and low T cell counts frequently develop lymphomas associated with EBV or KSV infecetion

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31
Q

Can one mutation cause cancer?

A

No, many mutations are required, a multistep process
Around 3-20 mutations

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32
Q

What is dysplasia?

A

Increase in growth of immature cells
Abnormal and variable appearance
Cell to cell interactions broken down

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33
Q

What is metaplasia?

A

One cell type changes into another

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34
Q

What causes neoplasia?

A

Neoplasia= cancer
Both dysplasia and metaplasia

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35
Q

What are the phases in carcinogenesis?

A

Initiation
Promotion
Progression
Metastasis

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36
Q

What occurs in the cell cycle if there are no growth factors present?

A

Cells go into resting (G0)

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37
Q

Name four growth factors and which receptor they activate:

A

Epidermal GF, Transforming GF a- activates EGFR
Hepatocyte growth factor- activates receptor c-met
Fibroblast GF

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38
Q

Which family does EGFR belong to?

A

Belongs to a family of erbB2 receptors

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39
Q

Describe EGFR signalling:

A

In the presence of a ligand, the EGFR comes together and form homodimers (EGFR) or heterodimers (HER1,2,3)
The receptors are phosphorylated in the intracellular tyrosine kinase domain
Specific adaptor proteins (Shc,Grb2,SOS) permit Ras/Raf/MAPK and PI3K pathway to be activated causing activation of cell growth

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40
Q

What is the consequence of a ligand binding to a EGFR?

A

From ligand binding cSrc and FAK signalling pathway promotes cell adhesion and invasion
From ligand binding, EGFR can undergo receptor endocytosis which acts as a transcription factor by being transported into nucleus by a protein called importin, which acts as a TF for cyclin D1 up regulation or as a co-regulator of other gene transactivators
Can undergo endocytosis and follow two possible routes:
-lysosomal degradation
-importin mediated nuclear translocation

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41
Q

What are proto-oncogenes?

A

Genes that regulate normal cell growth
These are genes at any point along the cell signalling pathway i.e Ras, Raf, ERK, EGFR, tyrosine kinase
Only progression through the cell cycle when ligand is present

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42
Q

What is the Ras proto-oncogene?

A

The product of the rasproto-oncogene are Ras proteins
Small G proteins
Involved in GTPase reactions cycles
Relay a GF signal from a GF receptor on the cell membrane to a cascade of tyrosine kinases

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43
Q

Describe a mutation in the Ras protoco-oncogene cause cancer?

A

Point mutation G to T changes glycine to valine
Just one single a.a substitution affected the function of Ras to convert it from a proto-oncogene to an oncogene
Mutations in the Ras gene are found in 30% of human cancers

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44
Q

How are proto-oncogenes and oncogenes related?

A

A mutated proto-oncogene is an oncogene

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45
Q

Describe the Weinberg’s experiment:

A

Immortalised cancer cells in mouse won’t cause a tumour
Took tumour from pt with bladder cancer and isolated DNA, then transfected DNA into cells
In microscope some cells got a transformed colony
Injected these into the mouse and found it caused a tumour
Isolated the human genes from the mouse and confirmed the Ras mutation

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46
Q

What is the consequence of the Ras mutation?

A

Ras can signal on its own if its mutated even if there is no ligand
The G protein is stuck on and there is a constant active signal so constantly switched on as Ras is a downstream GF of the signalling pathway

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47
Q

Name types of mutations that can occur and where are the possible sites of mutations in proto-oncogenes?

A

Gene amplification- too many copies of a gene so too much of a product
Gene rearrangements- promotor of gene in wrong place so normally a weakly expressed gene can be expressed at high levels
Large structural deletions
Subtle mutations- single nucleotide change

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48
Q

Name common mutations of signal transduction and which cancer does this occur in?

A

EGFR over expression; pancreatic, colorectal, lung
Ras mutation; pancreatic, thyroid, colon
B-Raf mutation; melanoma

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49
Q

What is an example of a gene that can cause breast cancer and a treatment:

A

HER2 gene is amplified and over expressed in 25% of breast cancers
Trastuzumab- humanised MC antibody, blocks HER2 activity

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50
Q

Describe the treatment and how it works for non small cell lung cancer:

A

Erlotinib and Gefitinib
Inhibit the tyrosine kinase portion of EGFR so prevents the receptor mediated signalling pathway from being activated

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51
Q

Describe the treatment and how it works for colorectal cancer:

A

Cetuximab and Panitumumab
MC antibodies that block EGFR activity

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52
Q

What causes Chronic Myeloid Leukaemia (CML)?

A

Philadelphia chromosome abnormality- as an activated Bcr-Abl caused it
BCR= break point cluster region
Abl= protein tyrosine kinase involved in cell differentiation, adhesion and growth
Normally chromosome 9 has the ABL gene and chromosome 22 has the BCR gene
These chromosomes break as during the translocation ABL loses its regulatory domain, the fusion emits contact growth promoting signals
This fusion protein causes CML

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53
Q

Describe the mechanism of action of BCR-ABL in CML:

A

Normally GFs activate RTKs leading to activation of Ras and PI3K/AKT
Phosphorylation of Tyr177 within the BCR part of BCR-ABL leads to activation of these pathways by interacting with the SH2 domains in GRB2 leading to PI3K downstream signalling pathways
BRCABL can produce more IL3 and GCSF so activates JAK and STAT 5 signalling pathway which causes more cell proliferation

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54
Q

What drug is used to help treat CML and how?

A

Imatinib mesylate binds to an intracellular pocket located within tyrosine kinases (between BCR-ABL and GRB2), inhibiting ATP and preventing phosphorylation and activation of GFR and downstream signalling pathways

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55
Q

What is the G1 checkpoint in the cell cycle?

A

Is the environment favourable

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56
Q

What is the G2 checkpoint in the cell cycle?

A

Is all the DNA replicated and all the damage repaired

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57
Q

What is the mitosis checkpoint?

A

Are all the chromosomes properly attached to the mitotic spindle

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58
Q

Name the 3 main tumour suppressor genes (TSG):

A

Cyclin/ CDKs and CKIs
Retinoblastoma protein
p53

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59
Q

How is the Rb protein involved in the cell cycle?

A

Acts as a brake on the cell cycle, keeping the cell in the G1 phase
Inhibits genes necessary for progression into S phase
Phosphorylation of Rb releases brake

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60
Q

What is the main occurrence when there is a mutation in Rb in cancer?

A

Mutation in Rb (inactivated) causing a constitutive activation of the cell cycle

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61
Q

How is G1-cdk and Rb involved in the normal process of the cell cycle?

A

Active G1-cdk phosphorylates and inactivates Rb
Phosphorylation of Rb releases E2F transcription factor
E2F activated transcription of genes that encode proteins required for S phase like G1/S cyclins and S cyclins

62
Q

What can happen if Retinoblastoma (eye cancer) is left untreated?

A

Pts die of intracranial extension and disseminated disease

63
Q

Describe how mutations in the Rb gene causes cancer:

A

Deletion of the Rb1 gene or point mutation
Deletion or mutation encourage cell division because they result in E2F-mediated transcription of S-phase genes
The control over G1 progression and S phase initiation is disrupted in cancer

64
Q

How do viruses affect the Rb gene?

A

Some viral proteins can bind to Rb and deactivate it e.g HPV protein E7

65
Q

What are inactivating mutations of the Rb gene called and how does this lead to mutations?

A

Requires recessive loss of function mutations
Retinoblastoma requires the loss of both functional copies of the Rb gene (recessive)
Caused by inheriting mutated gene but later the other one mutates
Require two mutational hits;
-random chance mutation
-chromosomal loss

66
Q

What is sporadic cancer?

A

Most cancers
No known cause
By chance with no relatives with a similar cancer

67
Q

What is familial cancer?

A

Caused by a combo of genetic and environmental factors with relatives showing the same type of cancer
No specific pattern of inheritance (not passed from parent to child)

68
Q

What is hereditary cancer?

A

An altered gene is passed down in the family from parent to child
People with hereditary cancers are more likely to have relative with the same type or related type of cancer

69
Q

What is the function of p53?

A

Acts as a brake, keeping the cell in G1 if there is DNA damage until there is either repair or apoptosis

70
Q

What does p53 do when there is no DNA damage?

A

p53 bound to MDM2 and degraded by proteasome

71
Q

What does p53 do when there is DNA damage?

A

p53 is phosphorylated and involved p21 gene transcription so cyclin/CDK complex is inactive and cell cycle arrest and DNA repair

72
Q

What happens if there is a mutation in p53?

A

The cell cycle won’t stop

73
Q

What are the two main cancer genes and describe them:

A

TSG: normally block mitosis and must be knocked our for cancer to occur
Proto-oncogenes: normally pass on signals to grow and must be stuck on the ‘on’ mode for cancer to occur

74
Q

Give examples of oncogenes:

A

Raf, Ras, Myc, Src

75
Q

When is p53 activated?

A

In response to low oxygen, nutrient deprivation and replicative stress

76
Q

If the DNA damage is too severe to repair, then what does p53 do and how?

A

Instigates apoptosis
p53 inhibits BCL-2 a pro-survival protein (inhibits BAX)
p53 activates BAX, a cell death effector
Activation of BAX causes mitochondrial outer membrane permeabilisation and release of cytochrome C into the cytosol
Cytochrome C triggers caspase-3 activation through formation of the cytochrome c/Apaf-1/caspase-9-containing apoptosome that dismantles the cell

77
Q

Which viral proteins inactivate p53?

A

Adenovirus protein E1B
Papilloma virus protein E6
HBV protein HBX
Mostly missesne mutations that disrupts DNA binding

78
Q

What is the Hayflick limit?

A

Cultured normal human cells have a limited capacity to divide, around 20-70 times
A type of cellular ageing called senescence or ceased proliferation
Telomeres are important in this process

79
Q

What are telomeres?

A

They are protective caps at the end of repetitive DNA at the end of chromosomes and consist of hexametric TTAGGG nucleotide repeats and a protein complex (shelterin)

80
Q

How do telomeres work?

A

Keep the chromosomes from unravelling- preventing chromosome damage or accidentally linking to eachother during cell division
Each time a cell divides the telomeres get shorter and shorter and eventually become frayed = crisis point

81
Q

What is the crisis point in telomeres and how does this help cells?

A

Is triggered when the cell identifies that there are damaged bits of DNA
This results in a long term sleep (senescence) or apoptosis- protects against neoplasia

82
Q

What is the function of telomerase?

A

Important in maintaining telomere length
A cellular reverse transcriptase that adds DNA sequences (TTAGGG) onto telomeres to prevent shortening

83
Q

How does telomerase cause immortalisation of cancer cells?

A

Telomerase detected in 85-90% of all malignant tumours
If tumours have telomerase then telomeres are kept at longer lengths and crisis point is never reached
Tumour cells can bypass this crisis by up regulating telomerase and avoiding cell cycle checkpoint genes e.g p53, Rb etc

84
Q

Describe telomerase mutations:

A

Telomerase promotor mutations are the most common point mutations in cancer
No approved anti-telomerase therapies yet

85
Q

What are the main cell types in a tumour cell?

A

Immune cells (mast, myeloid derived suppressor cells, bone marrow derived cells, macrophages, neutrophils)
Stromal cells (fibroblasts, mesenchymal SCs)
Epithelial cells (normal ECs and invasive tumour cells)
Vascular cells (endothelial cell, pericyte, lymphatic endothelial cells)

86
Q

Give two examples of tumour promoting inflammatory cells:

A

Neutrophils
Macrophages

87
Q

What are the functions of tumour promoting inflammatory cells?

A

Secrete proteases and break down extracellular matrix, releases requested growth factors
Also secrete growth factors like EGF which cause cancer cells to grow

88
Q

What are the functions of cancer-associated fibroblasts?

A

Secrete Hepatocyte GF which causes cancer cells to grow

89
Q

What are the functions of epithelial cells in cancer?

A

Release platelet derived GFs which effect pericytes

90
Q

What are the characteristics of tissue stem cells in a normal cell?

A

Self renewal
Control of stem cell numbers
Ability to divide and differentiate to generate all functional elements of that particular tissue

91
Q

Why can cancer stem cells (CSCs) form tumours in transplanted animals but normal stem cells can’t?

A

Can arise from normal stem cells, progenitor cells or more differentiated cells through multiple mutations or genes
Compared to normal SCs the CSCs are thought to have no control on their cell number; infinite proliferative capacity
CSCs constitute a small number of cells in the tumour (less than 1%) and are thought to be responsible for the growth of new tumour cells
-express specific markers
-undergo EMT, invasion and metastasis
-enchanced resistance to chemo drugs

92
Q

What is EMT?

A

Epithelial Mesochymal Transmission
Moving cells, means they’re being invasive

93
Q

What markers do cancer stem cells display?

A

CD133, CD44, CD24

94
Q

What enzyme does cancer stem cells secrete and what is it important for?

A

Aldehyde dehydrogenase - ALDH
Important for development, can resist chemo

95
Q

What transcription factor does a cancer stem cell have?

A

OCT4

96
Q

What do cancer stem cells have on their cell surface to resist chemo and describe:

A

Drug efflux pumps
Drug transporters and multidrug resistance transporter 1, MDR1
Form spheres in in vitro culture

97
Q

What signalling pathways do cancer stem cells have?

A

Wnt/ B caterin
Notch Hedgehog

98
Q

What areas of a cancer stem cell can be targeted for treatment?

A

Specific markers
Enzymes
Transcription factors
Drug efflux pumps
Activated signalling pathway

99
Q

What oxygen conc would be present in a tumour environment?

A

Both hypoxia and normoxia (normal oxygen)

100
Q

Describe the oxygen gradient in tumour cells:

A

Cancer tumours are heterogeneous tissues with a dynamic microenvironment
They exhibit an oxygen gradient with out regions of well oxygenated tissue along side poorly oxygenated regions experiencing hypoxia

101
Q

What can hypoxia do in a tumour?

A

Can make cells dormant

102
Q

Describe normoxic cancer cells:

A

Near the blood vessel
Low in HIF-1alpha expression
More susceptible to chemo and radiotherapy

103
Q

What does HIF-1alpha do?

A

Signalling pathways responds to oxygen

104
Q

Describe hypoxic cancer cells:

A

Increase genetic instability (increase in mutations)
Poor immune response
Influence extracellular matrix
HIF-1alpha expression results in altered angiogenesis
Less susceptibility to chemo and radiotherapy

105
Q

How could you identify hypoxia in the tumour environment?

A

Tumour labelled with CD31 antibody (receptor CD31 expressed on epithelial cells/BVs)
Dye- pimonidazole binds to thiol-containing proteins specifically in hypoxic cells, red shows hypoxic, no colour shows normal

106
Q

What is necrosis?

A

A bad form of apoptosis
Normally would be pushed through apoptotic cell pathway in a controlled manner not to damage other cells but in necrosis all the contents of the cell released in the environment

107
Q

What are the consequences of necrosis?

A

Lack of O2 delivery to cells and impaired waste removal causes necrosis
Necrosis results in spilling of cellular contents causing inflammation and injury to nearby cells
Evokes an inflammatory response (ROS)

108
Q

Describe the development of the tumour microenvironment:

A

Blood vessels are normal, tumour there but hasn’t invaded lots to change tissue morphology
As tumour grows, new blood vessels form providing tumour with O2 and nutrients
The cancer cell then invades the underlying tissue and blood vessels there for metastasis

109
Q

What is neoangiogenesis and why?

A

Promoting the formation of new blood vessels for the cancer cell to grow to receive O2, nutrients and the ability to evacuate metabolic waste and CO2

110
Q

What does it mean if the tumour is less than 2mm in diameter?

A

The tumour is dormant, all nutrients and O2 is provided by the host

111
Q

What is the angiogenic switch?

A

Structural changes occur within the blood vessels and stimulates the tumour cells to grow=proliferation
Rapid tumour growth and metastasis

112
Q

What is neurovascularization?

A

Makes tumour grow rapidly, possible by supplying O2 and nutrients removing waste
Facilitates metastais

113
Q

What does the tumour secrete for angiogenesis to start?

A

Angiogenic factors:
-Vascular endothelial GF (VEGF)
-Fibroblast GF (FGF)
-Platelet derived GF (PDGF)
They diffuse on endothelial cell so the tumour releases pro-angiogenic factors

114
Q

What does the extracellular matrix consist of?

A

Collagen, fibronectin, lanolin

115
Q

Name some pro-angiogenic factors:

A

Hypoxia, oncogenes, HIF1-a (VHL)

116
Q

Describe the stages involved in angiogenesis:

A

As a tumour grows, the BVs grow and tumour cells secrete matrix mettaloproteases (MMPS) and digest the extracellular matrix so can proliferate and grow towards the tumour
As well as the extraceullar matrix being degraded it leads to integrin expression at leading edge of sprouting endothelial
Endothelial cells form new aberrant BVs that support tumour growth and dissemination so can metastasise

117
Q

What is the function of VEGF?

A

Helps new endothelial cells to survive by up regulating inhibitors of apoptosis
VEGF activates ECs to express proteins necessary for BV formation

118
Q

What medications are there to target VEGF to stop angiogenesis?

A

Bevacizumab- Ab which binds to VEGF
Sunitinib- small molecule inhibitor with high affinity for VEGF

119
Q

What medications are there to target receptors on the extracellular space directly to stop angiogenesis?

A

Cetuximab- Ab that binds directly to epidermal GFR on normal and tumour cells and competitively inhibits the binding of EGF and TGFa

120
Q

What is the difference between blood vessel organisation in normal and tumour blood vessels?

A

Normal = highly structured
Tumour= disorganised, irregular, so less efficient in O2 and nutrient transport and interferes with the homogenous distribution of the drug

121
Q

What is the pathway from a mutation to going into the circulation?

A

Mutation- primary tumour- angiogenic switch- detachment- intravasation (into peripheral circulation by passing through vascular endothelial)

122
Q

How are cells sat next to eachother in an ordered fashion?

A

By E-cadherin, a cell adhesion molecule

123
Q

Describe how tumour cells can migrate by proteolytic degradation?

A

Macrophages produce MMPS and cleaves cell surface protein E-cadherin and tumour cell is released from tumour so no more connection between cells and form EMT (called epithelial to mesenchymal transmission) as the cell changes shape
MMPs cleaves ECM and tumour is released (as tumour cells sit there)
Bind to different structural proteins like collagen, lanolin and tumour cells bind to these by integrins
Different integrins expressed on tumour cells due to altered ECM
MMP can also process or activate cytokines of GFs in the tumour microenvironment

124
Q

Where are proteases produced for tumour progression?

A

By invasive cancer cells, bone marrow derived cells especially macrophages

125
Q

What things can macrophages secrete to cause tumour cell migration?

A

GFs, chemokine and MMPs
e.g epidermal GF

126
Q

What do tumour cells secrete to help with cell migration?

A

Factors that affect macrophage function/ chemotaxis

127
Q

What do pericytes secrete to help with tumour cell migration?

A

CXCLi2 that causes tumour cell migration through CXCR4R

128
Q

What is a marker for macrophages?

A

Cathepsin B

129
Q

What is the pathway from circulation to going into vascularisation?

A

Once tumour is in peripheral circulation, extravasation (into tissue), invasion, 2º tumour, vascularisation

130
Q

What is the protective mechanism that cancer cells can undergo after intravasation?

A

Protective tissue factor (TF)
Prevents lysis from NK cells by having platelet aggregates on them so are protected when migrating into the tissue

131
Q

What are 3 things a cancer cell can do when inside a tissue?

A
  1. Cell death
  2. Can become dormant (quiescent stromal cell)- sits in tissue which supports it to live but not grow
  3. Survival of cell, activate a stromal cell, required bone marrow derived cells and process of GFs
132
Q

How do cancer cells divert metabolism?

A

Normal cells and cancer cells have different metabolisms
Cancer cells alter their metabolisms to obtain energy from alternate sources that a normal cell doesnt use
Divert metabolites for useful anabolic processes e.g mitosis

133
Q

Describe the Warburg effect:

A

Normal cells typically break down glucose in a process called glycolysis-> pyruvate which provides ATP, done in mitochondria
Cancer cells are different where they can convert glucose to lactate irrespective of the presence of oxygen

134
Q

Draw the reactions for a normal cell and a cancer cell producing ATP from glucose and what does this mean?

A

Normal
Oxygen: ->pyruvate =36mol ATP
No oxygen: -> pyruvate->lactate =2mol ATP
Cancer
Regardless of oxygen: ->pyruvate ->lactate (85%)= 4mol ATP
So in low oxygen, cancer produces more ATP

135
Q

How can NK cells kill cancer cells?

A

Recognise stressed cells
Detect down regulation of MHC-1 in tumour cells
Can signal directly to T cells
Can present antigens to dendritic cells to start the process of CD8 cell activation

136
Q

What are tumour specific antigens?

A

An antigen that is the cause of the tumour such as mutation of TSG or oncogenes that leads to altered protein production

137
Q

What is a tumour antigen?

A

A protein with an abnormal structure caused by a mutation

138
Q

What are tumour associated antigens?

A

Present on tumour cells
It is a mutation in gene unrelated to the tumour formation but causes the synthesis of abnormal proteins

139
Q

How does a cytotoxic T cell kill the cancer cells?

A

Bind to Fas ligand
Releases Granzyme B perforin

140
Q

How can tumour cells stop T cell functioning by preventing recognition?

A

Stop the MHC antigen processing complex and prevents loading of antigenic peptides onto HLA/MHC molecules, preventing the recognition of tumour antigens

141
Q

How can tumour cells stop T cell functioning by deactivating them?

A

Can up regulate the expression of PDL1
PDL1 is a ligand expressed in tumour cells that binds to an inhibitory receptor in PD1 on T cells and deactivates them

142
Q

What are other ways how tumour cells can stop the functioning of T cells?

A

Cancer cells can produce cytokines e.g TGF-B and VEGF and IL-10 that cause immunosuppresion by recruiting T regs and myeloid derived suppressor cells
Tumour cells also compete for glucose with immune cells, taking away their energy source

143
Q

What is the correlation between pH and immune cell function in a tumour?

A

A lower pH occurs due to this altered metabolism, which through signalling intermediates such as VEGF and IFN-g can affect T cell maturation and recruitment of MDSCs (myeloid derived suppressor cells) including an immunsuppressive tumour environment

144
Q

What cytokines can tumour cells secrete?

A

Colony Stim Factor 1 (CSF1)
IL1B

145
Q

What are the properties of tumour associated macrophages (TAM)?

A

Cells of the IS can have both tumour-antagonising and tumour promoting effects

146
Q

What are anti-tumour macrophages activated by?

A

LPS (Lipopolysaccharides) / IFN-g

147
Q

Describe anti-tumour macrophages:

A

Immunostimulatory cytokines
Chemokine e.g lymphocytes
Tumor cell lysis
ROS and reactive nitrogen species (in a controlled way)
MMPs- MMP-7,9 and 12 (break down ECM in a controlled and specific way)

148
Q

What are pro-tumour macrophages activated by?

A

Hypoxia

149
Q

Describe pro-tumour macrophages:

A

Pro-angiogenic cytokines and enzymes (FGF and VEGF promote this)
ROS and RNS (more mutations)
Cytokines (mitogens and immunosuppressive factors)
Tissue factor/ uPA
MMPs
Chemokine

150
Q

Name some tumour promoting inflammatory cells:

A

Mast cells, neutrophils, T and B cells

151
Q

What is the main pathway of carcinoma cells?

A

Releases chemotactic factors (MCP-1, CSF-1, PDGF)
Attracts monocytes
Differentiate into macrophages (TAM)
Does actions of pro tumour macrophages
Facilitate tissue invasion and metastasis

Y2S2 (14 decks)

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