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EMS - JL > 30, 31, 32 > Flashcards

30, 31, 32 Flashcards

1
Q

Chemical carcinogens

A

PAHs, nitrosamines

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2
Q

Infectious carcinogens

A

HPV, H.Pylori

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3
Q

Radiation carcinogens

A

UV light, radon

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4
Q

Mineral carcinogens

A

Asbestos, heavy metals

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5
Q

Phsyiological carcinogens

A

Oestrogen, androgens

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6
Q

Chronic inflammation carcinogens

A

Free radicals and growth factors

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7
Q

What does aflatoxin cause

A 
Liver cancer (hepatocellular carcinoma)
Low in the UK, High in East asia
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8
Q

What produces alfatoxin

A

Aspergillus flavus

Also due to Hep A and Hep B

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9
Q

What does alcohol cause

A

Pharynx, laryns, oesophagus, liver

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10
Q

What does asbestos cause

A

Lung Pleura (mesothelioma)

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11
Q

What do X-rays cause

A

Bone marrow cancer (leukaemia)

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12
Q

What does UK light cause

A

skin cancer

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13
Q

What does oestrogen cause

A

breast cancer

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14
Q

What does Hep B cause

A

liver cancer

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15
Q

What does HPV cause

A

cervical cancer

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16
Q

What does tobacco smoke cause

A

Mouth, lung, oesophagus, pancreas, kidney and bladder cancer

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17
Q

What is a carcinogen

A

Any agent that significantly increases the risk of developing cancer

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18
Q

What is an initiator

A

Carcinogens that are genotoxic

Can chemically modify, damage/alter DNA

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19
Q

What is a promoter

A

Carcinogens that are non-genotoxic

Induce proliferation and DNA replication

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20
Q

What is complete carcinogen

A

A carcinogen that is an initiator and a promoter

E.g. UV Light

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21
Q

Who is bladder cancer high in

A

Higher incidence in men
Due to the dye and rubber industry
Due to beta napthyl-amine

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22
Q

How do initiatiors (mutation induction work)

A

Chemical modification of DNA
Replicating of DNA
Mis-incorporation by DNA polymerases

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23
Q

What happens with methylate guanine

A

Can only form 2H bonds
Read as an A not a G
2 rounds of cell division to fix the mutation

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24
Q

What is required for a promotor carcinogen

A

Stimulates 2 rounds of DNA replication - required for mutation fixation
Stimulates clonal expansino of mutated cells - enables accumulation of further mutation

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25
Q

How many rounds of DNA replication are needed for mutation fixation

A

2

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26
Q

Describe Initiation - Promotion - Progression

A

Genotoxic initiating agent damages DNA
Promoting agent fixes damage as mutation and converts normal cell to mutant cell
Promotor stimulates clonal expansion - papilloma
Further mutation and clonal expression causes papilloma to become a carcinoma

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27
Q

How are tumour suppressor genes inactivated

A

Aberrant methylation of CpG islands in the promotor regions of gene
Causes closed chromatin - stops it being expressed
Occurs normally but if hijacked then TSG switched off (most common way to cause cancer)

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28
Q

Mutation in oncogenes

A

Cause gain of function

Substitutions, ,amplification, translocations (to an area expressed more, inversion)

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29
Q

Mutation in tumour suppressor genes

A

Loss of functions

Frameshifts, deletions, substituions, chromosomal arrangements (all BUT AMPLIFICATION)

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30
Q

What are direct acting carcinogens

A

Directly act on the DNA

E.g. UV Light, ionising radiation, Oxygen free radicals

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31
Q

What are indirect carcinogens

A

Require metabolic activation before they react with the DNA

e.g aromatic amines, polycyclic aromatic hydrocarbons (PAHs)

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32
Q

How do we get rid of indirect carcinogens

A

Need to make them soluble

Unfortunately this can make them more toxic and cause more damage

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33
Q

What is benzopyrene

A

Indirect carcinogen found in tobacco smoke

Causes lung tumours in smokers

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34
Q

Benzopyrene activation path

A

Benzopyrene (P450 mixed function oxidases)
Benzypyrene 7-8 epoxide (Epoxide hydrolase)
Benzopyrene 7,8 dihydrodiol (P450 mixed function oxidases)
Benzopyrene 7,8, diol 9,10 epoxide

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35
Q

Describe path of damaging agents to disaese

A

Damaging agent - DNA lesions - Repair Process (same as in E. Coli) –> Disease syndrome

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36
Q

Name a compound involved in detoxification/exretion

A

Glutathione S. transferase

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37
Q

Defence against carcinogens

A

Exxposed to myriad carcinogenic agents
many levels of defence
Dietary antioxidants
Detoxification mechanism
DNA repair enzymes
Apoptotic responseto unrepaired DNA damage
Immune response to infection and abnormal cells

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38
Q

Carcinogens in tobaccos smokes

A

PAH - e.g. benzopyrene
Acrolein - acrid smell, direct acting
Nitrosamines - formed due to during of leaves
Radioactive lead and polonium - sit in alveoli for years
Heavy metals - cadmium and chromium

With alcohol, smoking increases the risk of head and neck cancer by 100x

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39
Q

How does alcohol cause cancer

A

Concerted to acetaldehyde - damages DNA
Increased levels of oestrogen and testosterone
Increased uptake of carcinogens in the upper GI
Reduces folate - needed for accurate DNA replication
Can kill surface epithelium causing unscheduled proliferation

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40
Q

How are we exposed to oestrogen

A 
HRT
Oral contraceptive
Early menarche
Late menopause
Post menopausal obesity
Age of 1 st pregnancy >30
Alcohol consumption
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41
Q

How does higher oestrogen cause breast cancer (and endometrium and uterine)

A

Increased exposure to oestrogen
Oestrogen binds to transcription factors
Induces DNA damage

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42
Q

How does chronic inflammation cause cancer

A

DNA damage and the release of free radicals by immune cells (INITIATOR)
Growth factor induced cell division to repair tissue damage (Promotion)

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43
Q

What cancers are associated with chronic inflammation

A 
Colitis
Hepatitis
Barret's metaplasia
Gastritis
Gallstones
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44
Q

50% of cancers are due to environmental or behaviour factors

A

Diet (most common)
Tobacco
Infection
Reproductive behaviour (4th most common)

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45
Q

What can epstein barr virus cause

A 
Bursts lymphoma (B cell)
Nasopharyngeal carcinoma
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46
Q

What can RNA retroviruses cause

A

T cell leukaemia/lymphoma

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47
Q

What is more dangerous than UV light

A

UV-B

Melanin is protective

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48
Q

What can androgenic and anabolic steroids cause

A

Hepatocellular tumours

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49
Q

What can schistosomiasis haematoburium cause

A

Bladder cancer

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50
Q

What can liver flukes cause

A

Dwell in bile ducts

Cause malignant cholangiocarcinoma

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51
Q

What do we need for carcinogenesis

A

Activation of protooncogenes
Inactivation of tumour suppressor genes

Carcinogens can do both of this

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52
Q

What is the process of carcinogensis

A

Darwinian Evolution and clonal expansion

Mutation - clonal expands providing big cell pop
Mutation in one of descendent cells
Cells accumulate mutations etc.

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53
Q

What are caretaker genes

A

Maintain genetic stability by repairing damaged DNA and replication errors!
Mutant forms cause genetic instability

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54
Q

Why is genetic instability/mutation in caretaker genes essential for carcinogenesis

A

As otherwise the rate of mutation isn’t high enough

Genetic instability is a common feature to most cancer

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55
Q

What do gate kaper genes do

A

Regulte normal growth
-ve regulation of cell cycle and proliferation
+ve regulation of apoptosis and cell differentiation

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56
Q

What does the 2 Hit hypothesis apply to

A

Only tumour suppressor genes

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57
Q

What do caretaker genes

A

Maintain genetic stability
DNA Repeaire genes, control access to mitosis
INDIRECT ROLE - just allows conditions for mutation to occur

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58
Q

Retinoblastoma due to what mutated gene

A

RB1 (gatekeeper gene)

59
Q

Li-Fraumeni due to mutation in what gene

A

p53 (gatekeeper/caretaker)

60
Q

What cancers does li-fraumeni cause

A

Sarcomas, breast

61
Q

Familial adneomatous polyposis due to mutation in what gene

A

APC (Gatekeeper gene)

Causes colorectal cancer

62
Q

What type of gene is RB1

A

gatekeeper

63
Q

What type of gene is P53

A

Gate/care

64
Q

what type of gene is APC

A

gate keeper

65
Q

Familial breast cancer due to mutation in what gene

A

BRCA1/2 (caretaker)

66
Q

What type of gene are BRCA

A

caretaker

67
Q

what type of gene are hMLH

A

caretaker

68
Q

Gene mutation in HNPCC

A

hMLH

69
Q

Cancer in familial breast cancer mutation

A

Breast/ovary

70
Q

Cancers in HNPCC

A

Colorectal/endometrial

71
Q

What are protooncogenes

A

Promote cell proliferation, survival, angiogenesis, negative reduction of apoptosis

These are normal

72
Q

What are oncogenes

A

Mutation - causes increased expression of protooncogene - causes gain of function

73
Q

How many mutated oncogenes do we need to cause cancer

A

Only 1 - mutant gene is dominant to normal gene

Contrast to TSG where both genes need to be mutated

74
Q

How are oncogenes activated

A

1) translocation - to a more transcriptionally active area
2) point mutation - base pair substitution becomes more hyperactive
3) amplificiation - multiple copies

75
Q

Minimum genetic alteration needed to transform a norma cell into a neoplastic cell

A

3

Commonly
APC - causes hyper plastic epithelium
TSG
p53

76
Q

What are the 6 key hall marks of cancer (need all 6 to become malignant)

A

1) self sufficency in growth signals
2) Insensitivity to negative growth signals
3) Limitless replication potential
4) Evading apoptosis
5) Sustained Angiogenesis
6) Tissue invasion and metastasis

77
Q

What is self-sufficiency in growth signals

A

Normal cells need +ve growth factors (most from outside cell) to proliferate
Tumour cells frown in the absence of these!

78
Q

What is typically activated to cause self-sufficiency in growth signals

A

RAS - an important oncgogene

79
Q

How dose RAS work

A

EGFR - activates RAS
RAS bound to GDP = inactive
Guanine-Exchange Factor (GEF) - swaps GDP for GTP and activated RAS
GAP needed t hydrolyse GTP and inactive RAS

Mutation in oncogene means can’t cleave GTP and RAS remains active

80
Q

Ras mutation common in which cancers

A

Pancreatic
Papillary thyroid
Colon
Non-small cell lung caner

81
Q

EGFR overexpression in which cancer

A

Colorectal
Pancreatic
Lung
Non-small cell lung

82
Q

How does Rb protein work

A

Key regulator of cell cycle
Negative growth factors active Rb
Arrests cell in G1 to S phase

83
Q

How are cancers insensitive to -ve growth signals

A

Usually due to mutation in Rb

84
Q

Why do normal cells have a limited productive life

A

Normal bit of telomere lost in each replication

Eventually enough is lost after a certain number of replications meaning cells die

85
Q

Why do cancer cells have limitless potential replication

A

Tumour cells have telomerase to replace lost material and cells become immortal

Abnormal telomerases seen in 86/90% of tumour cells

86
Q

Where are telomerase normally seen

A

Stem cells and angiogenesis

87
Q

What is the TP53 gene function

A

Main gene in apoptosis

Arrests cell cycle to allow DNA repair but if too much damage has occurred causes apptosis

88
Q

How do tumour cells evade apoptosis

A

Mutation in TP53!
Most common mutation in human tumours (>50%)
Inherited in Li Fraumeni syndrome

89
Q

When do cells need there own blood supply

A

When they are over 2mm

90
Q

How does angiogenesis occur

A

Hypoxia stabilizes HIF-1 transciption factor

This induced VEGF - an angiogenic factor that recruits endothelial cells to produce new capillaries and vesels

91
Q

What growth factors cause angiogenesis

A

VEGF and fibroblast growth factor

92
Q

Why can’t normal cells invade

A

Normal cells unable to detach from neighbouring cells or grown into new compartments outside of their own tissue

93
Q

How can tumour cells invade

A

Malignant tumours can invade tissue, detach and migrate

94
Q

What is E-cadherin

A

Holds epithelial cells together

95
Q

What is often inactivated in solid tumour cells

A

E-cadherin

96
Q

How do E-cadherin mutations cause tissue invasion/metastasis

A

Inactivation due to mutation/hypermethylation
Results in Epithelial-Mesenchymal Transition - cells become floppy mobile and spindly
Mesenchymal cells are mobile and secrete proteases - allows them to break through the basement membrane and invade the underlying stroma!

97
Q

What can we use tumour markers for

A

Screening
Diagnosis
Prognosis Therapy
Monitoring

98
Q

What is CA-125

A

A serum antigen
Commonly seen in ovarian cancer
But not good at detecting early stage disease

99
Q

Why are genetic markers good for prognosis in CML

A

As there are subtypes with different translocation

Each translocation correlates with a prognosis outcome can be used for diagnosis and prognosis outcome

100
Q

What is HER2

A

A positive growth factor receptor

101
Q

What is HER2 overexpressed in

A

30% of breast tumours

102
Q

What can we treat HER2 overexertion with

A

Herception - dampens the effect of HER2

103
Q

What is metastasis

A

Spread from site f origin to distant sites and forms new tumours
Kills half of all patients

104
Q

What is needed for cells to invade ore

A

Increased motility
Decreased adhesion
Production of proteolytic enzymes
Mechanial pressure

105
Q

What are cadherins needed for

A

Cell to cell adhesion molecules

Mutation in E. Catherine leads to loss of cell to cell adhesion and contact in inhibition (e.g. breast cancer)

106
Q

What are integrins

A

Cell to matrix/BM adhesion molexules

Change in intern decreases cell-matrix adhesion

107
Q

What is Epithelial-Mesenchymal Transition

A

Epithelial cells usually tightly connected, polarised and tethered
Mesenchymal cells are loosely connected and can migrate

Cancer epithelial cells gain mesenchymal properties - can invade and migrate, cause increased motility and decreased adhesion

108
Q

What are the main proteolytic enzymes

A

Matrix metalloproteinases - these degrade the extracellular matrix

109
Q

What does interstitial collegenases degrade

A

Collagen types I, II, III

110
Q

What does getlitanases degrade

A

Collagen type IV, geltain

111
Q

What do stromolysina degrade

A

Collagen type IV, proteoglycans

112
Q

Why does mechanical pressure cause metastasis

A

Mass forms due to uncontrolled proliferation
Pressure occludes vessels
Pressure atrophy
Cancer cells spread along the lines of least resistance

113
Q

What is often the first presenting sign of a tumour

A

Metastasis

Metastasis often occurs at different stages in differenttumours

114
Q

Why is the secondary tumour burden ofthen worse than that of the primary site

A

Due to the metabolic burder

115
Q

What are the route of tumour metastasis

A

Lymphatic
Blood
Transcoloemic
Implantation

116
Q

What is transcoloemic spreading

A

Across peritoneal, pleural and pericardial cavities of the CSF

117
Q

What is most commonly affected in blood metastasis

A

Liver, lung, bone, brain

118
Q

What is implantation metastasis

A

Spillage of tumour during biopsy or surgery

119
Q

What type of cancer can be spread particularly well by implantation

A

Mesothelioma

Can cause skin cancer due to biopsy

120
Q

Stages of metastasis

A

Detachment - invasion - intravasation - survives host defences - adherence (to blood vessel wall) and extravasation - angiogenesis - growth

121
Q

Pattern of metastases of carcinoma

A

Lymphatics

122
Q

Pattern of metastases of sarcoma

A

Haematogenous spread (check lungs, liver)

123
Q

Pattern of metastases bone

A

Breast, prostate, lung, kidney, thyroid

Can be lytic (lung) or sclerotic (prostate)

124
Q

Pattern of metastases of transcoeloma

A

Ovarian

125
Q

Pattern of metastases of brain and adrenal

A

Lung

126
Q

What is the mechanical hypothesis of metastasis defined by

A

Anatomy

127
Q

What is Paget’s seed and soil hypothesis

A

Seeds will go in all directions but seem to concentrate in certain areas

128
Q

What organs do not usually allow metastasis

A

Kidney and spleen

129
Q

When is angiogenesis needed

A

For metastases to grow larger than 1-2mm

Role of bone marroww derived endothelial stem cells uncertainty

130
Q

What are angiogenesis promoters

A

VEGF
PDGF
TGFB

131
Q

What are angiogenesis inhibitors

A

ECM proteins
Thrombospendin
Caristatin
Endostatin

132
Q

What is the stage of the tumour

A

How advanced is the tumour
Has is spread and to what extent?

Stage correlates well with survival

133
Q

What is the grade of the tumour

A

How aggressive is the tumour?

How quickly will it progress and hoe different does it look from the tissue of origin

134
Q

How do we Stage tumours

A 
TMN system
T- tumour
M- metastasis
N- nodes
TMN combined to give an overall stage of I to IV
135
Q

Treatment of cancers

A

Surgery when not spread
Radiotherapy if locally spread
Chemo if distant spread

136
Q

What do we stage colorectal cancer with

A

Duke’s stages

137
Q

Discuss the Duke Stages

A

A - invades into but not through bowel wall
B - Invades into the bowel wall but no lymph node metastases
C - Local lymph nodes involved
D - distant metastasis

138
Q

What does grading take into acount

A 
Differentiation
Nuclear pleomorphism and size
Mitotic activity
Necrosis (as can outgrowth supply)
Grades G1 to G4 = G4 completely unifferentiated
139
Q

What do we grade endometrial carcinomas with

A

FIGO grades

140
Q

What are the most important indicators of prognosis

A

Grading and Staging

141
Q

What is CEA a marker of (Carcinoembryonic antigen)

A

Colon cancers

142
Q

What is the MLH1 an indicator of

A

Good indicator in colorectal cancer

143
Q

Prognosis with p53 mutation

A

Poor prognosis

Reduced response to chemo

EMS - JL (10 decks)

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