Cancer Flashcards
1
Q
Define
Cancer
A
occurs when abnormal cells grow in an uncontrolled way. These abnormal cells can damage or invade the surrounding tissues, or spread to other parts of the body, causing further damage
2
Q
Define
Immortalisation
A
Evasion of replicative senescence and proliferation without restriction
3
Q
Define
Telomerase
A
a ribonucleoprotein that adds a species-dependent telomere repeat sequence to the 3’ end of telomeres
4
Q
Define
Solid malignancy
A
An abnormal mass of tissue that usually does not contain cysts or liquid areas
5
Q
Define
Haematological malignancy
A
cancers that begin in these cells, and are subdivided according to which type of blood cell is affected
6
Q
Define
Tumour suppressor genes
A
normal genes that slow down cell division, repair DNA mistakes, or tell cells when to die (a process known as apoptosis or programmed cell death)
7
Q
Define
Oncogenes
A
a gene which in certain circumstances can transform a cell into a tumour cell.
8
Q
Define
Carcinogenesis
A
the formation of a cancer, whereby normal cells are transformed into cancer cells
9
Q
Define
Initiation
A
genetic alteration arising spontaneously or induced by a carcinogenic agent. Dysregulation of biochemical signaling pathways associated with cellular proliferation, survival, and differentiation
10
Q
Define
Promotion
A
epigenetic changes, may be relatively lengthy during which preneoplastic cells accumulate. May be altered by chemopreventive agents and affect growth rates
11
Q
Define
Progression
A
final stage of transformation. Further genetic changes associated with acquisition of invasive and metastatic potential.
12
Q
Define
DNA adduct
A
a segment of DNA bound to a cancer-causing chemical. This process could be the start of a cancerous cell, or carcinogenesis
13
Q
Define
Cancer-associated fibroblasts
A
an abundant and active stromal cell population in the TME, function as the signaling center and remodeling machine to aid the creation of a desmoplastic tumor niche
14
Q
Define
Intravasation
A
the invasion of cancer cells through the basement membrane into a blood or lymphatic vessel
15
Q
Define
Extravasation
A
the movement of cells out of a blood vessel into tissue during inflammation or metastasis (the spread of cancer)
16
Q
Define
E-cadherin
A
found on the surface of cells and can bind with those of the same kind on another to form bridges. It is indicated that the loss of this cell adhesion molecule is causally involved in the formation of epithelial types of cancers such as carcinomas
17
Q
Define
p53
A
a gene that codes for a protein that regulates the cell cycle and hence functions as a tumor suppression
18
Q
Define
Angiogenesis
A
the growth of blood vessels from the existing vasculature
19
Q
Define
Senescence
A
loss of a cell’s power of division and growth.
20
Q
Define
Epithelial-to-mesenchyme transition (EMT)
A
a process by which epithelial cells lose their cell polarity and cell-cell adhesion, and gain migratory and invasive properties to become mesenchymal stem cells; these are multipotent stromal cells that can differentiate into a variety of cell types
21
Q
Define
Matrix metalloproteases (MMPs)
A
a group of enzymes that in concert are responsible for the degradation of most extracellular matrix proteins during organogenesis, growth and normal tissue turnover
22
Q
Define
Two-Hit Hypothesis
A
the hypothesis that most tumor suppressor genes require both alleles to be inactivated, either through mutations or through epigenetic silencing, to cause a phenotypic change
23
Q
Define
Epidermal growth factor receptor (EGFR)
A
involved in cell signaling pathways that control cell division and survival. Sometimes, mutations (changes) in the gene cause the proteins to be made in higher than normal amounts on some types of cancer cells
24
Q
Define
DNA mismatch repair genes
A
encode proteins responsible for repairing errors that occur during the normal replication of DNA
25
# Define
Receptor tyrosine kinase (RTK)
the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Mutations lead to activation of a series of signalling cascades which have numerous effects on protein expression
26
# Definition
occurs when abnormal cells grow in an uncontrolled way. These abnormal cells can damage or invade the surrounding tissues, or spread to other parts of the body, causing further damage
Cancer
27
# Definition
Evasion of replicative senescence and proliferation without restriction
Immortalisation
28
# Definition
a ribonucleoprotein that adds a species-dependent telomere repeat sequence to the 3' end of telomeres
Telomerase
29
# Definition
An abnormal mass of tissue that usually does not contain cysts or liquid areas
Solid malignancy
30
# Definition
cancers that begin in these cells, and are subdivided according to which type of blood cell is affected
Haematological malignancy
31
# Definition
normal genes that slow down cell division, repair DNA mistakes, or tell cells when to die (a process known as apoptosis or programmed cell death)
Tumour suppressor genes
32
# Definition
a gene which in certain circumstances can transform a cell into a tumour cell.
Oncogenes
33
# Definition
the formation of a cancer, whereby normal cells are transformed into cancer cells
Carcinogenesis
34
# Definition
genetic alteration arising spontaneously or induced by a carcinogenic agent. Dysregulation of biochemical signaling pathways associated with cellular proliferation, survival, and differentiation
Initiation
35
# Definition
epigenetic changes, may be relatively lengthy during which preneoplastic cells accumulate. May be altered by chemopreventive agents and affect growth rates
Promotion
36
# Definition
final stage of transformation. Further genetic changes associated with acquisition of invasive and metastatic potential.
Progression
37
# Definition
a segment of DNA bound to a cancer-causing chemical. This process could be the start of a cancerous cell, or carcinogenesis
DNA adduct
38
# Definition
an abundant and active stromal cell population in the TME, function as the signaling center and remodeling machine to aid the creation of a desmoplastic tumor niche
Cancer-associated fibroblasts
39
# Definition
the invasion of cancer cells through the basement membrane into a blood or lymphatic vessel
Intravasation
40
# Definition
the movement of cells out of a blood vessel into tissue during inflammation or metastasis (the spread of cancer)
Extravasation
41
# Definition
found on the surface of cells and can bind with those of the same kind on another to form bridges. It is indicated that the loss of this cell adhesion molecule is causally involved in the formation of epithelial types of cancers such as carcinomas
E-cadherin
42
# Definition
a gene that codes for a protein that regulates the cell cycle and hence functions as a tumor suppression
p53
43
# Definition
the growth of blood vessels from the existing vasculature
Angiogenesis
44
# Definition
loss of a cell's power of division and growth.
Senescence
45
# Definition
a process by which epithelial cells lose their cell polarity and cell-cell adhesion, and gain migratory and invasive properties to become mesenchymal stem cells; these are multipotent stromal cells that can differentiate into a variety of cell types
Epithelial-to-mesenchyme transition (EMT)
46
# Definition
a group of enzymes that in concert are responsible for the degradation of most extracellular matrix proteins during organogenesis, growth and normal tissue turnover
Matrix metalloproteases (MMPs)
47
# Definition
the hypothesis that most tumor suppressor genes require both alleles to be inactivated, either through mutations or through epigenetic silencing, to cause a phenotypic change
Two-Hit Hypothesis
48
# Definition
involved in cell signaling pathways that control cell division and survival. Sometimes, mutations (changes) in the gene cause the proteins to be made in higher than normal amounts on some types of cancer cells
Epidermal growth factor receptor (EGFR)
49
# Definition
encode proteins responsible for repairing errors that occur during the normal replication of DNA
DNA mismatch repair genes
50
# Definition
the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Mutations lead to activation of a series of signalling cascades which have numerous effects on protein expression
Receptor tyrosine kinase (RTK)
51
\_\_\_\_\_\_\_\_\_ cancers make up the majority of cancers
**Epithelial** cancers make up the majority of cancers
52
Approximately how many cancers have been identified?
Over 200
53
What is the suffix for benign tumours?
"oma"
54
What is the suffix for malignant tumours?
"carcinoma" or "sarcoma"
55
What are some known risk factors for cancer?
Tobacco
Alcohol
Radiation
Reproductive factors
Occupational exposure
Unhealthy diet
Certain microbes
Obesity
Family history
56
Epigenetic and genetic changes lead to loss of _______________ expression and gain of ____________ expression, causing cancer
Epigenetic and genetic changes lead to loss of **tumour supressor gene** expression and gain of **oncogene** expression, causing cancer
57
What are the phenotypic differences between normal cells and cancer cells?
58
What happens to the amount of reactive oxygen species (ROS) and antioxidant enzymes following initiation of carconogenesis?
↑ ROS
↓ Antioxidant enzymes
59
What happens to the amount of growth factors, apoptosis and cell-cycle arrest following carconogenesis promotion?
↑ Growth factors
↓ Apoptosis
↓ Cell-cycle arrest
60
What happens to the amount of angiogenesis, invasion and metastasis following carconogenesis progression?
↑ Angiogenesis
↑ Invasion
↑ Metastasis
61
What are the three steps of carcinogenesis?
1. Initiation
2. Promotion
3. Progression
62
What happens during carcinogenesis initiation?
Genetic alternation
Chromosomal abberation
DNA adduct formation
63
What happens during carcinogenesis promotion?
Higher cell proliferation
Altered gene expression
Epigenetic changes
64
What happens during carcinogenesis progression?
Chromosomal abnormalities
Onogene activation
Tumour suppressor gene inativation
65
Starting with primary tumour formation, what are the steps to the colonisation and formation of a macrometastasis?
1. Primary tumour formation
2. Localised invasion
3. Intravasation
4. Transport through circulation
5. Arrest in microvessels of various organs
6. Extravasation
7. Formation of micrometastasis
8. Colonisation - formation of a macrometastasis
66
What are the six hallmarks of cancer?
1. Sustaining proliferative signalling (e.g. via growth factors)
2. Evading growth suppressors (e.g. via E-cadherin and/or p53 loss)
3. Activating invasion and metastasis (e.g. via MMPs and/or loss of E-cadherin)
4. Enabling replicative immportality (e.g. via telomerase)
5. Inducing angiogenesis (e.g. via VEGF)
6. Resisting cell death (e.g. via p53 loss)
67
List the common positive and negative regulators of proliferation in a health cell
**Negative regulator (anti-proliferation):** E-cadherin
**Positive regulator (pro-proliferation):** Heterotypic growth factor and integrin signalling
68
How does E-cadherin downregulate proliferation?
Contact inhibition
69
How do cancer cells aquire pro-proliferative signalling?
1. Acquire the ability to synthesise their own growth factors (autocrine positive feedback)
2. Overexpression of growth factor receptors (cell hyperresponsive to growth signals)
3. Mutation/truncation of growth factor receptors (receptor always active)
70
How do cancer cells evade grwoth suppressors?
Loss of E-cadherin transmembrane protein (TSG that suppressors proliferation through contact inhibition)
71
What happens to E-cadherin in cancer cells?
the expression/activity of E-cadherin is lost/reduced
72
How do cancer cells resist cell death?
Loss of p53 TSG which prevents apoptosis
73
How does p53 cause apoptosis?
During overwhelming cell stress, such as DNA mutations, the expression of p53 increases to allow Bax/Bak oligomerisation and cytochrome C release leading to intrinsic cell death (apoptosis)
74
What is the most commonly mutated tumour supressor gene in cancer?
p53
75
How do cancer cells induce angiogenesis?
Tumours secrete pro-angiogenic factors vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) which bind cognate receptors on endothelial cells to promote angiogenesis.
Oncogene expression in cancer cells and/or tumour hypoxia promotes the secretion of angiogenesis factors.
76
How do cancer cells enable replicative immortality?
Cancer cells often express the enzyme telomerase, which regenerates the telomeres, rendering the cells resistant to replicative senescence
77
How do cancer cells degrade and invade surrounding tissue?
78
True or False:
All cancer cells acquire hallmark capabilities but the order is variable depending on the cancer
True
79
Which of these characteristics is typical of cancer cells? (choose one or more)
A) cancer cells lack contact inhibition
B) cancer cells induce angiogenesis
C) cancer cells lack differentiation
D) cancer cells are immortal
Which of these characteristics is typical of cancer cells? (choose one or more)
## Footnote
**A) cancer cells lack contact inhibition**
**B) cancer cells induce angiogenesis**
**C) cancer cells lack differentiation**
**D) cancer cells are immortal**
80
The formation of new blood vessels is called \_\_\_\_\_\_\_\_\_
A) carcinogenesis.
B) metastasis.
C) differentiation.
D) angiogenesis.
The formation of new blood vessels is called \_\_\_\_\_\_\_\_\_
A) carcinogenesis.
B) metastasis.
C) differentiation.
**D) angiogenesis.**
81
Angiogenesis occurs during the phase of carcinogenesis called \_\_\_\_\_\_\_\_\_\_
A) Promotion
B) Initiation
C) Progression
D) metastatis
Angiogenesis occurs during the phase of carcinogenesis called \_\_\_\_\_\_\_\_\_\_
A) Promotion
B) Initiation
**C) Progression**
D) metastatis
82
How many copies of a tumour suppressor gene must be lost to cause cancer?
2 (both)
83
How many copies of a oncogene must be gained to cause cancer?
One
84
What are the two critical gene types that regulate cancer?
1. Oncogenes
2A. Tumour suppressor genes
2B. DNA mismatch repair genes
85
What are protooncogenes?
Protooncogenes are normal cellular genes required for cell survival in normal healthy cells
86
Other than regulation of the cell cycle, what are some other functions of TSGs?
Cell adhesion
DNA repair
Apoptosis
87
How can mutation of the EGFR gene contribute to cancer?
a) Wild-type RTK’s such as EGFR are activated via ligand binding, dimerization and auto-phosphorylation
b) In cancer, RTKs are mutated leading to ligand independent hyperactivated signalling
c) Are amplified leading to increased expression and thereby ligand-dependent hyperactivated signalling
d) In cancer, chromosomal rearrangements causes expression of fusion proteins that elicit ligand-independent hyperactive signalling
e) Duplication of the kinase domain leading to ligandindependent hyperactive signalling
f) Autocrine secretion of growth factors leading to liganddependent hyperactive signalling
88
What three mechanisms can produce oncogenes from the corresponding proto-oncogenes?
* **Point mutations (dominant)** in a proto-oncogene that result in a constitutively active mutant protein. Mutation is only one allele is required.
* **Localized reduplication (gene amplification)** of a DNA segment that includes a protooncogene, leading to overexpression of the encoded wild-type protein
* **Chromosomal translocation** brings a growth-regulatory gene under the control of a different promoter that causes increased expression of a wild-type or mutant protein
89
How is cancer epigenetically influences?
Expression of a different methylation profile meaning that the chromatic ins loosely packed
90
# Define
Skin Cancer
the out-of-control growth of abnormal cells in the epidermis, the outermost skin layer, caused by unrepaired DNA damage that triggers mutations
91
# Define
Nucleotide Excision Repair (NER) Enzymes
group of enzymes which control a mechanism in which a damaged region of DNA is cut out and replaced by DNA synthesized using the undamaged strand as template
92
# Define
Xeroderma Pigmentosa (XP)
a genetic disorder in which there is a decreased ability to repair DNA damage such as that caused by ultraviolet (UV) light that results from loss of NER enzymes
93
# Define
Gorlin Syndrome
a condition that affects many areas of the body and increases the risk of developing various cancerous and noncancerous tumors due to a mutation of the Ptch allele
94
# Define
Basal cells
found at the bottom of the epidermis and produce new skin cells
95
# Define
Basal cell carconoma
the most common form of skin cancer and the most frequently occurring form of all cancers
96
# Define
Squamous cell
the thin, flat cells that make up the epidermis, or the outermost layer of the skin
97
# Define
Squamous cell carcinoma
a common form of skin cancer that develops in the squamous cells that make up the middle and outer layers of the skin
98
# Define
Melanocytes
melanin-producing neural crest-derived cells located in the bottom layer (the stratum basale) of the skin's epidermis, the middle layer of the eye (the uvea), the inner ear, vaginal epithelium, meninges, bones, and heart
99
# Define
Melanoma
a serious form of skin cancer that begins in cells known as melanocytes
100
# Define
Keratinocytes
an epidermal cell which produces keratin
101
# Define
UVA light
also known as long-wave light, accounts for about 95% of the UV light that reaches our skin
102
# Define
UVB light
Medium wavelength light responsible for skin cancer
103
# Define
Cyclobutane pyrimidine dimers (CPDs)
contains a four membered ring arising from the coupling of the two double-bonded carbons of each of the pyrimidines. Such dimers interfere with base pairing during DNA replication, leading to mutations
104
# Define
Translesion polymerases
bypass DNA damage lesions during DNA replication - if a lesion is not repaired or bypassed the replication fork can stall and lead to cell death. However, these polymerases have low sequence fidelity during replication (prone to add wrong nucleotides)
105
# Define
RAS
a guanosine-nucleotide-binding protein. Specifically, it is a single-subunit small GTPase, which is related in structure to the Gα subunit of heterotrimeric G proteins (large GTPases)
106
# Define
Patched (Ptch)
a conserved 12-pass transmembrane protein receptor that plays an obligate negative regulatory role in the Hedgehog signaling pathway in insects and vertebrates
107
# Define
MAPK signalling pathway
a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell promoting proliferation
108
# Define
B-RAF
An isotype of RAF commonly mutated in cancer and is involved in sending signals inside cells which are involved in directing cell growth
109
# Define
Vemurafenib
an inhibitor of the B-Raf enzyme developed by Plexxikon (now part of Daiichi-Sankyo) and Genentech for the treatment of late-stage melanoma
110
# Define
6-4 photoproduct
an alternate dimer consisting of a single covalent bond between the carbon at the 6 position of one ring and carbon at the 4 position of the ring on the next base. This type of conversion occurs at one third the frequency of CPDs but is more mutagenic
111
# Definition
the out-of-control growth of abnormal cells in the epidermis, the outermost skin layer, caused by unrepaired DNA damage that triggers mutations
Skin Cancer
112
# Definition
group of enzymes which control a mechanism in which a damaged region of DNA is cut out and replaced by DNA synthesized using the undamaged strand as template
Nucleotide Excision Repair (NER) Enzymes
113
# Definition
a genetic disorder in which there is a decreased ability to repair DNA damage such as that caused by ultraviolet (UV) light that results from loss of NER enzymes
Xeroderma Pigmentosa (XP)
114
# Definition
a condition that affects many areas of the body and increases the risk of developing various cancerous and noncancerous tumors due to a mutation of the Ptch allele
Gorlin Syndrome
115
# Definition
found at the bottom of the epidermis and produce new skin cells
Basal cells
116
# Definition
the most common form of skin cancer and the most frequently occurring form of all cancers
Basal cell carconoma
117
# Definition
the thin, flat cells that make up the epidermis, or the outermost layer of the skin
Squamous cell
118
# Definition
a common form of skin cancer that develops in the squamous cells that make up the middle and outer layers of the skin
Squamous cell carcinoma
119
# Definition
melanin-producing neural crest-derived cells located in the bottom layer (the stratum basale) of the skin's epidermis, the middle layer of the eye (the uvea), the inner ear, vaginal epithelium, meninges, bones, and heart
Melanocytes
120
# Definition
a serious form of skin cancer that begins in cells known as melanocytes
Melanoma
121
# Definition
an epidermal cell which produces keratin
Keratinocytes
122
# Definition
also known as long-wave light, accounts for about 95% of the UV light that reaches our skin
UVA light
123
# Definition
Medium wavelength light responsible for skin cancer
UVB light
124
# Definition
contains a four membered ring arising from the coupling of the two double-bonded carbons of each of the pyrimidines. Such dimers interfere with base pairing during DNA replication, leading to mutations
Cyclobutane pyrimidine dimers (CPDs)
125
# Definition
bypass DNA damage lesions during DNA replication - if a lesion is not repaired or bypassed the replication fork can stall and lead to cell death. However, these polymerases have low sequence fidelity during replication (prone to add wrong nucleotides)
Translesion polymerases
126
# Definition
a guanosine-nucleotide-binding protein. Specifically, it is a single-subunit small GTPase, which is related in structure to the Gα subunit of heterotrimeric G proteins (large GTPases)
RAS
127
# Definition
a conserved 12-pass transmembrane protein receptor that plays an obligate negative regulatory role in the Hedgehog signaling pathway in insects and vertebrates
Patched (Ptch)
128
# Definition
a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell promoting proliferation
MAPK signalling pathway
129
# Definition
An isotype of RAF commonly mutated in cancer and is involved in sending signals inside cells which are involved in directing cell growth
B-RAF
130
# Definition
an inhibitor of the B-Raf enzyme developed by Plexxikon (now part of Daiichi-Sankyo) and Genentech for the treatment of late-stage melanoma
Vemurafenib
131
# Definition
an alternate dimer consisting of a single covalent bond between the carbon at the 6 position of one ring and carbon at the 4 position of the ring on the next base. This type of conversion occurs at one third the frequency of CPDs but is more mutagenic
6-4 photoproduct
132
List the three types of skin cancer in order of increasing invasive potential
Basal cell carcinoma (BSS), Squamous cell carcinoma (SCC), Melanoma (MM)
133
True or False
Skin cancer is the most common cancer in Australia
True
134
Which of the skin cancers disrupt the basal lamina?
Squamous cell carconoma and Melanoma
135
What are the non-melanoma skin cancers?
Basal cell carcinoma
Squamous cell carcinoma
136
What is the main risk factor for skin cancer?
UV radiation
137
Which type of UV radiation is filtered by the atmosphere?
UVC
138
Which types of UV radiation reach our skin?
UVA
UVB
139
**BCC is associated with:**
**SCC is associated with:**
**Melanoma is associated with:**
**BCC is associated with:** intermittent UV exposure and childhood sunburn
**SCC is associated with:** sunspots (actinic ketatosis) and chronic UV exposure and older age
**Melanoma is associated with:** intermittent sun exposure, burning/blistering events and moles
140
What type of UV light induces cyclobutane pyrimidine dimers (DNA lesions)?
UVB
141
When exposured to UV, how many CPDs form in 1 hr per cell?
360,000
142
How does UV light induce cyclobutane pyrimidine dimers?
* UV light is absorbed by a double bond in C and T bases (breaks bond)
* Open bond allows C or T to react to an adjacent base and form a covalent bond
143
What is more common: 6-4 photoproducts or cyclobutane pyrimidine dimers?
Cyclobutane pyrimidine dimers
144
How does UV light induce 6-4 photoproducts?
A covalent bond forms between: C6 of the 5'-base and C4 of the 3'-base (involves the transfer of the hydroxyl group at C4 of the 3'-base)
145
What are the mechanims for dealing with UV-induced DNA lesions?
DNA/nucleotide excision repair (NER) enzymes such as UVrA-D recognises and removes UV-light induced damaged DNA such as CBDs.
146
What can cause kinks in the DNA due to UV exposure?
CBDs
6-4 photoproducts
147
What enzymes recognise kinks in the DNA and create cuts?
UvrA, B,C endonuclease complex
148
Which enzyme excises DNA kinks?
UvrD endonuclease
149
What is the Hallmark of UVB-induced DNA damage?
Hallmark of UVB-induced DNA damage is a CC-TT mutation
150
Which nucleotide dimer is the most mutagenic? Why?
CC dimers are most mutagenic as “translesion polymerases” are biased toward “AA”
151
How does a CC-TT mutation occur?
152
What it is the effect of UV-induced DNA mutations in squamous cells?
UV-induced DNA lesions in squamous cells often leads to mutations in the small GTPase Ras, as well as p53 leading to the development of SSC.
153
What happens when RAS is mutated in a squamous cell?
Mutation makes RAS constantly active which in turn costantly activates the MAPK pathway, promoting proliferation
154
What is a model for the initiation, promotion and progression of SSC?
155
What happens when the NER (UVrA-D) enzymes are dysfunctional?
Xeroderma Pigmentosa
156
The major pathway deregulated in Basal cell carcinoma is ___________ via the discovery of loss-of-function mutations of the _________ (TSG) in Gorlin syndrome (also called Basal cell nevus syndrome)
The major pathway deregulated in Basal cell carcinoma is **Hedgehog signalling** via the discovery of loss-of-function mutations of the **PTCH1 gene** (TSG) in Gorlin syndrome (also called Basal cell nevus syndrome)
157
How many mutant NER genes do people with XP have?
2
158
How many mutant PTCH alleles do people with Gorlin syndrome have?
1
159
What is patched? What happens when it is lost?
Patched is a tumour suppressor gene and repressor of Hedgehog (Hh) signalling
As a consequence of PTCH deletion or loss of function mutation, the Hh signalling pathway is hyperactivated
160
The primary risk factor for the development of skin cancer is \_\_\_\_\_\_.
The primary risk factor for the development of skin cancer is **UV radiation**.
161
UV light is absorbed by the _______ bond in cytosine or _________ bases and induces dimer formation
UV light is absorbed by the **double** bond in cytosine or **thymine** bases and induces dimer formation
162
Nucleotide excision repair (NER) enzymes repair UV-induced DNA lesions, however, if unrepaired the hallmark mutation is _____ to ______ base change
Nucleotide excision repair (NER) enzymes repair UV-induced DNA lesions, however, if unrepaired the hallmark mutation is **cytosine** to **thymine** base change
163
Loss of NER enzymes in humans results in \_\_\_\_\_\_\_\_.
Loss of NER enzymes in humans results in **Xeroderma Pigmentosa**.
164
Which cell type does melanoma originate from?
Melanocytes
165
How does melanin play a protective role against UV-induced DNA damage?
* Melanin is transport within cells via melanosomes/granules (small vesicles)
* Melanosomes accumulate over the nucleus to form a _“melanin cap”_
* Melanin absorbs UV light, protecting the nuclear DNA from damage
166
What usually happens in the B-RAF/MAPK signalling pathway?
* Upon receptor activation Grb2 and SOS (son of sevenless) are recruited
* SOS is a Guanine nucleotide exchange factor that activates Ras
* Ras-GTP binds to and activates B-Raf - B-Raf is a serine/threonine kinase that activates MEK
167
What happens when BRAF is mutated in melanoma?
168
What mutation of B-RAF allows it to act as a monomer independently of RAS-GTP?
V600E
169
True or False:
B-RAF(V600E) requires RAS activation
False
V600E mutant B-RAF acts independently of RAS
170
Is normal B-RAF a monomer or a dimer?
Homodimer
171
How does Vemurafenib inhibit B-RAF?
It acts as a ATP-competitive inhibitor of the kinase domain of B-RAF
172
Which domain of B-RAF does Vemurafenib act on?
Kinase domain
173
What cell signalling pathway does Vemurafenib block? What does this cause?
Vemurafenib blocks MAPK signalling and induces cell cycle arrest and apoptosis of melanocytes
174
How does resistance to Vemurafenib occur?
Resistance mediated by truncation of the B-RAF(V600E) mutant via deletion of exons 4-8 to yield p61B-RAF(V600E)
175
What domain does the p61B-RAF(V600E) domain lack?
RAS binding domain
176
Does the p61B-RAF(V600E) act as a monomer or dimer?
Homodimer
177
Does the B-RAF(V600E) act as a monomer or dimer?
Monomer
178
Summarise B-RAF actions and resistance to Vemurafenib in Melanoma
a, In normal cells, signal-activated RAS recruits B-RAF to the cell membrane and activates its kinase domain through dimerization. Active B-RAF, in turn, triggers MEK and ERK protein kinases, through phosphorylation (P), to promote cell proliferation and survival. b, The mutant molecule B-RAFV600E constitutively sends signals to MEK and ERK even in the absence of activation by RAS. B-RAFV600E is highly sensitive to inhibition by the anticancer drug vemurafenib. Poulikakos et al. report that B-RAFV600E essentially works as a monomer. c, The authors also show that p61B-RAFV600E — the truncated variant of B-RAFV600E — has an increased propensity to form dimers and that this is associated with resistance to vemurafenib as it prevents the inhibitor from binding.
179
B-Raf activates the ___________ signalling pathway and is composed of an catalytic ___________ domain and a ___________ domain.
B-Raf activates the **MAP kinase** signalling pathway and is composed of an catalytic **kinase** domain and a **RAS-binding** domain
180
The V600E mutation of B-Raf is within the ___________ domain and in contrast to wild-type B-Raf, does not form a \_\_\_\_\_\_\_\_\_\_\_.
The V600E mutation of B-Raf is within the **kinas** domain and in contrast to wild-type B-Raf, does not form a **homodimer**.
181
Plexxikon is a ___________ inhibitor
Plexxikon is a **B-RAF** inhibitor
182
The Plexxikon resistant mutant ___________ lacks the ___________ domain, and acts as a \_\_\_\_\_\_\_\_\_\_\_.
The Plexxikon resistant mutant **p61-V600E** lacks the **RAS-binding** domain, and acts as a **homodimer**.
183
True or False:
The Hedgehog signalling pathway is not usually active in adulthood
True
Growing evidence that signalling pathways that are predominantly active during and essential for embryogenesis, are aberrantly switched on in cancer
184
True or False
Hh signalling regulates the morphogenesis of many tissues and organs
True
185
What are the 3 ligands of the Hh signalling pathway?
Sonic hedgehog (shh)
Indian hedgehog (ihh)
Desert hedgehog (dss)
186
Indian hedgehog leads to development of what tissue?
Bone
187
Desert hedgehog leads to development in what tissue?
Male sexual development
188
What are the roles of shh signalling?
* Limb development
* Neural differentiation
* Facial morphogenesis
* Hair and feather development
* Forming the midline of the body
189
What is the role of Patched when it is active?
Represses Smo meaning that Gli remains in its inactive state and can't cause transcription of Hh genes. Hh signalling is repressed
190
What is SUFU?
* SUFU is (Suppressor of fused) is a central regulator of Hh signaling
* tumor suppressor, active in the absence of Hh ligand
* processes Gli transcription factors into inactive/repressor forms (GliR).
* With Hh ligand SUFU is inactive, allowing Gli to be active (GliA).
191
Without Hh, what states are the following in?
## Footnote
Patched:
Smoothened:
SUFU:
Gli:
Without Hh, what states are the following in?
## Footnote
Patched: **Active**
Smoothened: **Repressed**
SUFU: **Active**
Gli: **Repressed**
192
With Hh, what states are the following in?
Patched:
Smoothened:
SUFU:
Gli:
With Hh, what states are the following in?
Patched: **Repressed**
Smoothened: **Active**
SUFU: **Inactive**
Gli: **Active**
193
What does active SUFU do?
Inactivates Gli, converts in into its repressed form
194
What would you measure if you wanted to know whether the Hh signalling pathway is on in a cell?
The levels of Hh target genes such as PTCH1 and Gli1
195
How does the Hh signalling pathway act as a negative feedback mechanism?
When the pathway is active it results in the transcription of Hh target genes such as PTCH1 and Gli1. This increases the amount of Patched and Gli in the pathway making it more likely that the pathway will be repressed
196
Which part of the cell does Hh signalling occur at?
Primary cilia
197
Which stage of the cell cycle do cilia form?
Cilia form at G1 and resorb prior to mitosis
198
Without Shh present, where is Smo and Ptch located, and what state are they, plus Gli and SUFU, in?
**Smoothened:** located in normal cell membrane repressed by Ptch
**Patched:** Localised to cilia membrane actively inhibiting Smo
**SUFU:** Actively converting Gli into inactive form
**Gli:** In repressed or GliR form
199
How does Ptch move out of the cilia when Shh binds?
Moves laterally away from cilia into the plasma membrane
200
How does active Smo move into the cilia?
Active Smo is transported into the cilia by the IFT proteins along the microtubules
201
Summarise the Hh signalling pathway
1. Hh (also called Sonic, Sonic hedgehog, shh) is the ligand for Patched (PTC) to initiate signal transduction
2. Hh binds to transmembrane (12 pass) receptor PTC
3. Smoothened transmembrane (7 pass) receptor undergoes a conformational change and is enriched at the cilia and becomes activated (to transduce the signal)
4. Gli proteins (transcription factors 1-3) are processed into their active forms (SuFu is inhibited)
5. Active GliA translocates to the nucleus 6
6. Active GliA induces transcription of Hh target genes
7. Hh target genes include PTC, Gli, V-EGF, IGF, Myc and Cylcin D
202
Which of the following is a protooncogene and which are tumour suppressors?
## Footnote
Patched
Sonic hedgehog
Smoothened
SUFU
Gli
Patched: **Tumour suppressor**
Sonic hedgehog: **Protooncogene**
Smoothened: **Protooncogene**
SUFU: **Tumour suppressor**
Gli: **Protooncogene**
203
True or False:
Hh signalling effects only the resisting cell death and evading growth suppressors hallmarks of cancer
False
Hh signalling promotes all the hallmarks of cancer
204
What are the three types of Hh signalling driven cancers?
**Type 1:** Ligand-independent
**Type 2:** Ligand-dependent autocrine
**Type 3:** Ligand-dependent paracrine
205
What causes a type 1 (ligand-independent) Hh signalling driven cancer? What happens?
Loss of function (Ptch1), or gain of function mutation (Smo – SmoM2)
206
What causes a type 2 (ligand-dependent autocrine) Hh signalling driven cancer? What happens?
Tumour cells produce and respond to the Hh ligand
207
What 2 ways can cause a type 3 (ligand-dependent paracrine) Hh signalling driven cancer? What happens?
1) Tumour cells secrete Hh ligand, stromal cells respond and produce growth factors etc to support tumour growth eg. VEGF.
2) Stromal cells produce Hh ligand, which activates Hh signalling in the tumour cells.
208
What type of Hh-driven cancer is Medulloblastoma?
Type 1 (ligand-independent)
209
What genetic mutations of the Hh signalling pathway can result in Medulloblastoma?
* A loss of function mutation in Ptch1 (Patched), OR,
* A gain of function mutation in Smo (Smoothened)
210
Which of the following statement(s) about Hedgehog signalling is TRUE?
## Footnote
A. Sufu is activated upon Hh ligand binding to Patched.
B. Gli transcription factor is always processed into an active form (GliA).
C. Hh ligands bind the receptor Smoothened.
D. Activation of Hh signalling involves Patched entering the cilia.
E. Upon Hh ligands binding to Patched, Smoothened enters the cilia.
Which of the following statement(s) about Hedgehog signalling is TRUE?
## Footnote
A. Sufu is activated upon Hh ligand binding to Patched.
B. Gli transcription factor is always processed into an active form (GliA).
C. Hh ligands bind the receptor Smoothened.
D. Activation of Hh signalling involves Patched entering the cilia.
**E. Upon Hh ligands binding to Patched, Smoothened enters the cilia.**
211
What is the most common malignant brain tumour in children?
Medulloblastoma
212
Which part of the brain is effected by medulloblastoma?
Cerebellum
213
What are the symptoms of medulloblastoma?
* Headaches, nausea or vomiting.
* Problems with motor skills such as clumsiness or poor handwriting.
* Tiredness.
* Tilting of the head to one side.
* Walking difficulty and balance problems.
214
\_\_\_\_\_\_\_\_\_ secrete the Hh ligand that binds to \_\_\_\_\_\_\_\_on “granular cells” also called “granule cell precursors” (GCPs) and undergo massive cell proliferation in early post natal life (~P5-10).
**Purkinje cells** secrete the Hh ligand that binds to **Patched** on “granular cells” also called “granule cell precursors” (GCPs) and undergo massive cell proliferation in early post natal life (~P5-10).
215
What happens to granule cell precursors (GCPs) during normal cerebellum development ~10 days after birth?
* GCPs become unresponsive to the Hh signals, and exit the cell cycle.
* GCPs migrate from the external granular layer (EGL) to the internal granular layer (IGL) and differentiate into neurons
* Granule neurons are the only neuronal cell type/output in the cerebellum
216
Describe how Hh signalling is involved in cerebellum development
217
What must happen to the granule cell precursors in order for them to migrate?
They must become unresponsive to Hh signals and exit the cell cycle
218
What happens to the cells in the EGL if a Ptch loss of function mutation occurs?
* A common mutation in medulloblastoma is a loss of function mutation in Patched (Ptch)
* As a consequence, Smoothened (Smo) is not repressed
* Leads to constitutive hyperactivation of Hh signalling in the GCPs in the EGL
* GCPs continue to proliferate past day 10,
* Leads to medulloblastoma, and loss of neuronal cells in the IGL – symptoms.
219
How many alleles must be mutated in a Patched gene to cause medulloblastoma?
2; both alleles
220
How many alleles must be mutated in a Smoothened gene to cause medulloblastoma?
1; proto-oncogene
221
What happens to the Hh signalling pathway when there is a loss-of-function mutation of Patched?
* Individuals born with loss/inactivating mutation of one Patched allele
* LOH in Patched leads complete loss of Patched,
* Patched unable to repress Smoothened
* Constitutive hyperactivation of Hh signalling leading to MB.
222
What happens to the Hh signalling pathway when there is a gain-of-funtion mutation of Smoothened?
* Gain of function mutation in Smoothened (SmoM2 mutant)
* SmoM2 no longer inhibited by Patched
* SmoM2 is constitutively localised to cilia
* Constitutively active Smo at cilia results in MB
223
How many Patched alleles must be lost in mice for MB? What about humans?
Human: Loss of both alleles
Mice: Lose of only one allele
224
What is SmoM2?
* SmoM2 is oncogenic in MB, basal cell carcinoma and rhabdomyosarcoma (skeletal muscle cancer).
* SMO-L535W mutation leads to substitution of Leu for Trp at aa 535
* Smo is constitutively localised to cilia in an active conformation (even in the absence of Hh ligand)
* constitutive ligand-independent activation of Hh signalling.
* SmoM2 induces MB much more quickly in both mice and humans
225
What are the treatment options for medulloblastoma?
* Aggressive surgery, craniospinal radiotherapy and chemotherapy
* Currently, ~50% of children with medulloblastoma can expect to be free of disease 5 years later.
* ~80-90% of those without disseminated disease can be cured; however, treatment often results in significant endocrinological and intellectual issues including hormonal issues, height restriction, hearing loss, secondary tumours, secondary leukaemias, cognitive impairment
226
Which type of drug has shown the most promise to date for treating MB? What are their downsides?
Smo inhibitors
As Hh has a critical role in many developmental processes including the neural tube, skeletal and cartilage growth – use in prepubescent children is of concern
227
What does the choice of cancer therapy depend on?
1. Location of tumour
2. Grade/stage of tumour
3. Condition of Patient
228
What are the two types of chemotherapy?
Adjuvant
Neo-adjuvant
229
True or False:
Alkylating are cell-cycle non-specific agents
True
230
Which phase of the cell cycle do antimetabolites target?
S-phase
231
Which phase of the cell cycle do antimicrotubule agents target?
M-phase
232
Which phase of the cell cycle do topoisomerase inhibitors target?
S-phase
233
How do tumor cells limit chemotherapy drugs accumulation?
* modifying their membrane composition
* reducing drug transporters
* increasing efflux pumps.
* Mechanisms of detoxification lead to drug inactivation.
* Drug target modification or loss
* DNA damage and apoptosis induced by increased expression of DNA repair genes
* upregulation of prosurvival genes.
234
What chromosomal abnormality is a key feature of CML?
9/22 translocation (i.e. Philadelphia chromosome)
235
True or False:
CML is considered a solid tumour
False
It is a liquid tumour
236
What is the "fatal blast crisis" seen in CML?
Loss of mature granulocytes
237
What is the role of the Bcr coiled-coil domain of BCR-Abl?
Oligomerisation
238
What is the role of the F-actin binding domain of BCR-Abl?
Facilitates localisation to cytosol and F-actin structures, in contrast to wildtype Abl which shuttles between cytosol/nucleus
239
What does the loss of N-terminal "autoinhibitory cap" allow Bcr-Abl to do?
Loss of N-terminal “autoinhibitory cap” (from Abl) - allows the Bcr-Abl fusion to be constitutively active
240
Why is the wildtype Abl not constituitively active?
in the wildtype Abl, the myristoylated group masks the catalytic kinase domain placing it in an inactive conformation.
241
What is the “transforming” activity of BCR-Abl is mediated by?
Bcr coiled-coil domain (allows oligomerisation)
F-actin binding domain (localisation to cytosol)
Loss of N-terminal “autoinhibitory cap” (allows the Bcr-Abl fusion to be constitutively active)
242
How does Bcr-Abl activate many pro-survival signalling pathways?
* Bcr-Abl forms dimers and autophosphorylates (tyrosine residues) and is constitutively active.
* Bcr-Abl phosphorylates cytoskeletal proteins to regulate cell adhesion and migration.
* Bcr-Abl recruits adaptor proteins including Grb2 to facilitate the activation signalling cascades.
243
Which domains allow Bcr-Abl to form a dimer and autophosphorylate?
Coiled-coil domain facilitates dimerisation
Kinase domain autophosphorylates
244
What does Glivec do?
It is a ATP competitive inhbitor that selectively blocks the proliferation of Bcr-Abl-expressing cells in vitro and in a mouse model of CML
245
How does drug resistance to Glivec occur?
* mutation of the Abl kinase domain (50% of occurrences),
* Bcr-Abl gene amplification,
* increased expression of other tyrosine kinases (eg Lyn), or
* altered expression of drug transporter proteins
* **Mutation of the ‘gatekeeper’ residue threonine (T315I) to isoleucine**
* reduces Glivec binding because isoleucine cannot H-bond to the drug, and
* isoleucine is a bulkier residue and blocks drug access
246
What are the outcomes of monoclonal antibody therapy?
1. Block the activity and/or function of the protein antigen - via multiple mechanisms
2. Stimulate cell death via antibody dependent cellular cytotoxicity (ADCC)
3. Delivery of toxin or radioisotope (radioimmunotherapy)
247
What are the two types of Immune-mediated effects of tumour specific IgG?
**ADCC:** antibody dependent cellular cytotoxicity
**CMC/CDC:** complement mediated/dependent cytotoxicity
248
What are the direct effects of tumour-specific IgG?
249
What type of protein is HER2?
EGFR
250
What are the 3 domains of HER1-4? What is their function?
**Extracellular –** binds ligand
**Transmembrane –** anchors receptor in cell membrane
**Intracellular/kinase domain –** contains tyrosine kinase domain
251
How is HER2 activated?
HER2 does not bind ligands, is activated via hetrodimerisation with HER1/3/4.
252
What happens when HER2 loses its extracellular domain?
It become constituitively active
253
What signalling pathways does HER2 activate?
HER2 activates multiple signalling pathways including MAP kinase and PI3-kinase
254
How does Trastuzumab (Herceptin) treat breast cancer?
* Binds extracellular domain of HER2
* Blocks HER2 heterodimerisation
* Blocks HER tyrosine kinase activity
* Blocks e/c domain shedding
* Promotes HER2 degradation
255
How does resistance to Herceptin occur?
* Expression of the truncated p95HER2 (lacks e/c domain to prevent drug binding)
* Signalling by other HERs
* Hyperactivation of MAPK or PI3-kinase (via mutations in pathway components)
256
How do we overcome Herceptin resistance?
Combination treatments depending on mechanism of resistance.
