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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

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2
Q

Define

Immortalisation

A

Evasion of replicative senescence and proliferation without restriction

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3
Q

Define

Telomerase

A

a ribonucleoprotein that adds a species-dependent telomere repeat sequence to the 3’ end of telomeres

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4
Q

Define

Solid malignancy

A

An abnormal mass of tissue that usually does not contain cysts or liquid areas

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5
Q

Define

Haematological malignancy

A

cancers that begin in these cells, and are subdivided according to which type of blood cell is affected

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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)

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7
Q

Define

Oncogenes

A

a gene which in certain circumstances can transform a cell into a tumour cell.

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8
Q

Define

Carcinogenesis

A

the formation of a cancer, whereby normal cells are transformed into cancer cells

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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

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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

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11
Q

Define

Progression

A

final stage of transformation. Further genetic changes associated with acquisition of invasive and metastatic potential.

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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

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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

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14
Q

Define

Intravasation

A

the invasion of cancer cells through the basement membrane into a blood or lymphatic vessel

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15
Q

Define

Extravasation

A

the movement of cells out of a blood vessel into tissue during inflammation or metastasis (the spread of cancer)

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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

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17
Q

Define

p53

A

a gene that codes for a protein that regulates the cell cycle and hence functions as a tumor suppression

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18
Q

Define

Angiogenesis

A

the growth of blood vessels from the existing vasculature

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19
Q

Define

Senescence

A

loss of a cell’s power of division and growth.

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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

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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

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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

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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

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24
Q

Define

DNA mismatch repair genes

A

encode proteins responsible for repairing errors that occur during the normal replication of DNA

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25
Q

Define

Receptor tyrosine kinase (RTK)

A

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

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26
Q

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

A

Cancer

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27
Q

Definition

Evasion of replicative senescence and proliferation without restriction

A

Immortalisation

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28
Q

Definition

a ribonucleoprotein that adds a species-dependent telomere repeat sequence to the 3’ end of telomeres

A

Telomerase

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29
Q

Definition

An abnormal mass of tissue that usually does not contain cysts or liquid areas

A

Solid malignancy

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30
Q

Definition

cancers that begin in these cells, and are subdivided according to which type of blood cell is affected

A

Haematological malignancy

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31
Q

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)

A

Tumour suppressor genes

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32
Q

Definition

a gene which in certain circumstances can transform a cell into a tumour cell.

A

Oncogenes

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33
Q

Definition

the formation of a cancer, whereby normal cells are transformed into cancer cells

A

Carcinogenesis

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34
Q

Definition

genetic alteration arising spontaneously or induced by a carcinogenic agent. Dysregulation of biochemical signaling pathways associated with cellular proliferation, survival, and differentiation

A

Initiation

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35
Q

Definition

epigenetic changes, may be relatively lengthy during which preneoplastic cells accumulate. May be altered by chemopreventive agents and affect growth rates

A

Promotion

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36
Q

Definition

final stage of transformation. Further genetic changes associated with acquisition of invasive and metastatic potential.

A

Progression

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37
Q

Definition

a segment of DNA bound to a cancer-causing chemical. This process could be the start of a cancerous cell, or carcinogenesis

A

DNA adduct

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38
Q

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

A

Cancer-associated fibroblasts

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39
Q

Definition

the invasion of cancer cells through the basement membrane into a blood or lymphatic vessel

A

Intravasation

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40
Q

Definition

the movement of cells out of a blood vessel into tissue during inflammation or metastasis (the spread of cancer)

A

Extravasation

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41
Q

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

A

E-cadherin

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42
Q

Definition

a gene that codes for a protein that regulates the cell cycle and hence functions as a tumor suppression

A

p53

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43
Q

Definition

the growth of blood vessels from the existing vasculature

A

Angiogenesis

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44
Q

Definition

loss of a cell’s power of division and growth.

A

Senescence

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45
Q

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

A

Epithelial-to-mesenchyme transition (EMT)

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46
Q

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

A

Matrix metalloproteases (MMPs)

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47
Q

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

A

Two-Hit Hypothesis

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48
Q

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

A

Epidermal growth factor receptor (EGFR)

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49
Q

Definition

encode proteins responsible for repairing errors that occur during the normal replication of DNA

A

DNA mismatch repair genes

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50
Q

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

A

Receptor tyrosine kinase (RTK)

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51
Q

_________ cancers make up the majority of cancers

A

Epithelial cancers make up the majority of cancers

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52
Q

Approximately how many cancers have been identified?

A

Over 200

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53
Q

What is the suffix for benign tumours?

A

“oma”

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54
Q

What is the suffix for malignant tumours?

A

“carcinoma” or “sarcoma”

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55
Q

What are some known risk factors for cancer?

A

Tobacco

Alcohol

Radiation

Reproductive factors

Occupational exposure

Unhealthy diet

Certain microbes

Obesity

Family history

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56
Q

Epigenetic and genetic changes lead to loss of _______________ expression and gain of ____________ expression, causing cancer

A

Epigenetic and genetic changes lead to loss of tumour supressor gene expression and gain of oncogene expression, causing cancer

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57
Q

What are the phenotypic differences between normal cells and cancer cells?

A
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58
Q

What happens to the amount of reactive oxygen species (ROS) and antioxidant enzymes following initiation of carconogenesis?

A

↑ ROS

↓ Antioxidant enzymes

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59
Q

What happens to the amount of growth factors, apoptosis and cell-cycle arrest following carconogenesis promotion?

A

↑ Growth factors

↓ Apoptosis

↓ Cell-cycle arrest

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60
Q

What happens to the amount of angiogenesis, invasion and metastasis following carconogenesis progression?

A

↑ Angiogenesis

↑ Invasion

↑ Metastasis

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61
Q

What are the three steps of carcinogenesis?

A
  1. Initiation
  2. Promotion
  3. Progression
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62
Q

What happens during carcinogenesis initiation?

A

Genetic alternation

Chromosomal abberation

DNA adduct formation

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63
Q

What happens during carcinogenesis promotion?

A

Higher cell proliferation

Altered gene expression

Epigenetic changes

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64
Q

What happens during carcinogenesis progression?

A

Chromosomal abnormalities

Onogene activation

Tumour suppressor gene inativation

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65
Q

Starting with primary tumour formation, what are the steps to the colonisation and formation of a macrometastasis?

A
  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
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66
Q

What are the six hallmarks of cancer?

A
  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)
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67
Q

List the common positive and negative regulators of proliferation in a health cell

A

Negative regulator (anti-proliferation): E-cadherin

Positive regulator (pro-proliferation): Heterotypic growth factor and integrin signalling

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68
Q

How does E-cadherin downregulate proliferation?

A

Contact inhibition

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69
Q

How do cancer cells aquire pro-proliferative signalling?

A
  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)
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70
Q

How do cancer cells evade grwoth suppressors?

A

Loss of E-cadherin transmembrane protein (TSG that suppressors proliferation through contact inhibition)

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71
Q

What happens to E-cadherin in cancer cells?

A

the expression/activity of E-cadherin is lost/reduced

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72
Q

How do cancer cells resist cell death?

A

Loss of p53 TSG which prevents apoptosis

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73
Q

How does p53 cause apoptosis?

A

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)

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74
Q

What is the most commonly mutated tumour supressor gene in cancer?

A

p53

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75
Q

How do cancer cells induce angiogenesis?

A

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.

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76
Q

How do cancer cells enable replicative immortality?

A

Cancer cells often express the enzyme telomerase, which regenerates the telomeres, rendering the cells resistant to replicative senescence

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77
Q

How do cancer cells degrade and invade surrounding tissue?

A
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78
Q

True or False:

All cancer cells acquire hallmark capabilities but the order is variable depending on the cancer

A

True

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79
Q

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

A

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

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80
Q

The formation of new blood vessels is called _________

A) carcinogenesis.

B) metastasis.

C) differentiation.

D) angiogenesis.

A

The formation of new blood vessels is called _________

A) carcinogenesis.

B) metastasis.

C) differentiation.

D) angiogenesis.

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81
Q

Angiogenesis occurs during the phase of carcinogenesis called __________

A) Promotion

B) Initiation

C) Progression

D) metastatis

A

Angiogenesis occurs during the phase of carcinogenesis called __________

A) Promotion

B) Initiation

C) Progression

D) metastatis

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82
Q

How many copies of a tumour suppressor gene must be lost to cause cancer?

A

2 (both)

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83
Q

How many copies of a oncogene must be gained to cause cancer?

A

One

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84
Q

What are the two critical gene types that regulate cancer?

A
  1. Oncogenes

2A. Tumour suppressor genes

2B. DNA mismatch repair genes

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85
Q

What are protooncogenes?

A

Protooncogenes are normal cellular genes required for cell survival in normal healthy cells

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86
Q

Other than regulation of the cell cycle, what are some other functions of TSGs?

A

Cell adhesion

DNA repair

Apoptosis

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87
Q

How can mutation of the EGFR gene contribute to cancer?

A

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

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88
Q

What three mechanisms can produce oncogenes from the corresponding proto-oncogenes?

A
  • 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
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89
Q

How is cancer epigenetically influences?

A

Expression of a different methylation profile meaning that the chromatic ins loosely packed

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90
Q

Define

Skin Cancer

A

the out-of-control growth of abnormal cells in the epidermis, the outermost skin layer, caused by unrepaired DNA damage that triggers mutations

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91
Q

Define

Nucleotide Excision Repair (NER) Enzymes

A

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

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92
Q

Define

Xeroderma Pigmentosa (XP)

A

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

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93
Q

Define

Gorlin Syndrome

A

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

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94
Q

Define

Basal cells

A

found at the bottom of the epidermis and produce new skin cells

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95
Q

Define

Basal cell carconoma

A

the most common form of skin cancer and the most frequently occurring form of all cancers

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96
Q

Define

Squamous cell

A

the thin, flat cells that make up the epidermis, or the outermost layer of the skin

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97
Q

Define

Squamous cell carcinoma

A

a common form of skin cancer that develops in the squamous cells that make up the middle and outer layers of the skin

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98
Q

Define

Melanocytes

A

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

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99
Q

Define

Melanoma

A

a serious form of skin cancer that begins in cells known as melanocytes

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100
Q

Define

Keratinocytes

A

an epidermal cell which produces keratin

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101
Q

Define

UVA light

A

also known as long-wave light, accounts for about 95% of the UV light that reaches our skin

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102
Q

Define

UVB light

A

Medium wavelength light responsible for skin cancer

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103
Q

Define

Cyclobutane pyrimidine dimers (CPDs)

A

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
Q

Define

Translesion polymerases

A

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
Q

Define

RAS

A

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
Q

Define

Patched (Ptch)

A

a conserved 12-pass transmembrane protein receptor that plays an obligate negative regulatory role in the Hedgehog signaling pathway in insects and vertebrates

107
Q

Define

MAPK signalling pathway

A

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
Q

Define

B-RAF

A

An isotype of RAF commonly mutated in cancer and is involved in sending signals inside cells which are involved in directing cell growth

109
Q

Define

Vemurafenib

A

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
Q

Define

6-4 photoproduct

A

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
Q

Definition

the out-of-control growth of abnormal cells in the epidermis, the outermost skin layer, caused by unrepaired DNA damage that triggers mutations

A

Skin Cancer

112
Q

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

A

Nucleotide Excision Repair (NER) Enzymes

113
Q

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

A

Xeroderma Pigmentosa (XP)

114
Q

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

A

Gorlin Syndrome

115
Q

Definition

found at the bottom of the epidermis and produce new skin cells

A

Basal cells

116
Q

Definition

the most common form of skin cancer and the most frequently occurring form of all cancers

A

Basal cell carconoma

117
Q

Definition

the thin, flat cells that make up the epidermis, or the outermost layer of the skin

A

Squamous cell

118
Q

Definition

a common form of skin cancer that develops in the squamous cells that make up the middle and outer layers of the skin

A

Squamous cell carcinoma

119
Q

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

A

Melanocytes

120
Q

Definition

a serious form of skin cancer that begins in cells known as melanocytes

A

Melanoma

121
Q

Definition

an epidermal cell which produces keratin

A

Keratinocytes

122
Q

Definition

also known as long-wave light, accounts for about 95% of the UV light that reaches our skin

A

UVA light

123
Q

Definition

Medium wavelength light responsible for skin cancer

A

UVB light

124
Q

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

A

Cyclobutane pyrimidine dimers (CPDs)

125
Q

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)

A

Translesion polymerases

126
Q

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)

A

RAS

127
Q

Definition

a conserved 12-pass transmembrane protein receptor that plays an obligate negative regulatory role in the Hedgehog signaling pathway in insects and vertebrates

A

Patched (Ptch)

128
Q

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

A

MAPK signalling pathway

129
Q

Definition

An isotype of RAF commonly mutated in cancer and is involved in sending signals inside cells which are involved in directing cell growth

A

B-RAF

130
Q

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

A

Vemurafenib

131
Q

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

A

6-4 photoproduct

132
Q

List the three types of skin cancer in order of increasing invasive potential

A

Basal cell carcinoma (BSS), Squamous cell carcinoma (SCC), Melanoma (MM)

133
Q

True or False

Skin cancer is the most common cancer in Australia

A

True

134
Q

Which of the skin cancers disrupt the basal lamina?

A

Squamous cell carconoma and Melanoma

135
Q

What are the non-melanoma skin cancers?

A

Basal cell carcinoma

Squamous cell carcinoma

136
Q

What is the main risk factor for skin cancer?

A

UV radiation

137
Q

Which type of UV radiation is filtered by the atmosphere?

A

UVC

138
Q

Which types of UV radiation reach our skin?

A

UVA

UVB

139
Q

BCC is associated with:

SCC is associated with:

Melanoma is associated with:

A

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
Q

What type of UV light induces cyclobutane pyrimidine dimers (DNA lesions)?

A

UVB

141
Q

When exposured to UV, how many CPDs form in 1 hr per cell?

A

360,000

142
Q

How does UV light induce cyclobutane pyrimidine dimers?

A
  • 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
Q

What is more common: 6-4 photoproducts or cyclobutane pyrimidine dimers?

A

Cyclobutane pyrimidine dimers

144
Q

How does UV light induce 6-4 photoproducts?

A

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
Q

What are the mechanims for dealing with UV-induced DNA lesions?

A

DNA/nucleotide excision repair (NER) enzymes such as UVrA-D recognises and removes UV-light induced damaged DNA such as CBDs.

146
Q

What can cause kinks in the DNA due to UV exposure?

A

CBDs

6-4 photoproducts

147
Q

What enzymes recognise kinks in the DNA and create cuts?

A

UvrA, B,C endonuclease complex

148
Q

Which enzyme excises DNA kinks?

A

UvrD endonuclease

149
Q

What is the Hallmark of UVB-induced DNA damage?

A

Hallmark of UVB-induced DNA damage is a CC-TT mutation

150
Q

Which nucleotide dimer is the most mutagenic? Why?

A

CC dimers are most mutagenic as “translesion polymerases” are biased toward “AA”

151
Q

How does a CC-TT mutation occur?

A
152
Q

What it is the effect of UV-induced DNA mutations in squamous cells?

A

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
Q

What happens when RAS is mutated in a squamous cell?

A

Mutation makes RAS constantly active which in turn costantly activates the MAPK pathway, promoting proliferation

154
Q

What is a model for the initiation, promotion and progression of SSC?

A
155
Q

What happens when the NER (UVrA-D) enzymes are dysfunctional?

A

Xeroderma Pigmentosa

156
Q

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)

A

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
Q

How many mutant NER genes do people with XP have?

A

2

158
Q

How many mutant PTCH alleles do people with Gorlin syndrome have?

A

1

159
Q

What is patched? What happens when it is lost?

A

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
Q

The primary risk factor for the development of skin cancer is ______.

A

The primary risk factor for the development of skin cancer is UV radiation.

161
Q

UV light is absorbed by the _______ bond in cytosine or _________ bases and induces dimer formation

A

UV light is absorbed by the double bond in cytosine or thymine bases and induces dimer formation

162
Q

Nucleotide excision repair (NER) enzymes repair UV-induced DNA lesions, however, if unrepaired the hallmark mutation is _____ to ______ base change

A

Nucleotide excision repair (NER) enzymes repair UV-induced DNA lesions, however, if unrepaired the hallmark mutation is cytosine to thymine base change

163
Q

Loss of NER enzymes in humans results in ________.

A

Loss of NER enzymes in humans results in Xeroderma Pigmentosa.

164
Q

Which cell type does melanoma originate from?

A

Melanocytes

165
Q

How does melanin play a protective role against UV-induced DNA damage?

A
  • 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
Q

What usually happens in the B-RAF/MAPK signalling pathway?

A
  • 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
Q

What happens when BRAF is mutated in melanoma?

A
168
Q

What mutation of B-RAF allows it to act as a monomer independently of RAS-GTP?

A

V600E

169
Q

True or False:

B-RAF(V600E) requires RAS activation

A

False

V600E mutant B-RAF acts independently of RAS

170
Q

Is normal B-RAF a monomer or a dimer?

A

Homodimer

171
Q

How does Vemurafenib inhibit B-RAF?

A

It acts as a ATP-competitive inhibitor of the kinase domain of B-RAF

172
Q

Which domain of B-RAF does Vemurafenib act on?

A

Kinase domain

173
Q

What cell signalling pathway does Vemurafenib block? What does this cause?

A

Vemurafenib blocks MAPK signalling and induces cell cycle arrest and apoptosis of melanocytes

174
Q

How does resistance to Vemurafenib occur?

A

Resistance mediated by truncation of the B-RAF(V600E) mutant via deletion of exons 4-8 to yield p61B-RAF(V600E)

175
Q

What domain does the p61B-RAF(V600E) domain lack?

A

RAS binding domain

176
Q

Does the p61B-RAF(V600E) act as a monomer or dimer?

A

Homodimer

177
Q

Does the B-RAF(V600E) act as a monomer or dimer?

A

Monomer

178
Q

Summarise B-RAF actions and resistance to Vemurafenib in Melanoma

A

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
Q

B-Raf activates the ___________ signalling pathway and is composed of an catalytic ___________ domain and a ___________ domain.

A

B-Raf activates the MAP kinase signalling pathway and is composed of an catalytic kinase domain and a RAS-binding domain

180
Q

The V600E mutation of B-Raf is within the ___________ domain and in contrast to wild-type B-Raf, does not form a ___________.

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
Q

Plexxikon is a ___________ inhibitor

A

Plexxikon is a B-RAF inhibitor

182
Q

The Plexxikon resistant mutant ___________ lacks the ___________ domain, and acts as a ___________.

A

The Plexxikon resistant mutant p61-V600E lacks the RAS-binding domain, and acts as a homodimer.

183
Q

True or False:

The Hedgehog signalling pathway is not usually active in adulthood

A

True

Growing evidence that signalling pathways that are predominantly active during and essential for embryogenesis, are aberrantly switched on in cancer

184
Q

True or False

Hh signalling regulates the morphogenesis of many tissues and organs

A

True

185
Q

What are the 3 ligands of the Hh signalling pathway?

A

Sonic hedgehog (shh)

Indian hedgehog (ihh)

Desert hedgehog (dss)

186
Q

Indian hedgehog leads to development of what tissue?

A

Bone

187
Q

Desert hedgehog leads to development in what tissue?

A

Male sexual development

188
Q

What are the roles of shh signalling?

A
  • Limb development
  • Neural differentiation
  • Facial morphogenesis
  • Hair and feather development
  • Forming the midline of the body
189
Q

What is the role of Patched when it is active?

A

Represses Smo meaning that Gli remains in its inactive state and can’t cause transcription of Hh genes. Hh signalling is repressed

190
Q

What is SUFU?

A
  • 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
Q

Without Hh, what states are the following in?

Patched:

Smoothened:

SUFU:

Gli:

A

Without Hh, what states are the following in?

Patched: Active

Smoothened: Repressed

SUFU: Active

Gli: Repressed

192
Q

With Hh, what states are the following in?

Patched:

Smoothened:

SUFU:

Gli:

A

With Hh, what states are the following in?

Patched: Repressed

Smoothened: Active

SUFU: Inactive

Gli: Active

193
Q

What does active SUFU do?

A

Inactivates Gli, converts in into its repressed form

194
Q

What would you measure if you wanted to know whether the Hh signalling pathway is on in a cell?

A

The levels of Hh target genes such as PTCH1 and Gli1

195
Q

How does the Hh signalling pathway act as a negative feedback mechanism?

A

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
Q

Which part of the cell does Hh signalling occur at?

A

Primary cilia

197
Q

Which stage of the cell cycle do cilia form?

A

Cilia form at G1 and resorb prior to mitosis

198
Q

Without Shh present, where is Smo and Ptch located, and what state are they, plus Gli and SUFU, in?

A

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
Q

How does Ptch move out of the cilia when Shh binds?

A

Moves laterally away from cilia into the plasma membrane

200
Q

How does active Smo move into the cilia?

A

Active Smo is transported into the cilia by the IFT proteins along the microtubules

201
Q

Summarise the Hh signalling pathway

A
  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
Q

Which of the following is a protooncogene and which are tumour suppressors?

Patched

Sonic hedgehog

Smoothened

SUFU

Gli

A

Patched: Tumour suppressor

Sonic hedgehog: Protooncogene

Smoothened: Protooncogene

SUFU: Tumour suppressor

Gli: Protooncogene

203
Q

True or False:

Hh signalling effects only the resisting cell death and evading growth suppressors hallmarks of cancer

A

False

Hh signalling promotes all the hallmarks of cancer

204
Q

What are the three types of Hh signalling driven cancers?

A

Type 1: Ligand-independent

Type 2: Ligand-dependent autocrine

Type 3: Ligand-dependent paracrine

205
Q

What causes a type 1 (ligand-independent) Hh signalling driven cancer? What happens?

A

Loss of function (Ptch1), or gain of function mutation (Smo – SmoM2)

206
Q

What causes a type 2 (ligand-dependent autocrine) Hh signalling driven cancer? What happens?

A

Tumour cells produce and respond to the Hh ligand

207
Q

What 2 ways can cause a type 3 (ligand-dependent paracrine) Hh signalling driven cancer? What happens?

A

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
Q

What type of Hh-driven cancer is Medulloblastoma?

A

Type 1 (ligand-independent)

209
Q

What genetic mutations of the Hh signalling pathway can result in Medulloblastoma?

A
  • A loss of function mutation in Ptch1 (Patched), OR,
  • A gain of function mutation in Smo (Smoothened)
210
Q

Which of the following statement(s) about Hedgehog signalling is TRUE?

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.

A

Which of the following statement(s) about Hedgehog signalling is TRUE?

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
Q

What is the most common malignant brain tumour in children?

A

Medulloblastoma

212
Q

Which part of the brain is effected by medulloblastoma?

A

Cerebellum

213
Q

What are the symptoms of medulloblastoma?

A
  • 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
Q

_________ 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).

A

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
Q

What happens to granule cell precursors (GCPs) during normal cerebellum development ~10 days after birth?

A
  • 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
Q

Describe how Hh signalling is involved in cerebellum development

A
217
Q

What must happen to the granule cell precursors in order for them to migrate?

A

They must become unresponsive to Hh signals and exit the cell cycle

218
Q

What happens to the cells in the EGL if a Ptch loss of function mutation occurs?

A
  • 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
Q

How many alleles must be mutated in a Patched gene to cause medulloblastoma?

A

2; both alleles

220
Q

How many alleles must be mutated in a Smoothened gene to cause medulloblastoma?

A

1; proto-oncogene

221
Q

What happens to the Hh signalling pathway when there is a loss-of-function mutation of Patched?

A
  • 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
Q

What happens to the Hh signalling pathway when there is a gain-of-funtion mutation of Smoothened?

A
  • 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
Q

How many Patched alleles must be lost in mice for MB? What about humans?

A

Human: Loss of both alleles

Mice: Lose of only one allele

224
Q

What is SmoM2?

A
  • 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
Q

What are the treatment options for medulloblastoma?

A
  • 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
Q

Which type of drug has shown the most promise to date for treating MB? What are their downsides?

A

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
Q

What does the choice of cancer therapy depend on?

A
  1. Location of tumour
  2. Grade/stage of tumour
  3. Condition of Patient
228
Q

What are the two types of chemotherapy?

A

Adjuvant

Neo-adjuvant

229
Q

True or False:

Alkylating are cell-cycle non-specific agents

A

True

230
Q

Which phase of the cell cycle do antimetabolites target?

A

S-phase

231
Q

Which phase of the cell cycle do antimicrotubule agents target?

A

M-phase

232
Q

Which phase of the cell cycle do topoisomerase inhibitors target?

A

S-phase

233
Q

How do tumor cells limit chemotherapy drugs accumulation?

A
  • 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
Q

What chromosomal abnormality is a key feature of CML?

A

9/22 translocation (i.e. Philadelphia chromosome)

235
Q

True or False:

CML is considered a solid tumour

A

False

It is a liquid tumour

236
Q

What is the “fatal blast crisis” seen in CML?

A

Loss of mature granulocytes

237
Q

What is the role of the Bcr coiled-coil domain of BCR-Abl?

A

Oligomerisation

238
Q

What is the role of the F-actin binding domain of BCR-Abl?

A

Facilitates localisation to cytosol and F-actin structures, in contrast to wildtype Abl which shuttles between cytosol/nucleus

239
Q

What does the loss of N-terminal “autoinhibitory cap” allow Bcr-Abl to do?

A

Loss of N-terminal “autoinhibitory cap” (from Abl) - allows the Bcr-Abl fusion to be constitutively active

240
Q

Why is the wildtype Abl not constituitively active?

A

in the wildtype Abl, the myristoylated group masks the catalytic kinase domain placing it in an inactive conformation.

241
Q

What is the “transforming” activity of BCR-Abl is mediated by?

A

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
Q

How does Bcr-Abl activate many pro-survival signalling pathways?

A
  • 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
Q

Which domains allow Bcr-Abl to form a dimer and autophosphorylate?

A

Coiled-coil domain facilitates dimerisation

Kinase domain autophosphorylates

244
Q

What does Glivec do?

A

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
Q

How does drug resistance to Glivec occur?

A
  • 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
Q

What are the outcomes of monoclonal antibody therapy?

A
  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
Q

What are the two types of Immune-mediated effects of tumour specific IgG?

A

ADCC: antibody dependent cellular cytotoxicity

CMC/CDC: complement mediated/dependent cytotoxicity

248
Q

What are the direct effects of tumour-specific IgG?

A
249
Q

What type of protein is HER2?

A

EGFR

250
Q

What are the 3 domains of HER1-4? What is their function?

A

Extracellular – binds ligand

Transmembrane – anchors receptor in cell membrane

Intracellular/kinase domain – contains tyrosine kinase domain

251
Q

How is HER2 activated?

A

HER2 does not bind ligands, is activated via hetrodimerisation with HER1/3/4.

252
Q

What happens when HER2 loses its extracellular domain?

A

It become constituitively active

253
Q

What signalling pathways does HER2 activate?

A

HER2 activates multiple signalling pathways including MAP kinase and PI3-kinase

254
Q

How does Trastuzumab (Herceptin) treat breast cancer?

A
  • Binds extracellular domain of HER2
  • Blocks HER2 heterodimerisation
  • Blocks HER tyrosine kinase activity
  • Blocks e/c domain shedding
  • Promotes HER2 degradation
255
Q

How does resistance to Herceptin occur?

A
  • 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
Q

How do we overcome Herceptin resistance?

A

Combination treatments depending on mechanism of resistance.

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