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4th Year Unseen Exam > Hallmarks of Cancer > Flashcards

Hallmarks of Cancer Flashcards

1
Q

Which factors can influence cancer incidence?

A
  • lifestyle
  • environmental (e.g UV light)
  • dietary (fatty acids can lead to colorectal cancer)
  • hormonal
  • parasitic
  • viral
  • occupational
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2
Q

What are oncogenes?

A

Genes that are present in cancer cells, which accelerate cell growth and division

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3
Q

What are tumour suppressor genes?

A

Genes that prevent tumour growth. In tumour cells these are switched off

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4
Q

What is the difference between benign and metastatic tumours?

A

Benign tumours lack the ability to metastasise into neighbouring tissues

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5
Q

What is the process of tumourigenesis?

A

Initiation, promotion, progression

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6
Q

What happens in initiation during tumorigenesis?

A

The acquisition of irreversible genetic changes in cell. This genetic change can be caused by a carcinogen or can be inherited. An error in the genes involved with replication and DNA repair. Creates the pre-neoplastic state

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7
Q

What happens in promotion during tumorigenesis?

A

Further acquisition of genetic errors and growth rate. Pre-neoplastic state acquires more genetic changes (via exposure to carcinogens or cellular growth factors). This leads to genomic instability and mutation or tumour suppressor genes/initiation of oncogenes

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8
Q

What happens in progression during tumorigenesis?

A

Cells gain metastatic potential, cells have acquired many cellular pathways and there is errors in genes involved with proliferation, cell death

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9
Q

Describe cancer pathogenesis

A

Normal cells acquire DNA damaging events, which is not repaired due to inherited mutations/acquired mutations. This leads to mutations in genome somatic cells, leading to activation of growth-promoting oncogenes, alteration of genes that regulate apoptosis, inactivation of cancer suppressor genes, which leads to loss of regulatory function of cells and malignant cancer cells

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10
Q

What are the hallmarks of cancer?

A 
Sustaining proliferative signalling
Evading growth suppressors
Enabling replicative immortality
Activating invasion and metastases
Inducing Angiogenesis
Resisting cell death
Deregulating cellular energetics - Emerging
Avoiding immune destruction - emerging
Genome instability and mutation - enabling
Tumour-promoting inflammation - enabling
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11
Q

What is proliferation?

A

Predefined molecular mechanism to increase DNA and produce daughter cells. Increased in cancer cells

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12
Q

What are the stages of the cell cycle and what happens at each stage?

A

g1 - Hormones that trigger cell cycle
S - strand elongation
g2 - DNA confirmation
M - chromosomal segragation

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13
Q

Which drugs act on the S phase of the cell cycle?

A

Anthracyclines, antimetabolites, alkylating agents, platinum agents

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14
Q

Which drugs act on G1 phase of the cell cycle?

A

Akylating agents, platinum agents, hormonal agents such as tamoxifen, taxanes, anthracyclines

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15
Q

Which drugs act on the G2 stage of the cell cycle?

A

Anthracyclines, akylating agents, topoisomerase inhibitors, bleomycin

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16
Q

Which drugs act on the M phase of the cell cycle?

A

Alkylating agents, platinum agents, vinka alkaloids, taxanes, coclchicine

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17
Q

How do cancer drugs target the cell cycle?

A

Inhibit DNA duplication
Inhibit cell division
Inhibit cell growth (GFP)

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18
Q

How do drugs act on the S phase?

A

Terminate DNA strand elongation

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19
Q

How do drugs act on the G2 phase?

A

Stop cells synthesising and segragating

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20
Q

How do drugs act on the M phase?

A

Target microtubules that facilitate and stabilise/destabilise macrotubules

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21
Q

How do drugs act on the G1 phase of the cell cycle?

A

Target oestrogen/testosterone

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22
Q

Why are multiple cancer drugs used in regimens?

A

To target multiple areas of the cell cycle as all tumour cells are not always necessarily at the same point in the cell cycle

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23
Q

Which part of the cell cycle do platinum agents act on?

A

Platinum agents act independent of the cell cycle. They cause damage by cross linking DNA. They will target all rapidly dividing cells, not necessarily cancer cells and can lead to nephrotoxicity/neurotoxicity and this is dose limiting toxicity

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24
Q

Discuss the mode of action and major side effects of cisplatin

A

It is a DNA crosslinker

Side effects: nephrotoxicity, neurotoxicity, ototoxicity

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25
Q

Discuss the mode of action and major side effects of carboplatin

A

It is a DNA crosslinker

Side effects: nephrotoxicity, myelosuppression

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26
Q

Discuss the mode of action and major side effects of oxaliplatin

A

It is a DNA crosslinker

Side effects: Nephrotoxicity, neurotoxicity, pulmonary toxicity, hepatotoxicity

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27
Q

What are the main mechanisms of resistance to platinum agents

A

Decreased cellular uptake
increase efflux
increased DNA repair capacity
Failure of death pathways

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28
Q

Discuss the mode of action and major side effects of methotrexate

A

Prevents DNA synthesis by inhibiting DHFR

Side effects: myelosuppression, pulmonary toxicity, GI toxicity, hepatotoxicity, nephrotoxicity, neurotoxicity

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29
Q

What are the main mechanisms of resistance for methotrexate?

A

Increased DHFR expression, mutations in folate transporter genes

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30
Q

What is the mode of action and main side effects for doxorubicin/daunorubicin?

A

Topoisomerase 2 poison - intercalating agents

side effects: cardiotoxicity, myelosuppression

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31
Q

What is vasculogenesis?

A

Activation of endothelial cells precursors and new blood vessels

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32
Q

What is angiogenesis?

A

Recruitment of endothelial cells from existing blood vessels

33
Q

Discuss angiogenesis with reference to cancer cells

A

Angiogenesis is a key feature of malignancy, and gives tumour the ability to invade and spread. It provides the vasculature and gives the tumour an escape route into the blood stream. The tumour releases factors that attract Blood vessels and allow growth which leads to increased metastases and cancer spread

34
Q

What is the process of tumour angiogenesis?

A
  1. Hypoxia within tumour leads to development of VEGF
  2. tumour secretes pro-angiogenic factor VEGF
  3. VEGF binds to receptors on endothelial cells of pre existing blood vessels which leads to activation
  4. This interaction leads to the secretion and activation of proteolytic anzymes
  5. The degradation of the extracellular matrix allows activated proliferating endothelial cells to migrate to the tumour
  6. endothelial cells deposit a new basement membrane and secrete growth factors (PDGF) which attract supporting smooth muscle cells to stabilise the vessel
35
Q

What is VEGF and FGF

A

Angiogenic growth factors
Pro angiogenic, up regulated in tumour cells and hypoxic cells
VEGF widespread on endothelial cells
FGF receptors widespread

36
Q

How can angiogenesis be therapeutically inhibited?

A

Stop tumour cells stimulating and developing new blood vessels
Stop VEGF from reaching receptors
Aimed at inhibiting VEGF signalling

37
Q

How does Sunitinib work?

A

Blocks VEGF signalling, inhibits angiogenesis
Interacts with intracellular ATP binding sites on TK
TK pathway is not specific to cancer, so can have off target toxicity

38
Q

What is nintedanib and how does it work?

A

It targets 3x angiogenesis pathways in NSCLC in combination with docetaxel.

39
Q

How can resistance to nintedanib occur?

A

Growth factor redundancy leads to upregulation of a new version, although unlikely as it is derived from malignant cells

40
Q

Discuss mechanisms of resistance to targeted VEGF therapies in cancer

A

VEGF blockade aggravates hypoxia, upregulates production of angiogenic factors
Tumour cells acquire mutations, become hypoxia intolerant and less sensitive to VEGF blockade

41
Q

How can resistance to sunitinib occur?

A

It induces central tumour necrosis but peripheral viable tumour remains. Resistance may occur from tumour regrowth from the peripheral rim of viable well-vascularised cancer cells. Give alongside traditional cytotoxic chemotherapy

42
Q

What are the major steps in metastasis?

A
  1. Invasion/infiltration of surrounding normal host tissue with penetration of small lymphatic/vascular channels
  2. entry of malignant cells or small clumps, into the circulation
  3. survival in circulation
  4. Arrest in the capillary beds of distant organs
  5. penetration of the lymphatic or blood vessels follow by the growth of tumour cells
43
Q

What is the mechanistic theory of metastatic organ selectivity?

A

Tumour follows Pattern of blood flow, unlikely to be true as why would there not always be metastases in the liver

44
Q

What is the seed and soil theory of metastatic organ selectivity?

A

Environment in which compatable tumour cells could grow. Seed = cancer cells, soil = environment. Selective chemotaxis occurs with organ producing soluble attraction factors to tumour cells

45
Q

How are chemokines involved in cancer metastases?

A

Chemostatic proteins that cause directed migration of cells. Highest expression in lung, liver, bone marrow, lymph nodes and brain

46
Q

How does tumour invasion occur?

A

Translocation of cells across extracellular matrix barriers. There is degradation of matrix proteins and digestion of membrane by specific proteinases (serine and metalloproteinases) which leads to creation of invasion channels.

47
Q

What are matrix metalloproteinases?

A
  • central to tumour invasion, angiogenesis and metastases
  • can degrade extracellular matrix proteins
  • secreted in response to signals from tumour cells
48
Q

How do MMPI work?

A

Stop tumours from getting any bigger, but cannot reduce size
slow down growth of tumour
make cancer smaller, then give MMPIs

49
Q

Which drugs target DNA repair (proliferation)?

A

PARP inhibitors

50
Q

What is the purpose of PARP/BRAC1/2?

A

Repari dna damage. Allows cells to grow unless there is too much damage, too much damage will lead to cell death

51
Q

What is the simple purpose of PARP inhibitors?

A

to prevent DNA repair in cancer cells, leading to improved chemotherapy success

52
Q

What is apoptosis and why is it relevant to cancer cells?

A

Apoptosis is programmed cell death important for cell development. Deregulation of this is critical for cancer cell survival. Has an intrinsic and extrinsic signalling pathway

53
Q

What is the intrinsic apoptosis pathway and how is it relevant in cancer?

A

The intrinsic apoptosis pathway works in response to internal damage to DNA. Anticancer pathways can activate this via P53. Which leads to the up-regulation of pro apoptotic members of the BCL2 family of proteins. Inactivated in cancer cells

54
Q

What is the extrinsic apoptosis pathway?

A

The extrinsic apoptosis pathway involves t cell clonal deletion and is mitochondria dependant. The ligand induced activation of receptors lead to rapid assembly of the death inducing complex and recruitment of capsases leading to apoptosis of cells. Inactivated in cancer cells

55
Q

Which drugs target initiation of apoptosis pathways?

A

Dulanermin - extrinsic pathway
Driozitumab - extrinisic pathway
BCL2 inhibitors - intrinsic pathway

56
Q

What is the difference in ATP synthesis between normal cells and cancer cells?

A

In normal cells, ATP is synthesised by glycolysis in the cytoplasm mainly by oxidative phosphorylation in the mitochondria. In cancer cells, there is a shift towards glycolysis via the warburg effect, which is aerobic glycolysis

57
Q

What is the warburg effect?

A

Cancer cells produce ATP via aerobic glycolysis, leading to increased lactate and less ATP produced, independent of the presence of oxygen. Much less ATP is produced but it is much faster, and enables cancer cells to proliferate quickly. When there is a lack of 02, this is activated

58
Q

Discuss lactate and cancer cells

A

INSIDE cancer cells: pyruvate converts LDHA to lactate and NADH is produced which stimulates glycolysis.
OUTSIDE OF CELLS: NADH is an antioxidant which reduces reactive oxidant species and reduces apoptosis. Lactates lower the pH of the microenvironment which activates MMP, leading to metastasis and invasion.

59
Q

How is lactate involved in metabolic symbiosis?

A

Hypoxic tumour cells feed normoxic tumor cells with lactate, which convert it to pyruvate, leading to the TCA cycle which is an energetic source for cells

60
Q

How is lactate involved in immunosuppression?

A

Lactate is in a high concentration around immune cells, leading to an acidic cytoplasm, the action of CD8 and CD4 cells is inhibited by acidic pH

61
Q

Which drugs target lactate production?

A

LDHA inhibitors, MCT4 (lactate transport inhibitors), Glycolysis inhibitors

62
Q

Which drugs target amino acid metabolism (cellular energetics)?

A

L asparaginase

63
Q

How do cancer cells avoid immune destruction?

A

Elimination phase: tumours arise in a tissue, immune cells can recognise and kill them
Equilibrium phase: variant tumour cells arise that are more resistant to being killed, tumour variants develop and there is a balance between killed and surviving cells
Escape phase: one variant escapes the killing mechanism and recruits regulatory cells to protect it

64
Q

What are the 5 main mechanisms of avoiding immune destruction?

A

Low immunogenicity: no peptide MHC ligand, no adhesion molecules
Tumour treated as self antigen
Antigenic modulation: t cells lost antigens
Tumour induced immune suppression: factors secreted by tumours inhibit t cells directly
Tumour induced priveledge site: physical barrier to immune system

65
Q

How is immunotherapy used in cancer?

A

Monoclonal antibodies, CART

66
Q

When are monoclonal antibodies used in cancer therapy?

A

When tumour specific antigen is expressed on the tumour cell surface

67
Q

Give examples on monoclonal antibodies used in cancer therapy

A

Trastuzumab: HER2 receptor over expressed in breast cancer patients
Rituximab: CD20 antibody triggers apoptosis of B cells in NHL

68
Q

What is the issues with monoclonal antibodies and what are some solutions?

A

Inefficient killing of cancer cells, inefficient penetration of cells, soluble antigens mop up the antibody.
Solutions: link antibody to toxin (blinatumomab used for ALL to help penetrate the inner parts of the tumour)

69
Q

How is CAR therapy used?

A

Collecting T cells from the blood of the patient, infect with the retrovirus that codes for ANTI CD19 CAR, infuse back into the patient of the patient, and can recognise and kill B cell tumour

70
Q

How is the immune check point blockade strategy used in cancer therapy?

A

The immune response is controlled by positive and negative checkpoints. PD 1 - block activation of T cells. Inhibit checkpoint eg pembrolizumab

71
Q

How is vaccination used in cancer therapy?

A

Oncogenic virus - HPV vaccine, B hep in liver cancer
Against tumour antigens - surgically remove antigens from the tumour and vaccine prepared using cell extracts, which stimulate the immune response. APC cells stimulate cytotoxic t cells against the tumour

72
Q

How does Slip-T work in prostate cancer?

A

Monocytes in prostate cancer produced in vitro. Growth factor stimulates monocytes to become dendritic antigen presenting cells. Prostate cancer cells uptake these antigen presenting cells in the vaccine and present prostate cancer cells to cd4 T helper cells, which stimulates B cells to produce plasma cells and produce antibodies. Cytotoxic T cells that kill the prostate cancer cells.

73
Q

What are mitogens?

A

Mitogens stimulate cell proliferation and control movement of cell cycle from G1 to S, causing cell to proliferate. Mitogens overcome resistance of cell cycle. Overactivity of mitogens in cancer cells leads to uncontrolled proliferation.

74
Q

How do Cyclins control the cell cycle?

A

Levels of cyclins rise and fall during various phases of the cell cycle and interact with cyclin dependant kinases, which phosphorylate proteins that initiate or regulate cell cycle activity.

75
Q

What is retinoblastoma?

A

A tumour suppressor gene which plays a major role in the g1 to s phase of the cell cycle. Regulate CDKs

76
Q

What is erlotinib?

A

An EGFR targeted TKI

77
Q

What is dysregulation of the G1 to S transition?

A

Cancers exhibit mutations in genes that regulate G1 to S
Retinoblastoma = checkpoint function which stops movement from G1 to S, controls proliferation, loss of function in cancer cells leads to uncontrolled proliferation
Cancer cells don’t produce P16 protein, which inhibits G1 cyclin CDKs which phosphorylate and inactivate RB. Overexpression of Cyclin D in cancer cells.
Target this with CDK4-6 inhibitors

78
Q

Which hallmark do EGFR inhibitors act on?

A

Sustaining proliferative signalling

4th Year Unseen Exam (17 decks)

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