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MOD II > TBL 8 - Neoplasia: Principles of tumor Pathobiology and Carcinogenesis > Flashcards

TBL 8 - Neoplasia: Principles of tumor Pathobiology and Carcinogenesis Flashcards

1
Q

Describe a benign tumor.

A

Typically remains localized without destructive invasion or distant spread.

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2
Q

Describe a malignant tumor.

A

Typically invasive by nature and can spread to adjacent organs and/or distant tissues/ sites.

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3
Q

What is the definition of Hallmarks if Cancer?

A

A set of functional capabilities acquired by cells as they make their way from normalcy to neoplastic growth states.

Capabilities that are crucial for their ability to form malignant tumors.

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4
Q

What are proto-oncogenes?

A

Genes that encode normal cellular products involved in cellular growth and repair that, when over-expressed or form activating mutations, are converted to oncogenes.

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5
Q

What are some examples of genes that have point mutations, allowing them to have constitutive activation? (3)

A

K-RAS, EGF receptor, and BRAF

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6
Q

What are some examples of genes that become amplified or have over 2 copies of the coding DNA per cell? (6)

A

HER2, FGF3, MYC, CDK4, EGFR, and RAS

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7
Q

What are some examples of genes that are involved in translocation? (2)

A

BCL-ABL and EWS-FLI1

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8
Q

What are some examples of mechanisms leading to cancer gaining functional independence?

A
  • Point mutations
  • Gene amplification
  • Aberrant over-expression
  • DNA translocation
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9
Q

What happens when EGF (epidermal growth factor) receptor dimerizes?

A

1) Tyrosine phosphorylation
2) Cell proliferation due to HER2 over-expression

HER2: human epidermal growth factor receptor 2

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10
Q

What are some examples of HER-2 directed therapies? (5)

A

Trastuzmab, Lapatinib, Pertuzumab, Neratinib, Afatinib

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11
Q

What is B-Raf?

A

A proto-oncogene that is a downstream signal of RAS.

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12
Q

What would an activating mutation in BRAF cause?

A

Ras-independent activation of MAPK (MEK).

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13
Q

What is an example of a novel BRAF inhibitor?

A

Dabrafenib

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14
Q

What drugs worked better for patients: novel BRAF inhibitors or Ras targeting drugs?

A

Novel BRAF inhibitors

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15
Q

What is the normal function of PTEN?

A

1) Dephosphorylates PIP3 to PIP2
2) Antagonizes PI3K
3) Blocks AKT activation

PI3K: phosphoinositol 3-kinase

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16
Q

How can PTEN be silenced?

A
  • Mutation
  • Promotor hypermethylation
  • Post-translational modification (ubiquitination and methylation)
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17
Q

What are MYC, c-JUN, c-FOS, and REL?

A

Transcriptional proteins

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18
Q

What does the transcriptional protein MYC impact when it undergoes amplification or translocation?

A
  • Cell cycle progression genes like D cyclins
  • Ribosomal RNA and metabolic reprogramming
  • Up-regulation of telomerase and stem cell characteristics
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19
Q

What is NFkB?

A

A family of transcription proteins that have pro-cancer roles.

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20
Q

What do mutations in upstream NFkB effectors cause?

A

Activation of the NFkB pathway and then persistent activation of NFkB.

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21
Q

What is the retroviral oncogene v-Rel a homologue of?

A

It is a homologue of cRel which is one of the subunits if NFkB.

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22
Q

How are BRCA1 and the NFkB pathway connected?

A

Silencing of BRCA1 causes constitutive activation of the NFkB pathway.

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23
Q

What does persistent activation of the NFkB pathway cause?

A
  • Abnormal cell proliferation and differentiation
  • Enhanced metastasis
  • Treatment resistance
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24
Q

What is an important role in cancer for NFkB?

A

Regulating the energy metabolism in cancer cells.

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25
Q

What are some examples of inhibitors of mitogenic signaling pathways? (6)

A

APC, NF1, NF2, PTEN, SMAD2, and SMAD4

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26
Q

What is the role of NF1?

A

It is a negative regulator of Ras.

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27
Q

What is the role of NF2?

A

It is a contact-dependent inhibitor of proliferation.

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28
Q

What is the role of PTEN?

A

Inhibitor to PI3K.

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29
Q

What are some examples of inhibitors of cell cycle progression? (2)

A

RB and CDKN2A

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30
Q

What are some examples of inhibitors of growth of metabolism and angiogenesis? (4)

A

VHL, STK11, SDHB, and SDHD

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31
Q

What are some examples of inhibitors of invasion and metastasis? (1)

A

Cadherin-1

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32
Q

What are some examples of enablers of genome stability? (1)

A

p53

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33
Q

What are some examples of transcription factors that cause cancer when mutated? (2)

A

WTI and MEN-I

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34
Q

What is WTI mutated in?

A

Wilms tumor

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35
Q

What is MEN-I mutated in?

A

Multiple endocrine neoplasia type I

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36
Q

What is the gene product of APC and what is its inhibitory function?

A

Adenomatous polyposis coli protein that is a negative regulator of WNT signaling.

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37
Q

What is the gene product of NF1 and what is its inhibitory function?

A

Neurofibromin-1 is a GTPase activating protein and an inhibitor of RAS/MAPK signaling.

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38
Q

What is the gene product of PTEN and what is its inhibitory function?

A

Phosphatase and tensin homologue that inhibits PI3K/AKT signaling.

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39
Q

What is the gene product of RB and what is its inhibitory function?

A

Retinoblastoma protein that is a negative regulator of the cell cycle (G1/S).

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40
Q

What is the gene product of CDKN2A and what is its inhibitory function?

A
  • p16/INK4a that is a cyclin-dependent kinase inhibitor that augments RB phosphorylation.
  • p14/ARF which is an indirect activator of p53 pathway.
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41
Q

What is the gene product of VHL and what is its inhibitory function?

A

von Hippel-Lindau (VHL) protein that is an inhibitor of hypoxia-induced transcription factors (HIF1alpha)

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42
Q

What is the gene product of TP53 and what is its inhibitory function?

A

p53 protein that causes cell cycle arrest (upregulates p21) and promotes apoptosis.

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43
Q

What are two ways the G1/S checkpoint is bypassed?

A

1) Gain of function mutation/amplification of D cyclins (1, 2, 3) and/or cyclin-dependent kinase (CDK4).

2) Loss of function or hypermethylation in G1/S progression inhibitor (p16/CDKN2A), mutation in TP53 (induces p21/CDKN1A-D), or retinoblastoma gene.

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44
Q

What does HYPOphosphorylation of RB-E2F complex cause?

A

Deployment of anti-DNA replication enzymes leading to cell cycle arrest.

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45
Q

What does HYPERphosphorylation of RB cause?

A

Release of E2F transcription factor from the RB-E2F complex and cell progression to S phase.

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46
Q

What can cause HYPERphosphorylation to RB?

A
  • Mutation in RB or excessive CDK/D cyclin signaling.
  • Oncogenic proteins bind and inactivate Rb
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47
Q

In terms of RB, what do CDK inhibitors cause?

A

HYPOphosphorylated RB and sequestering of E2F.

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48
Q

In terms of p53, what does amplification of MDM2 cause?

A

Deregulation and degradation of p53.

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49
Q

How is p53 normally induced?

A
  • DNA damage and hypoxia through ATM and ATR expression.
  • Excessive oncogenic activation via RAS
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50
Q

What are some of p53’s normal functions?

A
  • Transient cell cycle arrest by increasing the expression of CDKN1A/p21, which inhibits CDK4/D cyclin-dependent progression to S phase (cellular repair).
  • Permanent cell cycle arrest (senescence)
  • p53-induced apoptosis through increased expression of the genes BAX and PUMA.
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51
Q

How do tumors with non-functional p53 stain?

A

Strongly for p53.

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52
Q

Why are tumors with p53 mutations resistant to treatments that induce DNA damage?

A

p53 normally stops cell cycle progression when it detects DNA damage. When p53 is mutated and can no longer function when DNA damage occurs, the cell cycle will continue to progress. Further DNA damage by chemotherapy will be met with non-functional p53 and allow the tumor to continue to grow.

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53
Q

What pathway is APC a component of?

A

WNT pathway

WNT = ligand
frizzled/FRZ = receptors

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54
Q

How does APC function?

A

Holds B-catenin, causing protesosome degradation of B-catenin.

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55
Q

What does WNT activation cause?

A

1) Dissociation of B-catenin from the APC/B-catenin complex.
2) Nuclear translocation
3) B-catenin combines with TCF and functions as a transcription protein
4) Growth of colonic epithelium by increasing MYC, CD1, and others.

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56
Q

What does a mutation in APC cause?

A

Failure of APC to sequester B-catenin, causing constant activation of B-catenin-dependent gene expression and growth.

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57
Q

What is the normal role of E-cadherin?

A

Sequesters B-catenin to the membrane during cellular stress, preventing nuclear translocation.

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58
Q

What is CDKN2A?

A

A tumor suppressor that encodes p16 and p14.

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59
Q

What does p16 do?

A

Blocks CDK4/cyclin-dependent phosphorylation of RB.

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60
Q

What does p14 do?

A

Increases p53 activity by inhibiting MDM2.

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61
Q

Under normal conditions, what does the activation of TGF-B receptor do?

A

Turns on anti-proliferative signaling and inhibition of MYC, cyclins, and CDKs.

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62
Q

Where are mutations impacting TGF-B signaling common?

A

Stomach, colon, and endometrial cancers.

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63
Q

What is PTEN and what does it do?

A

It is a membrane-associated phosphatase tumor suppressor for the PI3K/AKT signaling cascade.

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64
Q

What are some examples of cancers in which PTEN is lost?

A

Epithelial cancers such as breast, thyroid, and endometrial cancers.

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64
Q

What is VHL (von Hippel-Lindau) and what does it do?

A

A tumor suppressor that covalently links ubiquitin to a transcription protein to promote its proteasome degradation.

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65
Q

What is hypoxia-inducible transcription factor 1alpha (HIF1alpha)?

A

A critical protein substrate for VHL.

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66
Q

What happens to HIF1alpha in a hypoxic environment?

A

HIF1alpha escapes the recognition of VHL leading to the increase of VEGF, PDGF, and GLUT1.

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67
Q

What happens to HIF1alpha when VHL is mutated?

A

Loss of function of VHL causes HIF1alpha to escape degradation without the hypoxic condition.

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68
Q

What is the Warburg Effect?

A

Cancer cells have increased glucose uptake and have glycolysis dependence instead of oxidative respiration, despite available O2.

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69
Q

How is high glucose uptake achieved in tumor cells with altered cellular metabolism?

A

Increased glucose transporters and glycolytic enzymes stimulated by active PI3K/AKT signaling and MYC expression.

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70
Q

Why do cancer cells depend on glycolysis?

A

To obtain critical metabolic intermediates for lipid and amino acid synthesis.

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71
Q

How is high glucose uptake diagnosed?

A

PET scan.

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72
Q

How do onco-proteins and tumor suppressors affect the Warburg effect?

A

Onco-proteins such as RAS and MYC contribute to the Warburg effect.

Tumor suppressors such as PTEN, NF1, and p53 oppose it.

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73
Q

What do some cancer cells use when nutrients are low?

A

Autophagy

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74
Q

What happens in cells that have a mutation in isocitrate dehydrogenase (IDH)?

A

1) Accumulation of 2-hydroxyl-glutarate instead of alpha-ketoglutarate
2) Reduced tumor suppressor TET2 expression
3) Upregulation in RAS and abnormal methylation patterns.

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75
Q

What are some examples of pro-apoptotic factors?

A

BAX and BAK

76
Q

What are some examples of “anti-death” factors?

A

BCL2 and BCL-XL

77
Q

What happens for cellular resistance to apoptosis to occur during evasion of cell death?

A
  • Pro-apoptotic factors are silenced.
  • “Anti-death” factors dominate.
  • Activation of survival signals
  • Cellular death resistance
78
Q

What is the mechanism of BCL2 over-expression?

A
  • Anti-apoptotic gene.
  • Gene protein products stabilize the mitochondrial membrane, preventing apoptosis.
  • Increase inhibitors of apoptosis proteins (IAP)
79
Q

What is the mechanism of loss of p53 function, whether TP53 mutation or p53 inactivation?

A

Permits cellular survival despite stress/damage.

80
Q

What is senescence?

A

Terminal mitotic arrest.

81
Q

Do cancer cells become senescent?

A

No. Cancer cells lack senescence mediators such as p53 and INK4A (p16). Compromised checkpoint activity in cancer cells may “bypass” senescence signals and cause mitotic catastrophe.

82
Q

What does telomerase activation have to do with cancer cells?

A

Cancer cells feature telomerase reactivation, extended telomeric length, allowing for limitless replication potential.

83
Q

What does activation of non-homologous end joining cause?

A

Sustained mutation.

84
Q

How do growing tumors supplement their blood supply?

A

Stimulate neoangiogenesis with tumoral changes favoring a pro-angiogenic environment.

85
Q

How do tumors deal with a relative hypoxic environment?

A

Increase hypoxia-reduced factor 1 alpha (HIF1alpha) which increases the release of VEGF and Beta-FGF.

86
Q

How do tumors increase endothelial growth?

A

Tumors secrete IGF-1 and PDGF.

87
Q

How do tumors contribute to neovascularization?

A

Via their microenvironment components such as macrophages, fibroblasts, and ECM.

88
Q

How do tumors inhibit anti-angiogenic molecules?

A

By decreasing the expression or synthesis of them.

89
Q

What is thrombospondin-1?

A

An anti-angiogenic molecule that is normally induced by p53. Its expression is decreased in cells in which p53 is disabled.

90
Q

What is the relationship between tumors and pro-angiogenic molecules?

A

Tumors increase the expression of pro-angiogenic molecules such as VEGF, which is upregulated by RAS, MYC, and MAPK signaling.

91
Q

How do tumors increase the expression of pro-angiogenic growth factors?

A

By increasing their release in a protease-dependent manner.

92
Q

What contributes to increased VEGF expression?

A
  • Epidermal growth factor (EGF)
  • Platelet derived growth factor (PDGF)
  • Oncogenic mutations
93
Q

What is VEGF secreted by?

A

Malignant cells and the surrounding stromal cells.

94
Q

What can be used against VEGF when fighting cancers that over-express it?

A

Antibody targeting alone or in combination with cytotoxic agents.

95
Q

How do tumor cells have the ability to invade and metastasize?

A

Tumor cells loosen/dissociate from each other via alterations in IC adhesion molecules such as E-cadherin.

96
Q

How does the degradation of the basement membrane and interstitial CT allow tumors to invade and metastasize?

A

Proteolytic enzymes (MMPs) act on the basement membrane and interstitial CT MMPs release VEGF that is sequestered by the ECM, and produce ECM cleavage byproducts.

97
Q

What is tumoral migration stimulated by?

A

Pro-metastasis factors.

98
Q

What is a tumor emboli?

A

A clumping of cancer cells.

99
Q

What is tissue-specific colonization of tumor cells?

A

Chemoattraction by tissue cytokines that promotes the colonization of metastatic growths of cells that express the corresponding receptors.

100
Q

What are the results of defective cancer DNA polymerase?

A

Loss of replication fidelity with no proofreading.

101
Q

What mutations predispose cells to DNA breaks and mutations that cause lymphoid neoplasms?

A
  • Activation-induced cytosine deaminase (AID) in B lymphocytes.
  • Expression of RAG1 and RAG2 in both B and T lymphocytes.
102
Q

Define genomic instabilty?

A

Impairment of DNA damage recognition or defective DNA repair that causes persistent genetic damage with an accelerated rate of acquiring additional mutations.

103
Q

What normally happens during mismatch repair mechanisms?

A

Corrects errors during DNA replication that would cause point mutations.

104
Q

List the genes that cause impairment in mismatch repair mechanisms.

A
  • MSH2
  • MLH1
  • MSH6
  • PMS2
105
Q

What happens when mismatch repair mechanisms are impaired?

A

Cells lose their ability to proofread, causing an accumulation of DNA errors, particularly causing microsatellite instability.

106
Q

What is an example of a disease caused by impairment of the mismatch repair mechanism?

A

Hereditary nonpolyposis colon cancer (HNPCC) syndrome (Lynch Syndrome)

107
Q

What is the normal mechanism of nucleotide excision repair?

A

Corrects induced errors during excision of pyrimidine dimers caused by UV radiation.

108
Q

What occurs when the normal nucleotide excision repair mechanism is damaged?

A

Loss-of-function mutations in the involved genes cause an increased risk of skin cancers.

109
Q

What is an example of a disease caused by mutations in nucleotide excision repair?

A

Xeroderma pigmentosum

110
Q

What is the normal mechanism of homologous DNA recombination?

A

Repairs of multiple types of DNA damages including double-stranded DNA breaks and covalent cross-links.

111
Q

Where does loss of function of homologous DNA recombination occur?

A

Helicase

112
Q

What diseases are caused by mutation sin homologous DNA recombination?

A

-Ataxia-telangiectasia mutated (ATM)
- BRCA1 and BRCA2 (familial cancers including breast, ovarian, testicular, stomach, and prostate.

113
Q

How do inflammatory cells modify tumor cells and the local microenvironments to enable many of the hallmarks of cancer?

A
  • Removal of growth suppressor by the inflammatory protease activity.
  • Release of mitogenic (pro-proliferative) signals
  • Anti-apoptotic signals
  • Inducing angiogenesis, invasion, and metastasis
  • Evasion of immune destruction
114
Q

How do M2 macrophages and TGF-beta signals help tumor cells evade immune destruction?

A

They increase Treg activity thereby decreasing the body’s normal immune response to the cancer cells.

115
Q

How do chromosomal translocations activate proto-oncogenes?

A
  • Promoter/enhancer substitution
  • Formation of a fusion gene
116
Q

What is an example of a promoter/enhancer substitution in a chromosomal translocation?

A

Translocation of MYC that is under the control of the constitutively active immunoglobulin heavy chain (IGH).

Seen in Burkitt lymphoma.

117
Q

What is an example of the formation of a fusion gene?

A

Chimeric protein with oncogenic properties as seen in BCR-ABL fusion in chronic myelogenous leukemia and B cell acute lymphoblastic leukemias.

118
Q

What is one way that over-expression of oncogenes occurs?

A

DNA amplification

119
Q

What is the relationship between fusion genes and chimeric proteins?

A

Fusion genes can produce less effective chimeric proteins, which contributes to cancer formation.

120
Q

What is an example of a chimeric protein that contributes to the formation of cancer?

A

BCR-ABL

121
Q

The epigenetic control of gene activity is implemented by changes in:

A
  • Methylation status of DNA
  • Chromatin modifications such as histone acetylation, phosphorylation, and ubiquitination
122
Q

What are the 3 effects of epigenetic reprogramming that deal with methylation?

A

1) Tumor-related hypermethylation of specific CpG islands and coding regions which cause the silencing of previously active genes into a permanent state of inactivation.
2) Changes in methylation od differentially methylated regions can cause a loss of imprinting and reactivation.
3) Hypomethylation of previously silent repetitive DNA sequences causes chromosomal instability, mitotic recombination, chromosomal loss, and aneuploidy.

123
Q

What are the genes that are commonly hypomethylated (unsilenced) during early tumorigenesis?

A
  • Melanoma-associated antigen (MAGE)
  • CDH3
124
Q

What does hypomethylation of MAGE cause?

A

Development of melanoma and colorectal cancer.

125
Q

What does hypomethylation of CDH3 cause?

A

Overexpression of p-cadherin and the promotion of migration and invasion in breast cancer.

126
Q

What are the genes hypermethylated early that play a role in initiation, progression, and metastasis?

A
  • Cadhedin-1 (CDH1)
  • Cadherin-13 (CDH13) promoter
  • MLH1
  • Death associated protein kinase-1 (DAPK1)-TMS
127
Q

What does hypermethylation of CDH1 cause?

A

Promotes invasion and metastasis in gastric cancer.

128
Q

What does hypermethylation of the CDH13 promoter cause?

A

Increased tumorgenesis and metastasis in NSCLC

129
Q

What does hypermethylation of MLH1gene cause?

A

Abnormal DNA repair in gastric cancer.

130
Q

What does hypermethylation of DAPK1-TMS cause?

A

Breast cancer progression.

131
Q
A
132
Q

Where does methyl modification take place and what is it catalyzed by?

A

Takes place at the 5’ end of the CpG dinucleotide of the cytosine ring. It is catalyzed by DNA methyl transferase (DNMT).

133
Q

How does DNA methylation inhibit gene transcription?

A

Either by blocking access of a transcription factor to its binding sites or through recruitment of methylated domain binding-proteins that compete with the transcription proteins for the promoter motifs.

134
Q

During cancer development, where are many genes hypermethylated?

A

At their CpG island-containing promoters.

135
Q

What causes epigenetic silencing during early events of tumorigenesis?

A

Cellular stress such as hypoxia and inflammation.

136
Q

What has demonstrated excellent therapeutic potential for several types of cancer in regards to epigenetic changes?

A

DNMT inhibitors

137
Q

What is the primary event that causes gene silencing and what is the permanent event?

A

Chromatin remodeling because of histone deacetylation and methylation is most likely the primary event in initiating gene silencing, whereas DNA methylation establishes a permanent state of gene inactivation.

138
Q

What positive correlation has been made regarding epigenetic changes in cancer?

A

Between the degree of global hypermethylation and the grade of malignancy in tumors and chromosomal alterations.

139
Q

What can permanently impact the methylation status of DNA?

A

Chemical exposure such as DES and bisphenol-A.

140
Q

Why are tumor microenvoronment (TME) components intriguing targets for novel therapy.

A

They actively participate in tumorigenesis.

141
Q

How do cancer-associated fibroblasts contribute to tumorgenesis?

A

They produce TGF-B, VEGF, PDGF, and matrix metalloproteases.

142
Q

Why is TGF-B important for tumorigenesis?

A

TGF-B contributes to ECM remodeling and promotion of cancer cell proliferation, suppression of immune response, and induction of angiogenesis.

143
Q

During tumorigenesis, what is a high TGF-B concentration associated with?

A

Bad prognosis

144
Q

Why is VEGF important for tumorigenesis?

A

Promotes angiogenesis.

145
Q

Why is PDGF important for tumorigenesis?

A

Promotes tumor metastasis.

146
Q

Why are matrix metalloproteases (MMPs) important for tumorigenesis?

A

They promote invasion and metastasis.

147
Q

Why are cancer-associated macrophages important for tumorigenesis?

A

Cancer causes inflammation that doesn’t heal and the M2 macrophages help suppress the immune system.

148
Q

How do catecholamines contribute to tumorigenesis?

A
  • They activate MDM2 which causes p53 degradation.
  • They increase VEGF, MMP, and STAT signaling.
149
Q

How does GABA signaling contribute to tumorigenesis?

A

Increases breast cancer metastasis and chemoresistance.

150
Q

How do neuropeptides such as PNY contribute to tumorigenesis?

A

Increases cancer growth and angiogenesis.

151
Q

How does tumor denervation of the sensory and parasympathetic fibers contribute to therapeutic effects of tumorigenesis?

A

Causes tumor regression.

152
Q

How do beta-blockers contribute to therapeutic effects of tumorigenesis?

A

Decrease the risk of breast cancer and increase survival in cancer patients.

153
Q

How do selective glutamate receptor antagonists contribute to therapeutic effects of tumorigenesis?

A

Inhibit cancer cell proliferation.

154
Q

How does hypoxia of endothelial cells contribute to tumorigenesis?

A

Increases endothelial EGF and PDGF which increases tumor growth and angiogenesis.

155
Q

How can the ECM contribute to tumorigenesis?

A
  • Promotes migration via integrin receptors.
  • Sequestration of drugs leading to tumor resistance to therapy
  • Promotion of tumor vascularization
  • Sequestration and accumulation of growth factors and cytokines, leading to increased growth and angiogenesis.
156
Q

Define carcinogeneicity.

A

The capacity to unchain the process of cancer development in human and animals under the appropriate conditions.

157
Q

What are examples of factors that increase risk of cancer development?

A
  • Chemical compounds
  • Physical agents
  • Socioeconomic and lifestyle
  • Biological agents
  • Endogenous factors
158
Q

What are the 3 stages of carcinogenesis?

A

1) Initiation
2) Promotion
3) Progression

159
Q

What is the event that kick-starts carcinogenesis?

A

DNA damage

160
Q

Do promoters of tumorigenesis directly interact with the DNA?

A

No

161
Q

What defines a complete carcinogen?

A

Something that participates in both initiation and promotion.

162
Q

What defines a genotoxic carcinogen?

A

Something that is mutagenic, or interacts, either directly or indirectly, with the DNA and changes the nucleic acid structure.

163
Q

What defines a non-genotoxic carcinogen?

A

Something that acts as a promoter which does not interact with the DNA.

164
Q

What type of carcinogen requires activation and what activates it?

A

Indirect-acting carcinogens require activation and are typically activated by cytochrome P450.

165
Q

How do UV rays cause carcinogensis?

A

UVB rays form pyrimidine dimers.

166
Q

What HPV viruses are known human carcinogens?

A

HPV 16 and 18

167
Q

What are the viral oncoproteins used by HPV?

A

E6 and E7

168
Q

How do viral proteins E6 and E7 promote oncogenesis?

A

They dysregulate cell cycle and apoptosis through their action on p53 and inhibition of CDK-inhibitors.

169
Q

What does E7 specifically act on?

A
  • Members of the Rb family to release E2F and increase cell proliferation.
  • Suppresses cellular immune responses.
  • Disrupts the formation and function of mitotic spindles.
170
Q

How does HPV extend the life of infected cells?

A

Activate telomerase.

171
Q

How does Epstein-Barr virus induce oncogenesis?

A
  • Expression of latent genes (LMP1)
  • Expression of EBNA1
  • Expression of EBNA2
172
Q

What does LMP1 activation do?

A
  • Activates Her2/Her3 signaling
  • Activates NFkB, c-JUN, and p38 pathway which increases telomerase and cell migration
  • Inhibits pro-apoptotic signaling
  • Induces anchorage-independent growth
  • Increases angiogenesis
  • Impacts histone deacetylation.
173
Q

What does EBNA1 expression do?

A
  • Upregulates STAT
  • Upregulates AP-1
  • Downregulates TGF-B
  • Increases reactive oxygen species accumulation leading to DNA damage
174
Q

What does EBNA2 expression do?

A

Indirectly activates MYC.

175
Q

How does EBV affect DNA methylation?

A

Causes aberrant DNA methylation of tumor suppressors and inhibits demethylation pathways.

176
Q

What oncoprotein does human herpes simplex virus-8 express?

A

KSHV

177
Q

What does KSHV do?

A

Activates V-cyclin which expresses V-interferon regulating factor (V-IRF) causing latency associated nuclear antigen (LANA) and increased proliferation and survival of the host cell, leading to malignancy.

178
Q

How does human T lymphocytic virus cause malignancy?

A

HTLV-1 reverse transcription incorporates itself into dsDNA in the host genome causing chromosomal instability and expression of the TAX protein (p40^tax).

179
Q

What does TAX protein do?

A
  • Causes cell growth and angiogenesis
  • Causes inhibition of apoptosis
180
Q

How does Hep B cause malignancy?

A

Integration of the HBV viral DNA into the host genome causes chromosomal instability (CIN), insertional mutagenesis, and cis-activation of tumor-associated genes.

181
Q

Does Hep C virus integrate itself into the host DNA?

A

No

182
Q

What structures of Hep B and Hep C directly cause hepatocellular carcinoma?

A

Hep B-encoded antigen (HBx) and Hep C-encoded core, nonstructural proteins 5A and NS3.

183
Q

What is disrupted by Hep B and Hep C viruses?

A

Methyltransferase activity.

184
Q

How does H. pylori cause malignancy?

A
  • Produces ammonia leading to epithelium toxicity and chronic inflammation.
  • Secretion of VacA causes inhibition of T cell activation.
185
Q

How does Fusobacterium nucleatum cause malignancy?

A
  • Increases the risk of colorectal cancer by invasion and activation of proinflammatory cytokines.
  • Has the virulence factor Fap2 which causes inhibition of T lymphocyte activation.
186
Q

How does Schistosoma haematobium cause malignancy?

A

Eggs in the bladder induce granulomatous T helpers leading to chronic inflammation and DNA breaks and cause over-expression of FGF receptor 3.

187
Q

What protein induces urothelial proliferation and hyperplasia caused by Schistosoma haematobium?

A

H03-H-IPSE

188
Q

How does Aspergillus spp. cause malignancy?

A

Secretes aflatoxins (AFB1) which forms DNA adducts causing the formation of G-> T, G-> A, and G->C mutagenesis and single nucleotide deletions in p53.

MOD II (8 decks)

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