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SPM > Week 7 > Flashcards

Week 7 Flashcards

1
Q

What are the two types of epithelial cancers and what kind of cells do they arise from?

A
  • Adenocarcinoma – arise from specialized cells in epithelial tissue that secrete substances into ducts or cavities
  • Squamous cell carcinomas – arise from epithelial cells in epithelial tissue forming protective cell layers
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2
Q

What is the difference between normal cells and cancer cells in how they exhibit contact inhibition?

A
  • Normal cells exhibit contact inhibition of division and movement at confluence compared to cancer cells
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3
Q

What are the Six Essential alterations that can lead to cancer?

A
  1. Self-sufficiency in growth signals
  2. Insensitivity to anti-growth signals
  3. Evasion of apoptosis
  4. Limitless replicative potential
  5. Tissue invasion and metastasis
  6. Sustained angiogenesis
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4
Q

What are the 5 proteins involved with proto-oncogenes and controlling cell growth?

A
  1. Growth factors
  2. Growth factor receptors
  3. Intracellular transducers
  4. Nuclear transcription factors
  5. Pro- or anti-apoptosis proteins
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5
Q

What are the 3 proteins involved with tumor-suppresors?

A
  • Cell cycle control proteins
  • DNA repair proteins
  • Pro- or anti-apoptosis proteins
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6
Q

In proto-oncogenes, what occurs to the function and what is the inheritance pattern usually?

A
  • Two main characteristics of proto-oncogenes
    • Gain of function
    • Dominant (need one mutated allele)
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7
Q

In tumor-suppressor, what occurs to the function and what is the inheritance pattern usually?

A
  • Two main characteristics of tumor-suppressor
    • Recessive (need two mutated alleles)
    • Loss of function
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8
Q

What experiment laid the importance of oncogenic viruses as a genetic paradigm for cancer?

A
  • Experiment by Payton Rous with Rous Sarcoma Virus (RSV)
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9
Q

How was the experiment by Payton Rous with Rous Sarcoma Virus (RSV) conducted?

  • What was the impact and the conclusion?
A
  • Extracted sarcoma from chicken 1 → injected into chicken 2 → chicken 2 develops sarcoma
  • Impact: defines system for cancer research
  • Later found that cancer is derived from our own genome
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10
Q

Compare and contrast a typical RNA virus with a Rous Sarcoma Virus.

A
  • RNA Viruses
    • Typical RNA Virus: includes genes for core proteins, reverse transcriptase, and envelope proteins → no cancer
    • Rous Sarcoma Virus: includes typical RNA virus genes + src gene which causes cell transformation → cancer
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11
Q

What are the three differences between proto-oncogenes and oncogenes?

A
  • Critical difference between proto-oncogenes and oncogenes
    • Expression at inappropriate time in cell cycle (fos)
    • Constitutive activity (abl)
    • Failure to productively interact with negative regulator (ras)
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12
Q

What are the three mutational routes to the genesis of an oncogene?

A
  1. Deletion or point mutation: hyperactive protein made in normal amounts
  2. Gene amplification: protein overproduced
  3. Chromosome rearrangement: regulatory sequences rearrangned by fusion
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13
Q

What is an example of the deletion or point mutational route to the genesis of an oncogene?

A

Excessive Ras Activation (important in cell proliferation)

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14
Q

What is the normal pathway of Ras Activation?

A
  • Normal: growth exchange factor (GEF) binds Ras-GDP → exchange of GDP for GTP → Ras-GTP is active → GAP binds Ras-GTP → GAP hydrolyzes Ras-GTP → Ras-GDP is inactive
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15
Q

What is the pathway that Ras takes leading to cancer (compared to the normal)?

A
  • Cancer: Ras is unresponsive to GAP and cannot hydrolyze GTP, leaving Ras in active form
  • Normal: growth exchange factor (GEF) binds Ras-GDP → exchange of GDP for GTP → Ras-GTP is active → GAP binds Ras-GTP → GAP hydrolyzes Ras-GTP → Ras-GDP is inactive
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16
Q

What is an example of the gene amplification to the genesis of an oncogene?

A
  • Her2/neu overexpression leads to breast cancer
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17
Q

What are two examples of chromosomal rearrangement to the genesis of an oncogene and how do they occur?

A
  • Burkitt’s Lymphoma – t(8,14)
    • Results in fusion of c-myc (transcription factor) to immunoglobin gene → overexpression
  • Chronic myelogenous leukemia – t(9,22)
    • Results in fusion of abl (tyrosine kinase gene) and bcr genes → constitutively active tyrosine kinase
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18
Q

How does oncogene collaboration occur?

A
  • Protein components of cytoplasmic mitogen signaling pathways combine with cell cycle control proteins in the nucleus
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19
Q

What is the classical and non-classical presentation of the recessive inheritance of tumor supressor genes in familial cancer syndrome?

A
  • Recessive
    • Classic: presence of one WT allele prevents tumor
    • Non-classic: haploinsufficiency – only one allele needs mutation for tumor development
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20
Q

What effect does germ line inheritance have on tumor supressor mutations?

A
  • Germ-line inheritance (familial) increases susceptibility to somatic loss of second allele
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21
Q

Compare and contrast familial vs sporadic mutations.

A
  • Familial: inherited germline mutation + somatic mutation
  • Sporadic: two somatic mutations (two-hit hypothesis)
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22
Q

What are the six mechanisms that may lead to loss of hetrozygosity?

A
  • Six ways of eliminating one allele
    • Nondisjunction (chromosome loss)
    • Nondisjunction and duplication
    • Mitotic recombination
    • Gene conversion
    • Deletion
    • Point mutation
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23
Q

How can the disruption of apoptosis regulators lead to cancer?

  • Discuss this in terms of anti-apoptosis and prop-apoptosis.
  • Give examples of families of proteins related to each.
A
  • Disruption of apoptosis regulators in cancer
    • Anti-apoptosis: upregulation of these proteins leads to cancer
      • Bcl2 family of proteins
    • Pro-apoptosis: down regulation of these proteins leads to cancer
      • Bax family of proteins
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24
Q

Compare and contrast extrinisic vs intrinsic apoptotic pathways.

  • Where do they both converge?
A
  • Extrinsic: activation of death receptors → caspases pathway
  • Intrinsic: directly activates caspases
  • Both converge at mitochondria on caspase3 and release of cytochrome C from mitochondria → death
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25
Q

Explain the checkpoints in the cell cycle and the importance of having these checkpoints.

A
  • Importance: keeps the cell from moving too quickly through growth and division
  • G1 checkpoint: environment favorable for S phase
    • Restriction point – point at which cell commits to cell cycle
  • G2 checkpoint: all the DNA properly replicated to enter mitosis
  • Metaphase checkpoint: all chromosomes attached to spindle
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26
Q

What are two main regulators of the cell cycle and what are their pathways?

A
  • RTK activates Ras-GTP → → activates cyclin dependent kinases → phosphorylate Rb → allows for cell proliferation
  • P53 activates p21 → p21 deactivates cyclin
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27
Q

What is the physiology of a normal RTK (receptor tyrosine kinase) and a mutated RTK (two examples)?

A
  • Normal RTK: ligand-dependent firing/dimerization
    • Deactivation of RTK occurs through endocytosis
  • Mutated RTK
    • Signal point mutations or deletions in the tyrosine kinase receptor can cause ligand-independent firing/dimerization
    • Autocrine Signaling: through activation of GF gene, cells can self-produce ligand for RTK
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28
Q

Why is Ras important and what are its main three functions?

A
  • Ras proteins lies at the center of a network of interacting pathways and has influence in a large number of downstream processes
    • Promotes cell proliferation
    • Promotes cell differentiation
    • Contributes to differentiated cell functions
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29
Q

What is the role of GEF and GAP in Ras pathways?

A
  • GEF or GAP can be affected by multiple distinct upstream signals that allow them to act on Ras through multiple pathways
    • Different cell types use different combinations of pathways to regulate Ras
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30
Q

What is the Ras activation pathway? (Its huge and detailed)

A
  • Ligand binds to one subunit of Receptor Tyrosine Kinase (RTK) → cross-phosphorylation of RTK dimer at cytoplasmic tyrosines → SH2 domains on proteins bind to phosphotyrosine depending on the 3 AA residues after Y → recruits SOS → SOS complex acts on Ras-GDP to replace with Ras-GTP → Ras-GTP binds signaling partners → activates kinases → activate TFs → transcription
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31
Q

How does the loss of RB1 or the intervention of CKIs cause cells to proliferate?

A
  • RB1 controls the cell cycle at various checkpoints
  • Cyclin-dependent kinase inhibitors (CKIs such as p21) inhibit cyclin-dependent kinases (CDKs) → if CKIs have mutations, the RB pathway is disrupted → cancer
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32
Q

How does RB function in relation to E2F, p21, p53, and Cyc/CDK4?

A
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33
Q

What are the two main functions of p53?

A
  • Two functions of p53
    • Activates transcription of p21: stops cell cycle and allows for DNA repair
    • Activates expression of pro-apoptotic proteins (Bax)
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34
Q

What is an inhibitor of p53 and what does it result in?

A
  • Inhibitors of p53
    • MDM2 – binding to p53 leads to degradation and downregulation of transcription
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35
Q

What are the three consequneces of p53 mutation or loss?

A
  • Cell loses ability to produce CKIs that inhibit CDKs and block the cell cycle to allow for DNA repair
  • Cell loses ability to undergo apoptosis and die
  • Loss of p53 increases genomic instability – increase in accumulation of additional mutations due to lack of repair mechanisms
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36
Q

Does tumorigenesis require one route or multiple routes?

A
  • Multiple routes of acquire hallmark capabilities to the same endpoint: cancer
    • Does not occur in specific order
    • Mutations increase in age
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37
Q

Describe the fundamental pathway of colon cancer as an example of a cancer that takes multiple pathways to produce tumors.

A
  • Colon cancer: Beta-catenin (APC) → Ras Pathway → TGF-beta → p53
    • Each step has different genetic paths that end in colon cancer
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38
Q

What does the rate of tumor progression depend on (4 things)?

A
  • Cell number
  • Rate of cell division
  • Mutation rate (genomic instability)
  • Selective advantage of a particular mutation
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39
Q

What is “the genetic control of tumor progression” referring to?

A
  • specific mutations or deletions in DNA sequence
40
Q

What are three ways to control tumor progression epigenetically?

A
  • Promoter methylation
  • Histone modifications
  • miRNAs
41
Q

What is the fundamental basis of clonal evolution in tumor cells?

A
  • One cell sustains initial mutation → proliferates based on survival advantage → further mutations sustained → cancer
42
Q

Why are mutations not equal?

A

some mutations (i.e. p53) cause greater genomic instability, allowing for accumulation of mutations

43
Q

Define microsatellites and what dysfunction of them can cause?

A
  • Microsatellites: repeats of the same base in sequence typically found in non-translated (but they are transcribed!) regions that can be mis-copied by DNA polymerases and can affect gene expression (especially in MMR genes)
44
Q

What is Lynch Syndrome and how does it occur?

A
  • Lynch Syndrome: germline mutations in DNA mismatch repair (MMR) genes MSH2 and MLH1 → mutations accumulate → cancer at a younger age
45
Q

Why do steps in progression ≠ number of mutated genes?

A

different mutations may take several steps (two-hit hypothesis in tumor suppressor genes)

46
Q

What is meant by tumor heterogeneity?

A
  • Any two tumors show very little overlap in mutation profile but common pathways are implicated
  • Small fraction of mutations act as “driver” mutations in causing cancer
    • Others are “passenger” mutations
47
Q

Explain how driver mutations are passed down in generations of cancer producing cells?

A
  • Mutations that develop in a generation 1 stem cells are passed on to generation 1 of transit-amplifying cells
  • Driver mutations can only be passed on through stem cell generations and not transit-amplifying cell lines
48
Q

Does cancer therapy target stem cells or transit-amplifying cells?

A
  • Cancer therapy targets transit-amplifying cells, therefore allowing for metastasis of dormant mutated-stem cells
49
Q

Describe the example of Her2/Neu in resistance to therapy. What drug is involved initially and what drug is involved to circumvent the resistance?

A
  • Her2/Neu example of mutations that drive resistance to therapy
    • Trastuzumab can bind to Her2/Neu Receptor, signaling for immune response
      • Mutation in receptor leads to insensitivity to drug, requiring new treatment
    • Lapatinib is a 2nd generation Her2/Neu drug, but acts intracellularly on the receptor, tagging it for degradation
50
Q

What is the “Gleevac” example of mutations that drive resistance to therapy?

A
  • Minor populations of cells containing total resistance mutations in Bcr-Abl gene before treatment can grow up as new population in tumor
  • Overexpression of BCR-ABL leads to resistance
51
Q

How does the cancer immunity cycle work?

A
  • Tumor cell death → antigen acquisition by immune cells → T cell priming → T cell trafficking → T cell infiltration → tumor cell killing
52
Q

How do cancer therapies target cancer immunity cycles (in combination with regular therapeutic targets in cancer)?

A
  • Cancer therapies (in combination with regular therapeutic targets in cancer)
    • Enhance T-cell priming
    • Enhance T-cell activation
53
Q

If p53 is deactivated, what cancer therapy can be performed?

A
  • Reactivation of mutant p53 by antagonizing MDM2 → avoids degradation of p53
54
Q

How does the angiogenic switch in tumor cells occur allowing for metastasis?

A
  • Tumor cells become hypoxic → express HIF-1alpha → transcription of VEGF and PDGF → proliferation/migration and increase in “more permeable” tumor vasculature network
  • This permeable vasculature allows for tumor invasion and expansion (read: metastasis)
55
Q

What are some physiological regulators of the angiogenic switch (inhibitors and activators)?

A
  • Physiological regulators
    • Inhibitors such as angiostatin, endostatin, thrombospondin-1, turn-off the angiogenic switch
    • Activators such as VEGF turn on the angiogenic switch
56
Q

What do anti-angiogenic therapies target to prevent metastasis? What charactersitic ensures that normal cells are not affected?

A
  • Anti-angiogenic therapies target tumor associated endothelial cells to prevent metastasis
  • These cells are targeted because they are short lived, when compared to normal endothelial cells
  • No genetic changes between normal cells and tumor associated cells
57
Q

Define metastasis in general terms.

A
  • Metastasis – formation of primary tumor at secondary site
58
Q

What are the steps in the formation of metastases (in depth)?

A
  • Primary tumor formation → angiogenesis due to hypoxic conditions → permeable tumor vasculature → EMT → intravasation (enters blood) → transport through blood → arrest in microvessels → extravasation (leaves blood) → formation of micrometastasis site → dormant or colonization to create primary tumor at secondary location
59
Q

How does EMT occur?

A
  • Normal endothelial and tumor cells express e-cadherin → acts as cell-cell junction protein with tumor cells and binds beta-catenin intracellularly → e-cadherin repression → loss of cell-cell adhesion properties → tumor cell enters blood stream → beta-catenin is released → beta-catenin acts as TF (dangerous in the tumor cell)
60
Q

What is the reverse process of EMT and when is it used?

A
  • MET is the reverse process once the tumor cell lodges at secondary site
    • Secondary tissue lacks signals to induce EMT, so reverts to MET
61
Q

What are some examples of where metastasis first occurs in:

  • colorectal cancer
  • liver cancer
  • breast cancer
A
  • Metastases often arrest at the first capillary bed they encounter after leaving a tissue
    • Colorectal cancers use hepatic vein → liver
    • Liver cancers → lung
    • Breast cancers drain into lymph nodes → bone
      • Release of PTH; act like mammary gland
62
Q

What is sentinel node biopsy used for?

A
  • Sentinel node biopsy is an important marker of metastasis in cancers draining into lymph nodes
63
Q

Describe Paget’s “seed and soid” hypothesis in general terms.

  • What does it fail to explain?
A
  • Paget’s “seed and soil” hypothesis: metastasizing cancer cells (the seed) find a compatible home only in certain especially hospitable tissues (soil)
    • Does not explain the rarity of contralateral tumors
64
Q

How can genetic analysis predict disease progression?

A
  • In different stages of cancer progression, there are varying expression levels of specific genes. These expression levels create an “expression signature”. The signature between primary tumors and metastatic tumors differ and can be used to identity level of cancer progression.
  • Elevated expression patterns can even predict the tissue site of the metastases.
65
Q

What is genomic instability?

A

Genomic instability: is the natural tendency of genomes to undergo alterations under physiological conditions

66
Q

How does genomic instability occur?

A
  • Cellular metabolism (ROS) and environmental factors (UV light, smoke) → chemical damage → DNA damage response → DNA repair
    • If correct repair → normal cell
    • If incorrect repair → mutations/alterations of DNA sequence → cancer
    • Or can signal for apoptosis, aging
67
Q

Define DNA damage.

A

DNA damage: modifications to the normal chemical structure of DNA

Mismatch of base sequence

68
Q

Define DNA mutations.

NAME some examples.

TYPES of bases subsitution mutations.

TYPES of frameshift mutations.

A
  • DNA mutations: changes in the DNA sequence (occurs when DNA polymerase makes a mistake and fails to catch it)
    • Base substitution mutations
      • Nonsense mutation: premature stop codon
      • Missense mutation: creates codon for different AA
        • Sickle cell disease
      • Silent mutation: creates codon for same AA
    • Frameshift mutations
      • Insertion or deletion of nucleotides to change AAs
69
Q

List the sources of endogenous DNA damage

A

Water, Oxygen, Alkylation damage

70
Q

What are the mechanisms (2) of WATER based endogenous damage?

A

Depurination: water attacks guanine, creating abasic site

Deamination: water attacks cytosine, creating uracil

71
Q

What are the mechanisms of Oxygen based endogenous damage?

A

ROS attacks guanine to form 8-oxoguanine → pairs with A on opposite strand → A pairs with T at replication, eliminating G on original strand

72
Q

What are the mechanisms of ALKYLATION based endogenous damage?

A

Adds CnHn+2 group to bases

SAM and nitroso compounds (NOC) alkylate all DNA bases

73
Q

What are the mechanisms of UV based exogenous damage?

A
  • UV light → creates cross-linking between adjacent pyrimidines → base mispair during DNA replication → requires nucleotide-excision repair
  • UVB light cause DNA damage (cross links)
  • UVA causes oxidative stress (leading to endogenous damage)
74
Q

What are the mechanisms of X-RAY based exogenous damage?

A
  • X-rays → causes ss breaks → requires base excision repair (BER)
75
Q

What are the mechanisms of CHEMICAL based exogenous damage?

A
  • Chemical agents → creates bulky adducts → requires AGT/MGMT Direct Reversal Pathway
    • Benzo(a)pyrine from cigarette smoke gets metabolized in the body → BPDE (diol epoxide form) → guanine adduct → causes G:C to T:A transversion mutations
76
Q

What are the mechanisms of ALKYALTION based exogenous damage?

A
  • Alkylating agents: nitroso compounds (NOCs) come from cigarette smoke, exhaust, etc. → interstrand bulky ducts with guanine
  • Cisplatin binds to guanine in DNA to form bulky monoadduct
77
Q

Explain the roles of DNA damaging carcinogens and their metabolism in multi-stage carcinogenesis.

A

DNA damaging carcinogens, unless removed from the body, can result in base modifications and thus base mispair and mutagenesis

Direct carcinogens can directly damage the DNA, while indirect carcinogens need to first be activated by the cellular metabolism

Several rounds of mutations need to occur for a malignant tumor to form

78
Q

What is the general mechanism of DNA repair?

A
  1. Damage recognition by sensor proteins
  2. Recruitment of DNA repair enzymes
  3. Removal of damaged DNA by nucleases and glycosylases
  4. Restoration of original sequence by DNA polymerases and ligases
79
Q

What is Direct Repair?

2 Pathways.

A
  • Direct Repair (DR)
    • Alkylated bases (O6G) → unalkylated bases via AGT/MGMT
      • Not an enzyme because it must be degraded after one use
    • Methylated bases → unmethylated bases via ALKB family
80
Q

Why is Temozolamide usedto treat cancer?

A
  • Temozolamide (TMZ) is an alkylating agent that triggers glioblastoma cells for death
  • O6-benzylguanine is administered in conjunction with TMZ to inhibit MGMT
81
Q

What does Base Excision Repair used on?

A

Works on ss breaks and small endogenous lesions (oxidation, alkylation, deamination)

82
Q

What are the steps of Base Excision Repair?

A
  1. DNA glycosylase identifies and excises damaged base → abasic site
  2. An endonuclease creates nick in strand
  3. dRpase removes ribose
  4. DNA polymerase inserts correct nucleotide
  5. DNA ligase seals nick on strand
83
Q

What does a nonfunctional MYH result in?

Why?

A
  • MYH – a DNA glycosylase for 8-oxoG
    • Cells with mutated MYH show increased G to T mutations in original strand
    • G to T mutations in APC gene → familial adenomatous colon polyposis (FAP)
84
Q

What does Nucleotide Excision Repair act on?

What are the two types?

A

Repair bulky adducts

  1. Global Genome Repair
  2. Transcription Coupled Repair
85
Q

What are the steps of Global Genome Repair (GGR)?

A
  1. XPE or XPC binds NER lesions
  2. Recruits XPA, which recruits helicase TFIIH
  3. TFIIH unwinds DNA strand
  4. XPG and XPF are endonucleases that cut each side of lesion
  5. DNA Polymerase and DNA Ligase fills and seals gap
86
Q

What are the steps of Steps of Transcription Coupled Repair (TCR)?

A
  1. Bulky adduct stalls RNA polymerase
  2. CSA and CSB binds to stalled polymerase and recruits XPA
  3. TFIIH unwinds DNA strand
  4. XPG and XPF are endonucleases that cut each side of lesion
  5. DNA Polymerase and DNA Ligase fills and seals gap
87
Q

What is the mechanims behind Xeroderma Pigmentosum?

A

Caused by autosomal recessive mutations in NER genes → increased mutations due to UV exposure

88
Q

What is the mechanims behind Cockayne’s Syndrome?

A
  • Mutations in CSA and CSB → defect in TCR pathway → unable to bind to stalled polymerase → premature aging with no increased risk for cancer
89
Q

What are the steps in Mismatch Repair (MMR)?

A
  1. Mismatches and single displaced bases are recognized by hMutS-alpha. Larger insertions and deletions are recognized by hMutS-beta
  2. Mut S recruits MutL, which recognizes the template strand based on the methyl groups or ss breaks on newly synthesized DNA
  3. MutH also attaches to form a Mut-complex and creates a kink in the DNA.
  4. Mut-complex then directs exonucleases to nick in daughter strand
  5. DNA polymerase and ligase fill the strand and seal the nick.
90
Q

What is the mechanims behind Lynch Syndrome?

A
  • Loss of heterozygosity in mismatch repair gene → deficient MMR function → no way to replace mismatched base pairs → predisposed for cancer
  • Show increased degree of microsatellite instability
91
Q

What are the two types of Double Strand Break Repair (DSBR)?

A

HR

NHEJ

92
Q

When does HR (homologous recombination) occur?

Error rate?

A

Occurs in S-phase and G2 phase

Error-free because it uses sister chromatid as template

93
Q

When does NHEJ (non-homologous end joining) occur?

Error rate?

A

Occurs in G1 phase

Error-prone because it has no template to work from

94
Q

Steps in HR (homologous recombination)?

A
  1. BRCA1 does 5’-3’ resection (creates sticky ends)
  2. BRCA2 attaches to sticky ends and recruits Rad51
  3. Rad51 mediates strand invasion into homologous chromatid
  4. Formation of Holliday Junction
  5. Branched migration via RNA polymerase
  6. Two strands form
95
Q

Steps in NHEJ (non-homologous end joining)?

A
  1. Ku70/80 binds DSBs and recruits DNA-PK kinase
  2. DNA-PK activates Artemis exo- and endonucleases which trim sticky ends
  3. DNA Polymerase and DNA Ligase combines strands
96
Q

What happens if a mutation in BRCA2 occurs?

A
  • Mutations in BRCA2 (tumor suppressor gene)
  • In the absence of active BRCA2, HR is defective and other, more error-prone pathways such as NHEJ take over, leading to mutations, genomic instability and transformation
97
Q

Explain the PARP inhibitor mechanim.

A

Normal PARP1: repairs SSBs

PARP inhibition causes accumulation of SSBs → cause DSBs because no BRCA2 to repair via HR → apoptosis

PARP inhibitors do not affect normal cells because they have BRCA2 and functioning HR pathway

SPM (17 decks)

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