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CMOD-Block 2 Path > Neoplasia 3 > Flashcards

Neoplasia 3 Flashcards

1
Q

How does cancer change over time?

A
  1. They become more aggressive

2. They become Less Responsive to Therapy

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2
Q

T or F: most cancerous cells make the switch from autocrine to paracrine signaling to become less reliant on host signals

A

False, cancer cell usually switch TO AUTOCRINE signaling so that they can get caught in a positive feedback loop and proliferate

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3
Q

What are two common growth factors that cancers secrete to upregulate their own growth?
- what do cells have to change about themselves so that they can do autocrine signaling?

A
  • PDGF (glioblastomas)
  • TGF-alpha (sarcomas)

They either have to:

a. Make/Overexpress a receptor for a molecule they normally secrete (which is usually prevented in cells)
b. They have to produce/Overproduce a molecule that they have a receptor for (usually not allowed either)

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4
Q

As an alternative to autocrine signaling, how do some malignant cells upregulate their own growth?

A

They can Instigate surrounding stromal cells to secrete the factors they need

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5
Q

What are two receptors that cancer cells commonly overexpress to upregulate their own growth?
- what is the benefit of this overexpression

A

EGFR
Her-2

Benefit: They become hypersensitive to growth signals

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6
Q

What are some downstream signaling proteins that cancers often upregulate or alter the activity of to upregulate transcription?

A

Ras

ABL

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7
Q

In Common Myeloid Leukemia, what is the mutation that leads to the disease state?
- ***What is the normal function of the gene product?

A

Common Myeloid Leukemia = Philadelphia Chromosome created by BCR-ABL fusion via balance translocation t(9,22)

**Normal Gene Produce = ABL -TYROSINE KINASE this activates everything downstream of Ras

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8
Q

What should you expect if you administer a chemo drug to a patient that is specific to EGFR, but the patient doesn’t response (and you are confident that the EGFR pathway is involved)?

A
  • Mutations Downstream of EGFR often occur
  • When this happens EGFR drugs or drugs that target anything upsteam from EGFR will not work because the mutant protein can still act.

(e.g. Ras and BRAF both lie downstream of EGFR and their activation will lead to a continuation of the same pathway even w/o EGFR)

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9
Q

BRAF is mutated in more that 60% of what cancer type?

A

Melanomas (remember the BRAF V600E mutation is tested to determine eligability for Melanoma drug)

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10
Q

What EGFR inhibiting drug works on Breast cancer?

A

Trastuzimab

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11
Q

What EFGR inhibiting drug works best on lung and colorectal cancer?

A

Cetuximab

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12
Q

A mutation in c-kit typically causes what type of cancer?

- what target-specific drug can we use to treat this cancer?

A

GIST (gastrointestinal stromal cancer)

  • Treat with Imatinib
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13
Q

What protein often incidentally gets up regulated when the cell cycle become dysregulated in cells?

  • **What is a major affect of this?
  • **How might you detect this?
A

MYC upregulation often happens

MYC is believed to be a major factor that helps the cell make the switch to GLYCOLYSIS even in the presence of Oxygen - WARBURG EFFECT

**These cells tend to consume a lot of Glutamate

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14
Q

What is believed to be the physiologic advantage of the Warburg Effect?

A
  • Glycolysis produces many of the metabolites need tor growth
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15
Q

What type of Gene is RB?

- what is the job of its hypophosphorylated form?

A

Tumor Suppressor Gene

Hypophosphorylated is the active form that blocks E2F from mediating transcription so that chromatin can be remodeled

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16
Q

What cells in the body does HPV affect?

A

Basal Epithelial Cells - of the skin, throat, genital Tract and Anus

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17
Q

What are E6/E7?

- what is their function?

A

HPV Proteins that bind RB, p53, and p21 that cut the brakes on the cell and proliferation is allowed

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18
Q

What viruses other than HPV are believed to have proteins that bind to p53 to inhibit its function?

A

EBV and HBV

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19
Q

Why does p53 have such a short half life?

A

MDM2 targets it for destruction

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20
Q

What are the 3 possible outcomes of p53 activation?

- what are the main mediators in each of these events?

A
  1. Quiescence - CDKN/p21 transcriptional upregulation
  2. Senescence - upregulation of p53 and/or Rb as well as CDKIs
  3. Apoptosis - via BAX/BAK
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21
Q

What is the advantage of cancer cells secreting TGF-ß?

A

TGF-ß works in the favor of malignant cells by causing:
1. Autoinduction of VEGF production - this is advantageous for growth

  1. Immunosuppression of T cells - this prevents death and immune surveillance
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22
Q

What cancers should you automatically think of when you hear TGF-ß?

A
  1. Pancreatic (100%)

2. Colon (83%)

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23
Q

What is the significance of E-cadherin?

- what cancers are associated with E-cad defects?

A
  • E-Cadherin - important in maintaining Cell-Cell contact as well as contact inhibition
  • Loss of E-cadherin in a cancer cell line gives is a greater ability for metastasis because it can break away from the pack

**Implicated in Lobular Carcinomas of the Breast

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24
Q

When you do an E-Cadherin Stain, what color should it show up as?

A

Should be brown

  • No brown = No E-Cad = BAD
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25
Q

What mutation causes APC?

  • what does APC mutation lead to?
  • What biochemical explanation underlies this phenotype?
A

APC = Adenomatous Polyposis coli

Mutation leads to Development of polyps on the colon

APC is involved in Degradation of ß-catenin, without APC ß-catenin goes to the nucleus upregulating gene transcription and you get cell overgrowth and proliferation

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26
Q

What is FAP?

  • phenotype?
  • what causes it?
A

FAP = Familial Adenomatous Polyposis Syndrome

  • Causes Hundreds of Polyps to form on the colon
  • 2 hit knockout of the APC gene causes this (1st hit is the inherited germline mutation)
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27
Q

T or F: somatic mutations of APC are responsible for only a small number of sporatic colon cancers

A

False, somatic (non-inherited) mutations in APC account for 70% of colon cancers

28
Q

What are the two general divisions of the apoptotic pathway?

A
  1. Upstream Regulators

2. Downstream Effectors

29
Q

What group of molecules belongs to the 2 groups of upstream effectors in the apoptotic pathway?
- examples of these groups

A
  1. Receptors that Receive extrinsic signals (TNF receptor family, Fas (CD95)
  2. Molecules that interpret intracellular signals like DNA damage (p53)
30
Q

What proteins act as an intersecting point of both the intrinsic and extrinsic apoptotic pathways?

A

BAX/BAK

31
Q

What molecules act to down regulate BAX/BAK?

A

Bcl-2 and Bcl-xL

32
Q

What specific mutation is found in nearly 85% of Follicular B cell lymphomas?

  • how can this mutation help you distinguish from benign tumors?
  • what is the growth rate of these tumor?
  • Explain this ^
A

t(14,18) (q32,q21) = Follicular B cell lymphoma in which Bcl-2 has been inserted into the heavy chain region of the B cell receptor causing overexpression

  • Immunohisochemical staining can be done to differentiate these SLOW GROWING lymphomas from benign tumors
  • Slow Growth may be attributed to Bcl-2 preventing cell death rather than promoting cell growth
33
Q

How can caspases be inhibited?

A

IAPs (inhibitors of Apoptosis)

34
Q

Why does autophagy often become important in the later stages of tumor cells?

A

Metabolites of Autophagy may supply critical building blocks for growth and survival in the nutrient-poor environments that tumor cells inhabit

35
Q

What is the effect of replication in cells that lack telomerase?

A

Shortened Telomeres generated by cell division eventually activate checkpoints leading to senescence and placing a limit on the number of divisions a cell may undergo

36
Q

How do cancer cells use telorerase to become immortal?

A

Cancer cells can endure many double stranded breaks leading to mutated genomes, this is allowed because TELEMORASE is upregulated in these cells and ADD TELOMERES to these fucked up chromosomes

  • Chromosomes evade detection and can persist (AVOID MITOTIC CATASTROPHE)
37
Q

Differentiate between Neoangiogenesis and Vasculogenesis.

A

Neoangiogenesis - new vessels sprout from existing capillaries already in the vicinity

Vasculogenesis - New endothelial cells are recruited from the bone marrow

38
Q

How big can a tumor get without vascularization?

A

1 or 2 mm

**they require oxygen, nutrients, and removal of waste products

39
Q

Describe the cascade that leads to tumor vacularization?

A
  • Von Hippel-Lindau (VHL) Protein under normoxic conditions binds to HIF-1alpha and cause degradation
    a. Under hypoxic conditions von Hippel-Lindau protein lets go of HIF-alpha
    b. HIF-alpha activates the transcription of VEGF
40
Q

What are Germline mutations in VHL associated with?

A
  • HEREDITARY RENAL CANCERS
  • pheochromocytomas
  • hemangiomas of CNS
  • retinal angiomas
  • renal cysts
41
Q

Why do you think that melanomas are so good at acquiring vessels as they grow and metastasize?

A

TIF-1alpha is commonly more upregulated in the skin which is largely hypoxic

*since melanoma is derived from melanocytes in the skin it is already equipped with the appropriate technology

42
Q

***What are the 6 steps of the invasion-metastasis cascade?

A
  1. Local Invasion
  2. Intravasation into blood and Lymph Vessels
  3. Transit Through the Vasculature
  4. Extravasation from the vessels
  5. Formation of Micrometastases
  6. Growth of Micrometastases into macroscopic tumors
43
Q

Why does a tumor emboli need protection while in the bloodstream?
- in what way can it do this?

A

A tumor embolus may coat itself in platelets to evade the immune cells within the bloodsteam

44
Q

How can we may at least somewhat of a prediction as to where a tumor cell will end up?

A

Metastasized cells will most often in end up in places with microenvironments similar to the one that the primary tumor grew in

45
Q

What are the 4 general steps of cancer cell invasion into the ECM?

A
  1. Loosening of Tumor Cells
  2. Local Degradation of the Basement Membrane
  3. Changes in attachment of tumor cells to ECM proteins
  4. Locomotion
46
Q

How does Loosening of Tumor Cells occur in step 1 of ECM invasion?

A
  • E-cadherins holds cells together and have cytoplasmic portions linked to ß-catenins

E-cadherins lose their function by:

  • E-cadherin mutation
  • ß-catenin activation
  • SNAIL or TWIST overexpression
47
Q

How does local degradation of the Basement membrane occur in step 2 of ECM invasion?

A

Tumor cells secrete self made proteolytic enzymes or they induce stromal cells (fibroblasts and inflammatory cells) to do it

*Metalloproteases that cleave type IV collagen are common, VEGF released in this cleavage

48
Q

How does the tumor cell change its attachment to ECM protein in step 3 of ECM invasion?

A

Attaches via Laminin and Fibronectin receptors (however, I’m sure there can be others)

49
Q

How does a tumor cell initiate locomotion in step 4 of ECM invasion?

A

No Idea…cytoskeletal rearrangements??

50
Q

What are SNAIL and TWIST?

- what major process do they play a role in?

A

SNAIL and TWIST work to down regulate E-cadherin function allowing for Loosening of Tumor cells (Step 1 of ECM invasion)

51
Q

What is the major treatment implication of tumor heterogeneity?

A

Many Different mutations exist among the cells in any given tumor so treatment with a drug will only select for tumor cells that are not susceptible

52
Q

Besides cancer, what other collection of rapidly dividing cells switches to glycolysis to live (temporarily)?

A

Cells withing the Embryo

53
Q

T or F: issues in mismatch repair, nucleotide excision repair, and recombination repair are only implied in inherited cancers.

A

False, mismatch repair, nucleotide excision repair, and recombination repair are important in somatic cancers too

54
Q 
Microsatellite instability (MSI) implies a defect in what protein type? 
- in what heritable disease is this seen?
A

**Mutations and mismatch repair genes are implied with this

***Seen in LYNCH SYNDROME (HNPCC) - about 4 mismatch repair genes are messed up in this cancer

55
Q

What are microsatellites?

A

Tandem Repeats of one to six nucleotides found throughout the genome

56
Q

T or F: while highly associated with HPNCC microsatellites are found in a fairly large amounts of other cancers

A

True

57
Q

What 4 genes may be mutated leading to NPNCC aka Lynch Syndrome/

A

MSH2
MSH3
MSH6
PMS2

58
Q

Differentiate the Genomic Effects of Ionizing radiation vs. UV rays?

A

Ionizing Radiation:

  • Chromosome Breakage
  • Translocations
  • Point Mutations etc.

UV:
- Thymidine Dimers

59
Q

What disease results from the inability to fix pyrimidine dimers?

A

Xeroderma Pigmentosum

60
Q

T or F: chemotherapy drugs are indirect carcinogens

A

False, Chemo. Drugs are carcinogens

61
Q

Is Alfatoxin B a direct or indirect carcinogen?

  • where does it come from?
  • what type of cancer is caused?
A

Alfatoxin B:
- Indirect Carcinogen

  • Found on Moldy Grains
  • Hepatocellular Cancers are caused by this (found in poorer countries where people have to each the food whether its moldy or not)
62
Q

What is the phenotype of bloom syndrome?

  • gene locus?
  • Inheritance
A
  • Growth Retardation
  • Chromosomal Instability
  • Predisposition to Leukemias, Lymphomas, etc.
  • Sun induced Erythema
  • Hypo- and Hyper pigmented skin areas

**Autosomal Recessive at 15q26.1

63
Q

What is the Phenotype of Fanconi Anemia?

  • gene locus?
  • Inheritance?
A
  • Growth Retardation with Skeletal defects in RADIUS and THUMB
  • Bone Marrow Failure
  • Skeletal and Kidney malformation
  • Localized Pigment changes

**Autosomal Recessive at Several Loci

64
Q

What is the Phenotype of Ataxia Telangiectasia?

  • gene locus?
  • Inheritance?
A
  • Cerebellar Ataxia
  • Immune Defects
  • Telangiectases of the Conjunctivae
  • Predisposition to Tumors (lymphoma, leukemia)

EXTREME radiation Sensitivity

**Autosomal Recessive

65
Q

Why is it believed that chronic inflammation increases your risk of cancer?

A
  • Lots of cells are dying and getting replaced

- Inflammatory cells like neutrophils are releasing ROS

66
Q

What are some diseases that lead to cancer through chronic inflammatory processes?

A
  • Barrett’s Esophagus
  • Ulcerative Colitis
  • H. Pylori Gastritis
  • Hep B and Hep C
  • Chronic Pancreatitis
  • Hashiomoto’s Thyroiditis
67
Q

What enzyme is often responsible for indirect activation of carcinogens?

A

p450s

CMOD-Block 2 Path (22 decks)

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