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MCB132 > LECTURE 2 + 3: Experimental Approaches to Cancer > Flashcards

LECTURE 2 + 3: Experimental Approaches to Cancer Flashcards

1
Q

slides i haven’t finished

A

3.7, 3.30, 4.5

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2
Q

Hallmarks of cancer importance

A

cancer isn’t a single disease
collection of diseases w similar characteristics
unification factors
enable therapeutic treatment

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3
Q

Tumours by tissue of origin:
blood cells (B, T, myeloid…)

A

hematopoietic

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4
Q

Tumours by tissue of origin:
epithelial cells (lung, breast…)

A

carcinoma

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5
Q

Tumours by tissue of origin:
connective tissues (muscle, bone…)

A

sarcoma

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6
Q

Tumours by tissue of origin:
nervous system (glio-, retino-blastomas…)

A

Neuroectodermal

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7
Q

Tumours by tissue of origin:
small cell lung cancer, melanoma

A

Non-neuroectodermal

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8
Q

Cancer tumors are divided into ____ and ______ tumors

A

liquid, solid

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9
Q

Totally liquid tumors

A

Leukemia

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10
Q

What is leukemia?

A

excessive proliferation of circulating cells
usually white blood cells (leukocytes)
totally liquid

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11
Q

Semi-solid/liquid tumors

A

Lymphoma

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12
Q

What is lymphoma?

A

elevated numbers of lymphocytes in the peripheral blood
also present as solid masses in lymph
nodes (often multi-focal)

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13
Q

Solid tumors

A

Lumps - localized cell proliferation
Found/associated with a multicellular organ
Spread around the body by metastasis

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14
Q

Why are leukemias and solid tumours treated differently?

A

Leukemias can’t be surgically removed
Etiology of the cancers is different

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15
Q

Most prevalent & deadly cancer

A

carcinomas (cancers of the epithelium)

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16
Q

Leading sites of new cancer and deaths (male)

A

Prostate, lung & bronchus, urinary bladder, colon & rectum, pancreas (deaths)

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17
Q

Leading sites of new cancer and deaths (female)

A

breast, lung & bronchus, uterine corpus, colon & rectum, pancreas (deaths)

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18
Q

basement membrane

A

cell-free matrix between epithelial cells and connective tissue

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19
Q

malignant cancer

A

disruption of the basement membrane

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20
Q

degrees of malignancy

A

normal -> hyperplasia -> dysplasia -> cancer
cancer only when it breaks past the basement membrane

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21
Q

malignant growth

A
  • break past the basement membrane
  • invade adjacent tissue
  • enter blood and lymph
  • metastasis
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22
Q

Approaches to Studying Cancer

A

Observational (Human/Patient)
- epidemiological
- genomic
- clinical

Experimental (hypothesis driven)
- carcinogens
- tissue culture assays
- mouse cancer models

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23
Q

Approaches to Studying Cancer: Epidemiology

what are the different ways we study it?

A
  1. Age incidence curves
  2. Cancer risk factors
  3. Incidence in different populations
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24
Q

Approaches to Studying Cancer: Epidemiology - Age incidence curves

what do you learn from the curves?

A
  • cancer risk increases with age (curve steeper with age)
  • cancer results from multiple events that accumulate over your life (at least 5-6 independent random events)
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25
Q

Why is cancer not subject to forces of evolutionary selection?

A

Post-reproductive age disease

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26
Q

Approaches to Studying Cancer: Epidemiology - Risk Factors

what are the top risk factors?

A

Tobacco use&raquo_space;>obesity»pathogens
»» physical inactivity, diet > alcohol > reproductive factors > UV light > environmental pollutants

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27
Q

Cigarettes and lung cancer

A
  • lots of smoking after WW1, WW2
  • 30-35 year lag
  • lung cancer rates peak in 1990 in the US
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28
Q

Approaches to Studying Cancer: Incidence in different populations

genetic vs environmental factors

A

environmental factors outweigh genetic factors for most cancers

eg. incidence of prostate (10x) , breast (10x) and stomach (5x) in Hawaiian-Japanese immigrants adopt rates of Hawaiians, not Japanese

29
Q

Approaches to Studying Cancer: Genomic Studies

what is the goal of the genomic studies

A

survey the entire genome for transcriptional changes and changes at the DNA level (point mutations, insertions, deletions)

30
Q

no of base pairs in human genome

A

3 billion

31
Q

cancer genome sequencing allows us to identify

A

MIRA
mutations
insertions/deletions
rearrangements
amplifications

32
Q

next gen sequencing technology

A

explain what it is

33
Q

challenges of genomic studies

A

tumor heterogeneity
1. mixture of cell types (immune cells, fibroblasts, endothelial cells, neoplastic cells)
2. diversity of neoplastic cells (clones)

34
Q

solution to tumor heterogeneity

A

single cell analysis

35
Q

Approaches to Studying Cancer:
Clinical Studies

phases

A

Phase 1: SAFETY
- small groups, 50
- how the agent affects the body
- safe dosage

Phase 2: EFFECTIVENESS
- medium group, 200
- is the agent effective against the disease

Phase 3: BETTER THAN STANDARD
- large group, 2000
- randomized trial

36
Q

Pharmacokinetics (PK)

A

Time course of drug concentration in body, usually monitored in blood

37
Q

Pharmacodynamics (PD)

A

Time course of activity of drug in target tissue, e.g. cancer

38
Q

Therapeutic Index

A

Dose range of drug that is therapeutically active against cancer without being highly toxic

39
Q

Biomarkers

A

Molecules, cells, phenotypes that are identified as predictive of responsiveness to drug

40
Q

Carcinogen

A

Agents that contribute to tumor formation

41
Q

Cancers associated with occupation

A
  1. Radium girls - radium in watches increased risk of multiple cancers
  2. Chimney sweeps increased risk of skin cancers of scrotum
  3. Silver ore miners increased risk of lung cancer
  4. Tobacco snuff users increased risk of nasal cancer
  5. X-ray technicians increased risk of cancers
  6. Shipbuilders exposed to asbestos increased risk of mesothelioma
  7. Smokers increased risk of lung cancer
42
Q

Yamagiwa and Ichikawa (1915)

A

First successful induction of cancer
by a specific agent

Induced cancer in the skin of rabbit
ears by painting them with coal tar
repeatedly for hundreds of days

43
Q

Ames Test: Goal/ Accomplishments

A

Approach: compare carcinogenicity to mutagenicity in bacteria

Confirmed carcinogens are mutagens (altered DNA, genetic alteration)!!

44
Q

Ames Test: Procedure

A
  • Suspected carcinogen + homogenized rat liver
  • metabolic activation by rat liver enzymes
  • add to Salmonella with mutation that prevents synthesis of histidine
  • mutagens revert defective gene, so bacterial colonies grow
45
Q

Approaches to Studying Cancer:
Experimental - 2D cell cultures

title card no question

A

title card no question

46
Q

Hayflick Limit

A

max 60 doublings of normal cells in cell culture, they always hit senescence
due to telemore shortening

47
Q

normall cells in tissue culture

A

Finite lifespan (extra serum and media = extended survival, but they eventually die)
always reach senescence

48
Q

HeLa cells

A

First immortal human-cell line (cervical cancer)

49
Q

Cell culture consists of __, __ , ___

A

cells, medium, substrate

50
Q

Cell Culture: Cells

A
  1. Fibroblasts (cells generally of mesenchymal origin that make extracellular matrix)
  2. Epithelial cells are harder to grow
51
Q

Cell Culture: Medium

A

Contains salts, energy source (glucose), amino acids, vitamins, buffer (CO2/HCO3–) and growth factors (in serum)
Eg. DMEM, RPMI

52
Q

Cell Culture: Substrate

A

Surface on which cells are grown on

Cells are plated and adhere to treated plastic/glass

Most cell types are anchorage-dependent (adhere to plastic) for growth and proliferation

Undergoes treatment to become more hydrophilic to facilitate cell attachment

53
Q

Properties of normal cells in tissue culture

A
  1. GO
    Growth arrest in low serum - growth factor signalling required for proliferation
  2. STOP
    Contact inhibition - cellular growth & division stops due to contact with other cells
  3. DIE
    Anchorage dependent growth - epithelial cells require attachment for survival
54
Q

Properties of cancer cells in tissue culture

A
  1. Growth factor independent growth
  2. Loss of contact inhibition (they grow on top of each other)
  3. Anchorage independent growth
55
Q

Assays to measure cell transformation (for cancer)

A

gold standard: tumorigenesis in nude mice

in vitro

  • Growth factor independent growth => Serum indepndent growth
  • Loss of contact inhibition => focus forming assay
  • Anchorage independent growth => soft agar assay
  • immortalization => infinite proliferation
56
Q

focus

A

group of cells clustered together

57
Q

soft agar assay

A

used to test for anchorage independent growth

base agar matrix
cell suspension + agar matrix
formation of cell colonies
counted using colorimetric detection (MTT soln)

58
Q

hallmarks of cancer seen in cell culture assays

A

S - sustaining proliferative Signaling
A
D - resisting cell Death
I - replicative Immortality
S - evading growth Suppresors
M

59
Q

pros of using cell culture to study cancer

A
  • use of animals reduced
  • Homogenous cell population, same growth requirements
  • Control of the extracellular environment
  • Minimize interference from other biological molecules that may occur in vivo
  • Screens for cancer-causing genes (Lec. 4) or for cancer therapies
60
Q

cons of using cell culture to study cancer

A
  • Impossible to re-create in vivo environment
  • Remove interaction with other cells, hormones, support structures (ECM) that would be present in vivo (the tumor microenvironment)
  • Artificial conditions could cause cells to de-differentiate or change phenotyp
61
Q

Lecture 3

A

Breakpoint go stretch :D

62
Q

Approaches to Studying Cancer:
Experimental - Mouse Models

what are the different types of mouse models?

A

GSOX

GEMMs
Syngeneic
Orthotopic
Xenograft

63
Q

Syngeneic mouse model

A

Transplant tumor cells from mouse to mouse

64
Q

Xenograft

A

Transplant tumor cells from human to mouse

Grafts from human primary tumors or cell lines
Have to be injected into an immuno deficient mouse

65
Q

Orthotopic

A

Transplant tumor cells into their native location
Can be both xenograft and syngeneic

66
Q

GEMMs

A

Genetically engineered mouse models arise in situ

67
Q

Nude mice

A

FOXN1 mutation
Blocks development of thymus (and hair) => no T cells
Tumors easy to monitor

68
Q

SCID mice

A

Severe Combined Immunodeficiency (SCID)
Can’t complete VDJ recombination (DNA-PK mutation) and lack T or B cells

69
Q

Limitations of Mouse Models

A
  • Different lifespans (2 vs 80)
  • Different size
  • Different physiology
  • Different metabolic response (PK)
  • Fewer mutations required (mice fibroblasts require ~2 mutations
  • Different tumors from same deficiencies (p53 mice -> sarcomas, p53 humans -> carcinomas)
  • Less metastasis

MCB132 (7 decks)

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