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Pathophysiology 2.0 > Week 4 Tut - From cancer to cell injury & death > Flashcards

Week 4 Tut - From cancer to cell injury & death Flashcards

1
Q

What are the 8 hallmarks of cancer?

A
  1. sustained proliferation signal 2. Evading growth suppressors 3. Activating invasion and metastasis 4. Enabling replicative immunity 5. Inducing Angiogenesis 6. Resisting Cell Death 7. Emerging hallmarks 8. Enabling hallmarks
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2
Q

How does sustained proliferation signalling occur? (~6 things)

A

cancer cells ;

  • produce growth factors
  • can stimulate surrounding stomal (normal) cells to produce growth factors
  • signalling deregulated by increased expression of GFR (growth factor receptors) = e.g. HER2
  • may have constitute activation of signalling pathway = e.g. mutations in BRAF, KRa
  • Amplification of receptor
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3
Q

How do cancer cells evade growth suppressors? give an example?

A
  • inactivation of tumour suppressor genes
  • RB and p53 = 2 prototypical tumour suppressor genes as they involved in cell proliferation, senescence and apoptosis
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4
Q

What are the 2 most common prototypical tumour suppressor genes and what % of cases are mutations present

A

are RB and p53

present in 70% of cases

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5
Q

How does a tumour or cancer cell resist cell death?

A
  • via loss of p53
  • increase the expression of anti-apoptotic factors (Bcl-2)
  • downregulation of pro-apoptotic factors (Bax, Bim)
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6
Q

How do cancer cell enable replicative immortality?

A

telomerase = an enzyme that repairs damage to telomeres which is present in stem cells

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7
Q

How do cancer cells induce Angiogenesis?

A

cancer cells produce VEGF and its expression is upregulated;

a. in a hypoxic environment (as in tumours)
b. by oncogenes signalling

peri-tumoral inflammation cells also help induce

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8
Q

How do tumour cells activate invasion and metastasis? (8 step process)

A
  1. Intravasion (cancer cell into blood vessel)
  2. Interaction with immune system cells and evasion of destruction
  3. Formation of tumour cell embolus (micro-metastasis)
  4. Adhesion to basement membrane
  5. Extravasion (cancer cells from vessel leak into tissue)
  6. Metastatic deposition
  7. Angiogensis
  8. Growth (colonisation)
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9
Q

What is the main physiological response being “hijacked” by cancers during activation of invasion and metastasis?

A

Epithelial-Mesenchymal Transition (EMT)

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10
Q

What is the normal process of Epithelial-Mesenchymal Transition (EMT)?

A

is the process of embryonic morphogenesis and wound healing where cells transform between the epithelial state and the mesenchymal state via transcription factors to have an ideal function and resist apoptosis during healing

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11
Q

What is the difference between the epithelial state and the mesenchymal state?

A

Epithelial

  • poly/columnar shape
  • Apico-basolateral polarization
  • stong cell-to-cell communication
  • limited migratory potential

Mesenchymal

  • spindle shaped
  • anterior-posterior polarization
  • focal cell-cell contacts
  • strong migratory
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12
Q

What are the markers for the Epithelial and Mesenchymal states ?

A

Epithelial

  • E-cadherin
  • certain cytokeratins
  • occludin
  • claudin

Mesenchymal

  • Vimentin
  • N-Cadherin
  • Fibronectin
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13
Q

How do cancer cells induce invasion?

A

Hijack the EMT

epithelial state to mesenchymal state = increased metastatic ability do to reduced cell-to-cell adhesion

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14
Q

What is the difference between emerging and underlying hallmarks?

A

Emerging hallmarks

  • reprogramming of energy metabolism
  • evasion of destruction by the immune system

Underlying Hallmarks

  • Genetic instability
  • inflammation
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15
Q

How do tumour cells alter energy metabolism and evasion of destruction

A
  1. Deregulating cellular energetic
    • cancer cells use glycolysis for energy metabolism = less effective than ATP from Kreb Cycle
    • occurs as host and tumour are competing for energy
    • glycolysis = good for cancer as glycolytic intermediates help in the production of rapidly dividing cells
  2. Avoiding immune destruction
    • Cancer cells undergo immuno-editing
    • only strong cancer cells survive as weaker ones get killed
    • stong cells or bits will form solid tumour
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16
Q

How do cancer cells alter enabling characteristics?

A
  1. Genome instability and mutation
    • Defects in genome = selective advantage for tumour cells
    • can accumulate more genetic mutations = bad
    • e.g. DNA mismatch repair defects
    • p53 mutations
  2. Tumour Promoting Inflammation
    • growth factors = sustained proliferation and angiogenesis
    • survival factor = reduce cell Death
    • Matrix modifying enzyme = EMT = metastasis
    • ROS = mutogenic effect = increase mutations for norm cells
    • inductive signalling = EMT
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17
Q

What is Venetoclax? How does it work

A

is an anti-apoptotic drug = increases change of cell to apoptose

Inhibits BLC-2 (as BLC-2 = increase cancer cell survival) by binding onto the BLC-2 protein and displacing the pro-apoptotic protein (Bim)

= mitochondria outer memb to increase perm and also activates caspases

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18
Q

What is tumour lysis syndrome (TLS)

A

When large number of tumour cells apoptose at once and release contents into blood

  • = abnormally high electrolyte conc. minus Ca which reduces
  • Proteins and nucleic acids -> xanthine oxidase -> uric acid

both can overwhelm the excretory system and increase conc. in blood

= increase H20 loss to reduce Potassium conc

= reduced BV = reduced perfusion = kidney go grrrrrr and thows tantrum = acute kidney injury

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19
Q

What is Cell Adaptation?

A

cell adaption occurs to physiological stress and pathogenic stimuli to maintain homeostasis or a new level of homeostasis

preserves cell viability but modulates function

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20
Q

What is Cell Injury?

A

occurs adaptive limits have been exceeded

is reversible but can lead to cell death

TRANSITION as either = adaptation or death

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21
Q

What is meant by cell death

A

When the cell has an irreversible injury and will then undergo necrosis or apoptosis as it is no longer functionally viable

22
Q

How do does cell adaption occur?

A
  1. cell can adapt many ways
    1. up-/down-regulation of surface receptor s
    2. New protein synth
    3. switch from producing one type of protein to another
23
Q

What is the difference between hyperplasia and hypertrophy

A

hypertrophy = increase cell size

Hyperplasia = increase number of cells

24
Q

What is atrophy?

A

shrinkage of cell due to loss of cell substance

causes;

decreased workload

loss of innervation

diminished blood supply

loss of endocrine stimulation

inadequate nutrition

aging

occurs as cell has increased survival at a small size

25
Q

What is Metaplasia

A

the reversible change from one cell type replaced by another

substitute of sensitive cells to type which can better withstand stress

e.g. columnar to squamous in respiratory tract as a result of chronic inflam

causes neg effects or loss of funct as in eg squamous cannot secrete = loss of mucus secretion

can lead to cancer

26
Q

What is infarction?

A
  • Area of ischaemic necrosis = occlusion of arterial supply or venous drainage
    • usually caused by thrombosis vs embolism
    • or compressed by vessel by twisting
    • e.g. venous occlusion, myocardial infarction
27
Q

What are the different types of infarctions?

A
  1. White = anaemic = arterial occlusion in arterial organs (e.g. heart, kidney, spleen, etc.)
  2. Red = haemorrhagic = venous occlusion, loose tissue, usually have double circulation or previously congested tissue (e.g. Lung, bowel, brain)
  3. Septic vs bland infarct = (presence or absence of bacterial infection)
28
Q

How does the cell morphology change of time during an ischaemic coagulative necrosis?

A

Ischemic coagulative necrosis = occlusion of arterial or venous vessels

  1. Few hours = no demonstratable change (not enough time)
  2. 12 to 18 hours = haemorrhage and swelling

inflammatory exudate at margins starts at the margins starts at a few hrs but is better defined within next few days

  1. 24 to 72 yours = scar formation - fibroblastic tissue replacing normal tissue
29
Q

What is shock?

A

is when your body is in “rush”

widespread hypo-fusion of tissue = inadequate effective circulating volume

not enough nutrients and O2 plus inadequate clearance of metabolites

due to lack of O2 = switch from aerobic to anaerobic = increase conc. of lactic acid

is initially reversible - BUT IF PERSISTENT = cell death

30
Q

What are the 4 major types of shock? briefly describe them

A
  1. Carcinogenic - Pump failure (MI, arrhythmia, tamponade)
  2. Hypovolaemic - Inadequate plasma volume (haemorrhage, burns, trauma)
  3. Septic - Severe infection (peripheral vasodilation, DIC)
  4. Neurogenic - Anaesthetic complications, spinal cord injury
31
Q

What are the different types of Cell Injury?

A
  • Hypoxia = impinges on aerobic oxidative respiration, inadequate oxygenation of tissue, adaption, injury or cell death
  • Physical Agents = mechanical trauma, temperature extreme, radiation, electric shock
  • Chemical Agents = androgenesis
  • Infective Agents = viruses, bacteria, fungi, parasites
  • Immunological reaction = usual function - but defence may cause injury
  • Genetic derangement = congenital malformation, coding for protein production
  • Nutritional imbalance = under micturition and over micturition
32
Q

What are the 4 common biomedical themes of cell injury?

A
  1. Oxygen and oxygen-derived free radicals
  2. Intracellular calcium and loss of calcium homeostasis
  3. ATP depletion
  4. Defect in membrane permeability
33
Q

During cell death what are the ultracellular reversible changes that occur?

A

Ultracellular changes

  • plasma membrane alterations
  • blebbing, blunting and distortion of microvilli
  • loosening of intracellular attachment
34
Q

During cell death what are the reversible mitochondria changes that occur?

A

swelling

rarefaction

appearance of densities

35
Q

During Necrosis what are the irreversible changes that occur that are seen under a light microscope?

A

increased eosinophilia = loss of RNA in cytoplasm & increased binding to denatured proteins

glassy homogenous

moth-eaten appearance

nuclear changes (karyolysis, pyknosis, karyorrhexis)

calcification

36
Q

What is karyolysis?

A

basophilia of chromatin fades

37
Q

What is Pyknosis?

A

nuclear shrinkage, increased basophilia

38
Q

What is karyorrhexis

A

pyknotic nucleus undergoing fragmentation?

39
Q

During necrosis what are the irreversible cell changes that are visible using an electron microscope

A

discontinuities in plasma and organelle membranes

marked dilation of mitochondria, large densities

myelin figures

amorphous debris

aggregated of fluffy material - denatured protein

40
Q

What are the different types of necrosis?

A
  1. Coagulative
  2. Liquefactive
  3. Gangrenous
  4. Caseous
  5. Enzymatic Fat Necrosis
41
Q

What are the characteristics of Coagulative Necrosis?

A

preservation of basic outline of cell

characteristic of hypoxic injury (except in the brain)

42
Q

What are the characteristics of Liquefactive necrosis?

A

usually due to bacterial infection

hypoxic cells in the CNS

43
Q

What are the characteristics of Gangrenous necrosis?

A

not a distinctive pattern but often used in clinical practice

loss of blood supply to a limb (coagulative)

wet gangrene = superimposed bacterial infection (liquefactive)

44
Q

What are the characteristics of Caseous Necrosis?

A

distinct form of coagulative necrosis seen in tuberculosis

fragmented coagulated cells within a granuloma

blood lymphoma = looks like cheese

45
Q

What are the characteristics of Enzymatic Fat Necrosis?

A

Focal area of fat necrosis - pancreatic lipase

shadowy outlines of necrotic fat cells

46
Q

During Apoptosis what are the irreversible changes that can be seen under a light microscope?

A

single cells or a small cluster of cells

round-oval mass

intensely eosinophilic cytoplasm, dense nuclear chromatin fragments

rapid process and quickly phagocytosed therefore considerable apoptosis in order to be seen under a light microscope

DOES NOT ELICIT INFLAMMATION

47
Q

During apoptosis what are the irreversible ultracellular changes that occur?

A

cell shrinkage

dense cytoplasm, organelles are tightly packed

48
Q

What is the most characteristic feature during apoptosis? describe it?

A
  • aggregates peripherally under nuclear membrane
  • cytoplasmic blebs and apoptotic bodies
    • extensive surface blebbing
    • fragmentation into membrane-bound apoptotic bodies
  • Phagocytosis
    • by macrophages, denatured by lysosomes
49
Q

Describe the steps leading to necrosis?

A
  1. Reversible cell injury (can recover and return to norm)
    - swelling of endoplasmic reticulum and mitochondria
    - membrane blebs
    - myelin figure
  2. progressive injury
    - breakdown of plasma membrane, organelles and nucleus = leaking of content
    - amorphous densities in mitochondria
    - myelin figures
    - inflammation
50
Q

Describe the steps leading to Apoptosis.

A
  1. Programmed cell death
  2. condensation of chromatin & formation of membrane blebs
  3. apoptosis = cell fragmentation and formation of apoptotic bodies
  4. phagocytosis of apoptotic cells and fragments

Pathophysiology 2.0 (19 decks)

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