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Pathology > Neoplasia - yeah but how (3&4) > Flashcards

Neoplasia - yeah but how (3&4) Flashcards

1
Q

what are hallmarks of cancer? (10)

A
  • evading growth suppressors
  • enabling replicative immortality
  • tumour promoting inflammation
  • activating invasion & metastasis
  • genomic instability (mutator phenotype)
  • inducing angiogenesis (make own blood supply for supply & growth - very important)
  • resisting cell death
  • deregulating cellular energetics
  • sustainable proliferative signalling
  • avoiding immune destruction

*picture the wheel picture in notes

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2
Q

what does carcinogenesis require? (8)

A
  • Self-sufficiency in growth signals
  • Insensitivity to growth-inhibitory signals
  • Altered cellular metabolism
  • Evasion of apoptosis
  • Limitless replicative potential
  • Sustained angiogenesis (own blood supply)
  • Ability to invade / metastasize
  • Ability to evade host immune response
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3
Q

what is the path that a normal cell follows to clonal expansion and then to malignant neoplasm?

A

normal cell →DNA damage →failure of DNA repair & mutations in genome of somatic cells (inherited mutations in genes affecting DNA repair & genes affecting cell growth or apoptosis) →activation of growth-promoting oncogenes & inactivation of tumour suppressor genes & alterations in genes that regulate apoptosis →unregulated cell proliferation & decreased apoptosis → CLONAL EXPANSION

clonal expansion with effects from angiogenesis, escape from immunity & additional mutations →tumour progression →malignant neoplasm →invasion & metastasis

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4
Q

what is heterogeneity?

A

result of genomic instability & clonality
heterogeneity = more diverse cells→can lead to hemorrhage or necrosis

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5
Q

what is the process of tumour clonality?

A

TRANSFORMATION:
normal cell -> carcinogen-induced change -> tumour cell

PROGRESSION:
tumour cell proliferating into tumour cell variants

PROLIFERATION OF GENETICALLY UNSTABLE CELLS

TUMOUR CELL VARIANTS = HETEROGENEITY

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6
Q

how do neoplastic cells become immortal?

A
  • normal cells have regulated growth & a limited life span (this is good)
  • neoplastic cells just keep proliferating - either because abnormal expression of oncogenes OR inactivation of tumour suppressor genes (the guardians of cell cycle)
    • so when you have 1 or both of these things you have abnormal growth
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7
Q

how do neoplastic cells have reduced apoptosis?

A

usually because of abnormal expression of genes which inhibit apoptosis (BCL-2)

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8
Q

how does telomerase lead to unlimited division?

A

telomeres are repetitive DNA sequences at the end of a chromosome and in normal cells telomeric shortening occurs in each cell division which restricts the number of cell division cycles

-telomerase normally just in germ cells & stem cells
- telomerase prevents this shortening
- so when normal cells get telomerase = they start to replicate and divide

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9
Q

what is a tumour suppressor gene?

A

genes which inhibit neoplastic growth e.g. TP53 which encodes for p53 protein

(2 categories = caretaker genes & gatekeeper genes)

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10
Q

what is function of caretaker & gatekeeper genes?

A

caretaker genes = repair DNA damage

gatekeeper genes = stop damaged cells from dividing (either by inhibiting proliferation, or inducing apoptosis)

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11
Q

what is p53?

A

-most frequently mutated gene in human cancer (“guardian of the genome”)

  • has both caretaker & gatekeeper function
  • it can lose function in variety of ways = mutations (missense & nonsense)
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12
Q

what is oncogene function?

A

they drive neoplastic behaviour of cells →produce oncoproteins

  • can be viral or can be genes that exist in normal cells
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13
Q

how do oncogenes drive neoplastic behaviour of cells?

A

as they act as:
- growth factors
- receptors for growth factors
- signalling mediator with tyrosine kinase activity (TSK’s regulate cell survival & proliferation ->signalling cascade)
- signalling mediator with nucleotide binding activity (also involved in regulation of growth & proliferation)

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14
Q

what is diploid?

A

normal amount of DNA, 2 copies of each chromosome

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15
Q

what is polyploidy?

A

When cell contains exact multiples of diploid state (e.g. tetraploidy (4N), octoploidy (8N))

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16
Q

what is aneuploidy?

A

When cell contains inexact multiples

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17
Q

what are karyotypic abnormalities?

A

additional chromosomes or chromosomes translocations/rearrangements

  • Some tumours have very specific ones which can be helpful in making correct diagnosis and informing targeted treatment
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18
Q

what allows immortalisation?

A

telomerase expression
(immortalisation is ability to divide indefinitely)

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19
Q

what makes removal of growth inhibition?

A

inactivation of tumour suppressor gene function

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20
Q

what allows autocrine growth stimulation?

A

oncogene activation e.g. Ras

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21
Q

what is a carcinogen?

A

environmental agent that participates in causing tumours (often more than 1 carcinogen is involved)
- this means they act on the DNA of the cells

  • they are mutagenic
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22
Q

how can carcinogens be identified?

A
  • epidemiological studies (can be complex - need to account for confounding variables)
  • occupational risks (like working in dye factories)
  • direct evidence (chernobyl→observation of thyroid carcinoma in children)
  • experimental testing = cell culture, animal testing
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23
Q

what type of chemical carcinogen causes carcinomas?

A

polycylic aromatic hydrocarbons -> carcinomas

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24
Q

what chemical carcinogen causes
a) bladder cancer
b) Gi cancer
c) bladder, liver cancer
d) liver angiosacroma

A

a) aromatic amines
b) nitrosamines
c) some azo dyes
d) vinyl chloride

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25
Q

what is an example of chemical carcinogen that acts directly?

A

polycyclic aromatic hydrocarbons

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26
Q

what is an example of chemical carcinogen that acts indirectly and how?

A

Procarcinogens undergo metabolic conversion into active / ultimate carcinogens e.g. conversion of dietary nitrates into nitrosamines by GI bacteria -> Gi cancer

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27
Q

what type of tumour is a result of Epstein-Barr virus?

A
  • Burkitts lymphoma (malaria = cofactor)
  • Nasopharyngeal carcinoma
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28
Q

what type of tumour is result of hepatitis B & C?

A

hepatocellular carcinoma

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29
Q

what type if tumour is result of human herpesvirus-8?

A
  • kaposi’s sarcoma
  • some lymphoma’s
    (immunodeficiency/AIDS association)
30
Q

what type of tumour is result of human T-cell lymphotropic virus-1?

A

adult T cell leukaemia/lymphoma

31
Q

what is tumour types as a result of human papillomavirus?

A
  • squamous cell papilloma (low risk) = warts
  • squamous cell carcinoma (high risk)

*not all HPV lead to cancers

32
Q

what cancers are associated with human papillomavirus?

A
  • anogenital regions (anal & cervix)
  • head & neck cancers
33
Q

what area is most prone to instability for HPV?

A

human papillomavirus = cancers in anogenital regions & head & neck cancers

  • transformation zone = region in the cervix where the columnar epithelium transitions to squamous epithelium
  • most prone to instability (specific area is more susceptible to genetic and cellular changes, which can include alterations in the DNA of cervical cells)
34
Q

how does HPV cause cancers? (hint - what are the proteins involved?)

A
  • HPV E6 binds to p53 which prevents DNA repair & apoptosis and means cell cycle is NOT arrested
  • HPV E7 also binds to pRB (retinoblastoma protein) and allows pRB to activate the expression of genes that promote cell cycle progression and DNA synthesis
    (pRB usually prevents promotion of the expression of genes involved in cell cycle progression- usually halts cell cycle if problem)
35
Q

what checkpoints do p53 and pRb usually act at?

A

pRb = G1-S
p53 = G2- M

36
Q

what does E6 HPV act on?

A

E6 viral oncoprotein acts on TP53 (a tumour suppressor gene that makes p53)

37
Q

what is p53 normal function?

A

Activating DNA repair proteins, holding cell cycle to allow repair, initiating apoptosis of badly damaged cells and senescence response to short telomeres

38
Q

what does E7 HPV act on?

A

E7 viral oncoprotein acts on RB (a tumour suppressor gene that codes for retinoblastoma protein)

39
Q

what does retinoblastoma protein normally do?

A

inhibits cell cycle progression until a cell is ready to divide

40
Q

what is Epstein-Barr virus?

A

EBV type of herpesvirus - most known for causing infectious mononucleosis = glandular fever

(90% of population usually end up with some kind, usually transient)

41
Q

how is Epstein-Barr virus and lymphomas linked?

A
  • latent EBV infection can reactivate drive B cells to proliferate & cause EBV driven lymphoproliferative disorder
42
Q

what lymphomas are EBV linked to?

A
  • hodgkin lymphoma
  • primary effusion lymphoma
  • burkitt lymphoma (originally associated with)
43
Q

how are EBV and carcinomas linked?

A

EBV can infect squamous cells
- act in combination with environmental factors/smoking to promote nasopharyngeal carcinoma

(thought to be underlying genetic risk associated)

44
Q

what is common initiating event of carcinomas by EBV?

A
  • inactivation of p16/CDKN2A and TGFBR2
    • This predisposes nasopharyngeal epithelial cells to persistent EBV latent infection, eventually leading to malignant transformation
45
Q

what tumours are most associated with UV light?

A
  • malignant melanoma
  • basal cell carcinoma

(commonly associated with skin cancer)

46
Q

what effect does exposure to ionising radiation have?

A

leads to many different cancers

47
Q

what are melanocytes?

A
  • Melanocytes are neural crest derived cells
  • Usually in basal layer of epidermis
  • Produce melanin pigment
48
Q

how do melanocytes lead to melanoma?

A

Melanoma is a type of skin cancer that originates from the melanocytes, the pigment-producing cells in the skin. The development of melanoma is a complex process involving genetic mutations and other factors

  • Malignant transformation can occur following UV damage (+/- genetic predisposition)
49
Q

what is Fitzpatrick scale & risk?

A

The Fitzpatrick scale is a classification system that assesses an individual’s skin type based on their response to sun exposure, hair color, eye color, and skin color

  • pale skinnier people more susceptible to UV damage
  • Multiple sunburns also increase risk
50
Q

what has protective risk against UV damage?

A

Melanin has protective properties against UV (ultraviolet) damage due to its ability to absorb and dissipate UV radiation

51
Q

what types of tissue are more sensitive to ionisation radiation?

A
  • bone
  • thyroid
  • breasts
  • hematopoietic tissue
52
Q

what is metastasis?

A

the process by which tumour cells get from their site of origin (primary) to another part of body (secondary)

53
Q

what are the 6 steps of metastasis?

A
  1. Detachment
  2. Invasion of surrounding tissue
  3. Intravasation into vessels
  4. Evasion of host cell defences
  5. Adherence to endothelium elsewhere
  6. Extravasation of cells from vessel into surrounding tissue
54
Q

what are the different routes of metastasis?

A
  1. Haematogenous - by blood
  2. lymphatic
  3. transcoelomic - across a body cavity (peritineum)
55
Q

what is ionising radiation effect and examples?

A

examples = gamma rays, x-rays, nuclear radiation

  • high doses can kill but also cause carcinogenesis
56
Q

why do some cancers behave badly? (like how do they spread)

A
  • decreased cellular adhesion = they get unstuck from each other
  • secretion of proteolytic enzymes = damage surrounding tissue
  • abnormal or increased cellular motility = they can move around easier
57
Q

what bacteria is a carcinogen?

A

helicobacter pylori
= linked with gastric adenocarcinomas & some lymphomas

= release toxins which activate oncoproteins
- CagA at SHP2 binding site

*other emerging links between bacteria & carcinomas

58
Q

what fungi is a carcinogen?

A

Aflatoxin (Aspergillus flavus) is a carcinogen produced by some fungal species

= exposure linked with hepatocellular carcinoma

59
Q

what hormone can act as carcinogen?

A

excess oestrogen:
- sometimes linked to excess adipose tissue
- obesity risk factor for some cancers

anabolic steroids:
- liver neoplasms

growth hormone & IGF1 related to many cancer types

60
Q

how does age influence tumour development?

A

older age = more susceptible

  • most cancers > 60 years
  • cancers mostly epithelial in origin = increase somatic genetic mutation & loss of immune competence

in children -> carcinomas are very rare, more commonly acute leukaemia/primitive CNS neoplasms & rhetinoblastoma etc

61
Q

what are some links between diet and carcinogenesis?

A

obesity = excess adipose tissue means higher levels of growth hormones

processed meats = nitrosamines (chemical carcinogen)

alcohol = acetaldehyde causes cell damage - effects of alcohol multiplied when paired with smoking

62
Q

what is inherited predisposition? and examples?

A

Some people have inherited mutations which predispose them to certain types of cancer

BRCA1, BRCA2 = breast & ovarian = tumour suppressor gene

MEN syndromes = endocrine

63
Q

what tumour is result of xeroderma pigmentosum?

A

skin tumours

64
Q

what tumour is result of familial adenomatous polyposis coli?

A

colorectal tumours (adenomas & adenocarcinomas)

65
Q

what tumour is result of lynch syndrome?

A

lynch syndrome = hereditary non polyposis colorectal cancer HNPCC

colorectal carcinomas & other tumours

66
Q

what tumour is result of Von Hippel-Lindau syndrome?

A

recal cell carcinoma

67
Q

what tumour is result of Li-fraumeni syndrome?

A

TP53 mutations ->lots of different tumours

68
Q

what tumour is result of retinoblastoma syndrome?

A

retinoblastomas

69
Q

what tumour is result of familial breast carcinoma?

A

BRCA mutations - breast & ovarian, prostate in males

70
Q

what tumour is result of fanconi anemia?

A

leukaemia, others

71
Q

what is the HPV concentration of squamous cell pappaloma?

A

HPV 6,11

72
Q

what is the HPV concentration of squamous cell carcinoma?

A

HPV 16,18

Pathology (10 decks)

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