Unit 4 - General Concepts of Cancer and Protecting the Genome Flashcards Preview

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1

cancer - biology vs molecular level

out of control cellular proliferation (bio)

damage to genetic material (mutations and epigenetic) that affect cellular proliferation

2

3 types of mutations in cancer cells

ONCOGENIC

TUMOUR SUPPRESSIVE

NEUTRAL

3

oncogenic mutation

ras

myc

cyclin D

normal growth promoting genes (proto-oncogenes) become either hyperactive or inappropriately active

dominant mutations = mutation of only 1 allele required

4

tumour suppressive mutation

normal growth restraining genes become lost or down-regulated

recessive mutation = mutation of both alleles required (to lose tumour suppressive function)

BRCA1 and 2

TP523

5

neutral mutation

cancer cells have 1000s of mutations to genes that have little or no effect on aetiology of cancer

cancer evolves a mutagenic phenotype

6

protooncogenes when mutated =

driving with foot on the accelerator

7

normal (stem) cells

low instability

no cells have genetic alteration required to overcome the selection barrier

NO TUMOUR

8

increased genetic instability

at least 1 cell contains the requisite genetic alteration to overcome the selection barrier (clonal selection)

barrier traversed and population of mutant cells eventually accumulates the new mutations required to cross the next selection barrier

significant step towards tumourigenesis

9

too much genetic instability

too many mutations accumulate to allow viability

cells die - apoptosis, necrosis

NO TUMOUR

10

6 selection barriers

reduced requirement for growth factors - autocrine stimulation

insensitivity to inhibitory signals

escape from senescence (cellular immortality)

evasion of apoptosis

stimulated angiogenesis

invasion/metastases

11

how are these selection barriers overcome

by inactivating tumour suppressors and activating oncogenes

tumours - hostile cellular environments

e.g. periods of anoxia, malnutrition

fluctuating hormonal influences and immune attack

a fertile breeding ground for mutations

similarly, bacteria with higher levels of genomic instability, but not too high, adapt to and eventually dominate new environments

12

challenge posed by the somatic mutation hypothesis

very low mutation rate - 1 x 10-10 nucleotides/cell/division for human somatic cells

diploid human genome = 6.4 x 109

1016 cell divisions in a human lifetime are insufficient to permit a single cell to obtain the estimated 5-7 advantageous mutations required to produce a cancer

⇒ cancer shouldn't occur with such a low mutation rate

13

the mutator (or genetic instability) hypothesis

cancer cells have significantly elevated (just-right) mutation rates

14

Min tumours

where is there instability

type of karyotype

prevalence

microsatellite instability

instability at the nucleotide level e.g. mutation of MMR results in 10-100 fold increase in mutation

most easily seen at microsatellites

normal karyotype

relatively uncommon e.g. 15% colorectal cancers

15

Cin tumours

where is there instability

karyotype

prevalence

chromosomal instability

instability at chromosomal level

not clear what mutational events initiate Cin tumours - loss of p53, mitotic checkpoints?

abnormal karyotype

most frequent - 85% of colorectal cancers

 

16

similarity between min and cin

NOT FOUND TOGETHER

same oncogenes and tumour suppressors appear to be targeted in both min and cin tumours

17

what is the lifetime risk of many cancers dependent on

the total number of divisions of adult stem cells in the particular tissue rather than on environmental or inherited mutations

the more cell divisions the more likely that random mutation to key cancer driver genes will occur during cell division - 65% of cancer

 

 

18

what explains the extreme variation in cancer incidence across different tissues

> cell divisions ⇒ the more likely that random mutation to key cancer driver genes will occur during cell division

 

19

cancer risk for different tissues

6.9% - lung

1.08% - thyroid

0.6% - brain

0.003% - pelvic bone

0.00072% - laryngeal cartilage

20

proportion of cancers that have an inherited component

5-10% of cancers

21

what effect does exposure to mutagens have

mutagens or viruses cannot account for a 24x variation of lifetime risk throughout alimentary canal

LI - 4.82%

stomach - 8.6%

oesophagus - 0.51%

SI - 0.2% - 3x LESS COMMON than brain tumours even though the brain is protected from environmental mutagens by the BBB

 

22

lifetime risk vs total stem cell divisions

23

tumour

an abnormal uncontrolled growth without physiological function, that can be either benign or malignant

24

benign tumour

confined and not life threatening

25

malignant tumour

invades surrounding tissue and may spread to other parts of the body

26

neoplasia

process of forming tumours (benign or malignant)

27

hyperplasia

small abnormal growth in a part of the body caused by an excessive multiplication of phenotypically normal cells

28

metaplasia

appearance of invading, microscopally normal cells of a type not normally encountered at that site

most frequent at epithelial transition zone e.g. oesophagus/stomach, cervix/uterus

29

dysplasia

small abnormal growth in a part of the body caused by an excessive multiplication of cytologically abnormal (variable size and shape, bigger nuclei, increased mitotic) cells

transitional state between benign and pre-malignant growths

30

transitional state between benign and pre-malignant growths

dysplasia

31

adenomas, polyps, papillomas

large benign tumours of epithelial origin

dysplastic but not malignant

usually grow to a certain size and them stop growing

 

32

carcinoma

most common (80% of cancer deaths)

malignant tumour derived from epithelial tissue

→ surface layer of an organ/body part

e.g. GI tract

skin

breast

pancreas

lung

liver

ovary

bladder

33

adenocarcinoma and squamous cell carcinoma

2 main classes of carcinoma that derive from epithelia

secrete substances into cavities/ducts e.g. breast or from simple protective layers e.g. skin

34

leukemia (dispersed)/lymphoma (solid)

 

2nd most common (16%) malignant tumour type derived from haematopoietic and lymphatic tissues

35

sarcoma

rare (1%) malignant tumour derived from CT/muscle

e.g. fibroblast

adipocyte

osteocytes

myocytes

36

neuroectodermal tumours

rare (2.5%)

malignant tumours derived from central and peripheral nervous system

e.g. gliomas, neuroblastomas

37

most common tumours

  1. carcinoma
  2. leukemia/lymphoma

38

germ cell tumours (GCT)

tumours derived from germ cells

germ cell tumours can be cancerous or non-cancerous

normally occur inside gonads (ovary and testis)

testicular cancer - curable

39

teratoma

tumours with tissue or organ components resembling normal derivative of all 3 germ layers

although resembling normal tissues, often dissimilar to surrounding tissues (teeth and hair)

encapsulated and hence usually benign

multiple fluid-filled cysts can form within the capsule

teratoma within a large cyst can sometimes form a structure resembling a foetus

immature teratomas occasionally malignant, rare but slightly more common in males

40

mature vs immature teratomas

mature

typically benign

rare

more common in females

immature

malignant

rare

more common in males

41

colorectal cancer - cin occurence

structures in colon

107 crypts in colon

each crypt has 1000s of differentiated cells (fast growing - lot of apoptosis - 1010 cells are lost)

1-10 stem cells (slow growing and self renewing)

mutation can occur in any 1 cell cycle

early studies of tiny adenomas ⇒ that >90% had allelic imbalances of 1+ of 5 chr tested

⇒ supports the idea that CIN occurs early

85% of cases of sporadic colorectal cancer initiated by inactivation of APC (adenomatous polyposis coli)

< 10% by activation of β-catenin as both function in WNT signalling

42

sporadic colorectal cancer causes

85% of cases of sporadic colorectal cancer initiated by inactivation of APC (adenomatous polyposis coli)

< 10% by activation of β-catenin as both function in WNT signalling

43

Wnt signalling

regulated by

target

what is included in its complex

 

proliferation of epithelial cells is regulated by mitogen Wnt

key target = β-catenin - activates transcription of genes involved in proliferation

no Wnt ⇒ no β-catenin - constitutively associated with an inhibitory cytoplasmic complex including APC, Axin and GSK3β (glycogen synthase kinase 3β) which regulates phosphorylation of β-catenin and thus targets it for destruction via the SCF E3 ubiquitin ligase

 

44

Wnt present ⇒

dissociation of APC complex and GSK3β inactivated, therefore releasing β-catenin to perform its function

45

loss of APC or activating mutations of β-catenin itself in colon cancer

constitutive activation of β-catenin signalling

46

where else does β-catenin function

in cell adhesion

47

where also does GSK3β function

in glycogenesis

48

familial adenomatous polyposis (FAP)

associated gene

early tumour initiation

APC gene regulates colorectal cell proliferation via wnt signalling

referred to as gatekeeper

49

hereditary non-polyposis colorectal cancer (HNPCC)

gene

also known as

rapid tumour progression

MMR mutations cause the MIN class of genome instability

15% of sporadic colorectal carcinomas display MIN phenotype

Lynch syndrome

50

function of gatekeeper genes

required for net cellular proliferation

maintenance of a constant cell number in renewing populations

51

mutation of a gatekeeper leads to

a permanent imbalance of cell division over cell death

52

role of gatekeepers in different tissues

can be expressed ubiquitously

may function as gatekeepers in only 1 or a few tissues

redundant, expendable or perhaps play different roles in other cell types

53

examples of gatekeeper genes

NF1 in schwann cells

Rb in retinal epithelium

VHL gene in kidney cells

** not yet reported for majority of human malignancies but will be important for our understanding and future treatment of cancer

54

Rb and gatekeeper concept

how can a retinoblastoma arise

human retinal progenitor (stem) cells give rise to 7 different cell types but only in 1 of these, the cone-precursor, does loss of Rb result in transformation (in others - either no effect or apoptosis)

molecular circuitry of cone-precursor (possibilities identified by authors include - high expression of N-myc, SKP2 and MDM2) allows them to proliferate and become transformed when Rb is lost

specific molecular circuitry likely to be a paradigm for all so-called gatekeeper genes 

55

what is DNA damage response (DDR)

biochemical signalling pathways that respond to structural perturbations in the genetic material e.g. DNA damage

transient "normal" structures generated during cell proliferation also sensed e.g. ongoing DNA replication prevents exit from S phase until replication is complete

DDR regulates co-ordinated cellular responses to DNA damage and replication structures = checkpoint responses

once repair is complete cells re-enter the cell cycle and resume proliferation in a regulated process - recovery

56

inefficient DDR =

genome instability

easily repairable lesions are converted into mutations

57

biological response to DNA damage

58

checkpoint in G1

prevents cells going into replication - damage is repaired

59

checkpoint in S

detects any damage

60

checkpoint in G2/M

prevents cells going into mitosis e.g. DNA double strand break

part of the chromosome is not attached to centromere - during mitosis chromosomes would segregate but broken fragment of chromosome would stay in the middle of the cell

BRCA1 and BRCA2

61

key players in the DDR

recruitment and activation of protein kinases

typical of signal transduction in general

2 TYPE OF PKs

  1. phosphatidylinositol 3-kinase-like kinases or PIK kinases e.g. ATM and ATR - do not phosphorylate the lipid - phosphatidylinositol, at the 3 position -OH of inositol ring, but instead serine/threonine directed protein kinases
  2. checkpoint kinases or CHK kinases e.g. CHK1 and CHK2

62

2 types of PKs - DDR

  1. phosphatidylinositol 3-kinase-like kinases or PIK kinases e.g. ATM and ATR - do not phosphorylate the lipid - phosphatidylinositol, at the 3 position -OH of inositol ring, but instead serine/threonine directed protein kinases
  2. checkpoint kinases or CHK kinases e.g. CHK1 and CHK2

63

ATM mutation names

pattern of inheritance

symptoms

when does it develop

ataxia telangiectasia, BOder-Sedgwick or Louis-Bar syndrome

rare, autosomal recessive disease (non-essential)

progressive loss of purkinje cells in the cerebellum, affecting motor skills (ataxia = poor co-ordination)

telangiectasia = prominent BVs in whites of eyes

symptoms develop in toddler years and post patients die by age 20 from bronchopulmonary infection and/or malignancy

increased incidence of tumours - lymphomas/leukemias

half of patients have immune problems

poor appetite

hypersensitivity to ionising radiation

64

ATR mutation names

pattern of inheritance

 

seckel syndrome

microcephalin primordial dwarfism

harper's syndrome

bird-headed dwarfism

rare autosomal recessive disease (ATR is an essential gene - caused by hypomorphic rather than null mutations - wouldn't get past early development)

1 of several proportionate dwarfisms of prenatal onset

severe microcephaly with a bird-like head appearance - protrusion of nose, large eyes, low ears, small chin, mental retardation

65

activation of PIK kinases (ATM/ATR)

ATM - DNA double strand break

ATR - single stranded DNA

66

activation of CHK kinases (CHK1/CHK2)

role of adaptors/mediators

CHK1 and CHK2 are released from lesion sites

67

G1 checkpoint

drives expression of p21

68

hypothesis - proto-oncogene and DNA

early in development of cancer oncogene activation of a proto-oncogene causes increased DNA replication stress resulting in activation of the DDR and cell cycle arrest or apoptosis

69

evidence to support that DDR is activated at early stages of lung cancer

  1. NSCLC, as well as for malignant melanoma that the DDR is activated at early (pre-neoplastic) stages of tumorigenesis
  2. bladder carcinoma, as well as for carcinomas of the breast, colon and lung that the DDR is activated at early stages of tumorigenesis
  3. DDR is not appreciably activated in any normal proliferating tissues e.g. normal colonic crypts, which have a higher proliferation index than most cancers, or even in tissues experiencing inflammation (hyperplasias)

IMMUNOHISTOCHEMISTRY, EXPERIMENTALLY INDUCED HYPERPLASIA, OVEREXPRESSION OF ONCOGENES

⇒ constitutive activation of the DDR pathway commonly occurs at pre-invasive stages of major types of human tumours

70

is the DDR activation in the earliest cancer lesions

yes - in hyperplasias as well as earliest cancer lesions

71

S phase promoting oncogenes and DDR

DDR induced in cultured cells upon expression of S phase promoting oncogenes

72

what does oncogenic activation result in

replication stress (SSBs/DSBs) which both activate DDR/checkpoint

activation of DDR

checkpoint dependent apoptosis (p53 dependent) and senescence suppress expansion of precancerous lesion i.e. tumour suppressive

subsequent mutations of DDR results in loss of these crucial tumour suppressive mechanisms and further evolution of cancerous phenotype

telomere attrition and hypoxia can also contribute to formation of DSBs

73

conclusions