cancer 1

Question 1

what environmental factors may cause cancer?

Answer 1

• altered immune response/altered conditions in the body

- exposure to carcinogens

Question 2

what does current work want to identify in cancer formation?

Answer 2

what to identify how benign tumour becomes metastatic

Question 3

what are fancy mice?

Answer 3

mice that started by being inbred by the chinese for desired characteristics
- 1930s - inbred strains kept by the jackson lab

Question 4

what was found in some of the inbred strains of mice in 1930s?

Answer 4

Some of the inbred stains were more suseptible to mammary tumours
- female mice developed mammary tumours at a high incidence in these strains

Question 5

what is a mammary tumour?

Answer 5

A tumour which develops in mammary glands (milk producing glands)

Question 6

in 1983 how was it discovered that mammary tumours form?

Answer 6

Mammary tumours form when a retrovirus (mmtv) integrates into DNA upstream of a proto-oncogene
- the virus causes increased transcription of the protoncogene which results in proliferation and tumour formation

Question 7

what was the transcriptionally upregulated gene identified in the mouse mammary tumours?

Answer 7

Int1

30% cases mmtv integrates upstream of int1

Question 8

what is mmtv?

Answer 8

mouse mammary tumour virus

LTR is strong promotor

Question 9

why were biochemical assays on int1 impossible?

Answer 9

As int1 was difficult to purify

- in the mean time studies in drosophila made enormous contribution to understanding int1

Question 10

what is int1 also know as?

Answer 10

Wnt1 in the drosophila

• patterning gene
• segment polarity gene

Question 11

how is wnt1 signalling mediated?

Answer 11

By B-catenin

- activation of B catenin so it accumulates in the nucleus and activates target genes

Question 12

what happens to Bcatenin in the absence of wnt?

Answer 12

• bound to destruction complex by apc
• is phosphorylated
• is ubiquitinated by slimb
• is destoyed
• groucho is repressor

(groucho displaced by Bcatenin when wnt is present)

Question 13

what are wnt1 levels like in mammary cells?

Answer 13

high wnt1 levels

Question 14

is there any evidence that wnt1 overepxression can lead to human cancers?

Answer 14

no

• but mutations in the wnt signalling pathway can lead to many pre-cancerous states and cancers
• mutations in wnt signalling components which lead to its upregulation.

Question 15

which pathway components elict supressive/negative effects on wnt signalling?

Answer 15

wnt5a
apc
axin
sfrp
tcf1
(tumour supressors - 2 LOF copies needed to upregulate wnt - cancer risk)

Question 16

which pathway components elict activating effects on wnt signalling?

Answer 16

Wnt1
B-catenin
frat
lgs

(one faulty copy needed to have an effect)

Question 17

what is the most common form of human cancer linked to abnormal wnt signalling?

Answer 17

Colon/colorectal cancer

• activation of Bcatenin
• 2x LOF apc

Question 18

what is seen in early colon cancers?

Answer 18

elevated levels of B catenin

ademona/tumours

Question 19

what was transgenic reporter mouse produced to respond/show wnt signalling?

Answer 19

Tg (Axin-lacZ)

• Axin urned on by wnt signalling
• lacz expressed where axin/wnt signalling is active

Question 20

what parts of the body are shown to be responsive to wnt signalling?

Answer 20

tissue specific stem cells

• proliferate(self renewal) in response to wnts
• uncontrolled self renewal - oncogenesis

Question 21

what is oncogenesis?

Answer 21

formation of cancer cells from healthy cells

Question 22

what genes are activated by wnt signalling? (2007)

Answer 22

-cell cycle regulator genes

cmyc, cyclinD1

Question 23

where is the best studied stem cell niche?

Answer 23

• in the gut - stem cells respond to wnts

- crypt base columner cells

Question 24

what gene was found and traced from CBC cells?

Answer 24

Lgr5 - expressed in cbc cells

• use CreERT2 to lineage trace
• shows lgr5+ cells are stem cells
• shows is a TAP population

Question 25

what pathway is needed to maintain proliferative gut progenitors?

Answer 25

notch

Question 26

what are GM mice and inbred mice used to identify?

Answer 26

• proto-oncogenes and tumour supressors
• signalling pathways which lead to tumour types
• which genes may give rise to cancers
• understand basic biology at cellular level
• impact of diagnostics and treatments

Question 27

what are BCSCs?

Answer 27

breast cancer stem cells

• showed have to target lots of signalling components to eliminate cancer (e.g. notch, wnt, hh)
• BCSCs resistant to anti-oestrogen treatment- so aim to treat with combination of anti-oestrogen and anti-notch/hh/wnt

Question 28

what can be done next in animal models to help understand cancer?

Answer 28

• correlate signalling pathways with tumour aggression

- find other genes that retard/accelerate tumour formation

Question 29

how is inflammation linked to cancer progression?

Answer 29

constititively active wnt 1 actives rac 1

• this activates ros and NF-kB
• this causes hyperproliferation of stem cells-tumorigenesis

Question 30

what is Nf-kB?

Answer 30

a proinflammatory factor

- activates pro-inflammatory genes e.g. cytokine, chemokines

Question 31

what is potential inflammatory mechanism which leads to tumour aggretion?

Answer 31

• tumour grows - demand for oxygen and nutrients strips the supply
• cancer cells secrete pro-inflammatory signals(cytokines)
• macrophages invade tumour and secrete more cytokines
• this kick starts ANGIOGENESIS - growth of new blood capillaries)
• inflammatory singals also help break down ECM - may help in metastasis

Question 32

what is required for a lgr5+ intestinal stem cell to transfrom into a metastatic tumour?

Answer 32

Rac1 (stimulates ros and nf-kB - stimulates inflammatory response)