cancer 1 Flashcards
what environmental factors may cause cancer?
- altered immune response/altered conditions in the body
- exposure to carcinogens
what does current work want to identify in cancer formation?
what to identify how benign tumour becomes metastatic
what are fancy mice?
mice that started by being inbred by the chinese for desired characteristics
- 1930s - inbred strains kept by the jackson lab
what was found in some of the inbred strains of mice in 1930s?
Some of the inbred stains were more suseptible to mammary tumours
- female mice developed mammary tumours at a high incidence in these strains
what is a mammary tumour?
A tumour which develops in mammary glands (milk producing glands)
in 1983 how was it discovered that mammary tumours form?
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
what was the transcriptionally upregulated gene identified in the mouse mammary tumours?
Int1
30% cases mmtv integrates upstream of int1
what is mmtv?
mouse mammary tumour virus
LTR is strong promotor
why were biochemical assays on int1 impossible?
As int1 was difficult to purify
- in the mean time studies in drosophila made enormous contribution to understanding int1
what is int1 also know as?
Wnt1 in the drosophila
- patterning gene
- segment polarity gene
how is wnt1 signalling mediated?
By B-catenin
- activation of B catenin so it accumulates in the nucleus and activates target genes
what happens to Bcatenin in the absence of wnt?
- 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)
what are wnt1 levels like in mammary cells?
high wnt1 levels
is there any evidence that wnt1 overepxression can lead to human cancers?
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.
which pathway components elict supressive/negative effects on wnt signalling?
wnt5a apc axin sfrp tcf1 (tumour supressors - 2 LOF copies needed to upregulate wnt - cancer risk)
which pathway components elict activating effects on wnt signalling?
Wnt1
B-catenin
frat
lgs
(one faulty copy needed to have an effect)
what is the most common form of human cancer linked to abnormal wnt signalling?
Colon/colorectal cancer
- activation of Bcatenin
- 2x LOF apc
what is seen in early colon cancers?
elevated levels of B catenin
ademona/tumours
what was transgenic reporter mouse produced to respond/show wnt signalling?
Tg (Axin-lacZ)
- Axin urned on by wnt signalling
- lacz expressed where axin/wnt signalling is active
what parts of the body are shown to be responsive to wnt signalling?
tissue specific stem cells
- proliferate(self renewal) in response to wnts
- uncontrolled self renewal - oncogenesis
what is oncogenesis?
formation of cancer cells from healthy cells
what genes are activated by wnt signalling? (2007)
-cell cycle regulator genes
cmyc, cyclinD1
where is the best studied stem cell niche?
- in the gut - stem cells respond to wnts
- crypt base columner cells
what gene was found and traced from CBC cells?
Lgr5 - expressed in cbc cells
- use CreERT2 to lineage trace
- shows lgr5+ cells are stem cells
- shows is a TAP population
