Cancer and senescence Flashcards
(29 cards)
What is the evidence that cancer development is a multistep procress?
- epidemiological data (coincidence increases with aging)
- Two-hit hypothesis
- Oncogene cooperation in cell culture transformation (Weinberg 1983 and 1999)
- Genetic model of colorectal tumourigenesis (Vogelstein 1990).
- Cancer genome and epigenome sequencing (post 2005)
What is the evidence that accumulation of mutations alone is not enough to explain later-life cancer?
- The adenoma to carcinoma of colon cancer only takes around 10 years. but aren’t diagnosed until 70s so why does it take so long? Don’t know yet.
- Osteosarcoma- diagnoses in adolescence, why so early accumulation?
3, In normal tissue, mutations accumulate in early development mainly. This is not the same as in cancerous cell and don’t know why it is different? Must be a reason and so doesn’t fit with the simple idea of accumulating mutations with age.
So other poorly defined changes in aging cells, tissues must contribute.
What are the two key phenotypes of senescent cells?
- irreversible proliferation arrest.
- the inflammatory secreatome.
Still metabolically active, just don’t divide.
What does SASP stand for?
senescene-associated secreatory phenotype.
How does senescence contribute to aging?
Block cell renew (senescent stem cells), chronic inflammation (damaging levels of IL-6 in the blood), accumulation of "damaged" dysfunctional cells (don't function correctly in the tissue)
How does senescence prevent cancer?
- Block cell proliferation
- Immune clearance- secrete immune cell regulators. ie. activate immune system to get rid of damaged, protentially cancerous, cells.
What are some triggers of senescene?
short telomeres, activated oncogenes, oxidative stress and other stresses.
What are the two functions of telomeres?
- prevent end-to-end chromosome fusion.
2. suppress DNA damage signals.
Which two properties of Pol cause the end replication problem?
- only synthesises 5’ to 3’,
2. Only initiated when a RNA primer is present.
How do activated oncogenes lead to senescence?
eg RASG12V. causes unscheduled dna synthesis, causing stalled replication forks. these are unstable and can break. The free DNA strand triggers DNA damage signalling.
How do we detect senescent cells?
Markers: no proliferation markers ie cycline. markers of autophagey and DNA damage. Expression of cycle inhibitors. chromatin changes.
What evidence links senescence to aging?
- senecent cells accumulate in normal tissues with ages (eg p16 positive melanocytes)
- senescent cells are associated with some age-pathologies eg oesterthrotis, atherosclerosis, liver cirrhosis.
- GWAS. linked genetic variation to prediclotion to aging diseases. in the p16 and its regulators loci.
- remove senescent cells form aging tissues to reverse the phenotype (reversal of premature aging phenotype in mice by removing senescent cells- caused them to die. less muscle, fat loss, no cataracts). baker et al 2011.
What is the evidence that in the long term senescene leads to cancer?
Loss/gain of DNA methylation in senescent cells is in a very similar pattern to cancerous cells (adams lab; Cruickshanks et al 2013).
What is the evidence that reactivating senescence may be theraputic for cancer?
Proof of principle experiments by Xue et al 2007. Injected cancer cells into liver of mice and the cancer progressed (grows). Reactivated p53 to prevent cancer growth (regresses), induce senescene in the cells as associated with the marker beta-galactosidase.
What does p16INK4a inhibit?
cyclinD/cdk4, allowing activation of pRB.
What does pRB inhibit?
E2F which drives cell cycle progression. Transcription factor for S phase genes.
Who may p16 be regulated?
epigenetically using the H3K27me mark at the INK4a gene promoter. In unstressed cells polycombs repress p16 expression by creating and binding to this mark to cause changes in the histone code and repress expression. Stress some how inhibits these by either a. a loss of EZH2 (part of PCR2) and so decreases the methylation b. an increase in histone demethylases and so a decrease in methylation c. using chromatin remodelling enzymes or d. involving transcription factors.
In what two ways does autophagy play a role in senescence?
- before it is senescent contributes to cell remodelling, eg the shape and chromatin state. 2. Once senescent it provide raw material to synthesis proteins which will be secreted.
Which 5 types of markers are used to detect senescent cells?
- Lack of proliferation markers eg K167.
- Signs of active autophagy pathways (low ph beta-galactosidase)
- Expression of cell cycle inhibitors (p16 and p21)
- Chromatin changes
- DNA damage markers (gammaH2AX and 53BP1)
What is the evidence that senescence mediated tumour suppression?
- senescent cells are associated with early stage/benign neoplasms eg melanocyctes in nevi. not found in melanoma.
- Senescent cells are absent from advanced neoplasms. (inactivate RB/p53 progresses to cancer).
- Inactivating genes that drive senescent, eg p53, accelerates progression of early stage lesions to advanced cancers.
- reactivation of p53 in tumours causes regression, associated with senescence.
Describe the progression of melanoma.
normal skin TO nevi TO radial growth phase melanoma TO lateral growth phase melanoma TO metastasis. BRAF/N-RAS mutations are associated with the progression form nevi to melanoma. PTEN and CDKN2A (codes p16/ARF) inactivating mutations are associated with metastasis.
Who looked at nevi and melanoma and found both had the same levels of BRAF mutations?
Pollock et al 2003, asked we didn’t all nevi then progress to melanoma. Analysed DNA sequences.
Who answered Pollock et al 2003’s question concerning melanoma progression?
Michaloglea et al 2005. The melanocytes in nevi were senescent, showed they were proliferation negative and had markers including p16 and beta-galactosidase. Concluded futher genetic or epigenetic changes were required for progression and senescence was a protect mechanism to this.
What is some genetic evidence of senescence acting as a cancer barrier?
A mouse model of pancreatic cancer: inactived p53/p16 pathways caused progression. PTEN insured senescence and its inactivation in one allele drove cancer progression.
