BG7 Flashcards
Cancer adaptations
- self-sufficiency of growth mechanism: most cells grow when stimulated by growth signals.
- HRAS mutations allow indep. growth. - antigrowth signals; some mutations prevent antigrowth working
- Rb mutations - PCD; cancers evade by produce IGF survival factors
- hayflick limit; remove by switching on telomerase
- angiogenic factors VEGF inducer: tumours get larger requrie bloood vessels
- metastasis: late stage cancer invade surrounding tissues
- E- cadherins mutations
NS in cancer
mutation arises increases proliferation - advantage
mutation arises allowing to break free of environment and spread = selected for
cancer phylogenies
can reconstruct e.g. breast cancer cell phylogeny shows all cancer cells are descended from a CA and belong to sub-clones with particular genotypes.
ancestral to metazoa?
appear in mollusca, arthopoda, vertebrata etc
failure of host adaptation to novel envrionment
- carcinogenes UV toxins etc
- growth mechanisms of animals not adapted to them - aging: no selection to maintain soma.
- cancer is special case of aging
james graham
aruged cancer was result of new cellular conditions arising in evolution and failure of adaptation
analogy: change product in factory = product decline, takes a while to fix the kinks
argued snail shells werent anti-predation but anti-cancer
- armand revived the theory
examples backing JG hypothesis
would expect more cancer in organisms with more rapid morphology changes
- large dogs = more likely to get sarcomas, likelyhood increases up to 40kg then plateus. = anti cancer mech yet to evolve?
- ovarian cancer in hens selected to produce more eggs
- hair follicle ovarian cancer - failure of anti-cancer mech to catch up in short length of time`
rapid evo in nature?
pediactic cancers are rare
increased risk of osteosarcoma in children tall for their age, occurs at puberty. suggests analagous to dogs. due to pubertal growth spurt
osteosarcoma due to rapid evo of growth rate, anti cancers havent had time to catch up and suppress extra proliferation
growth rate in humans compared
macaques dont have pubertal growth spert
paleontologists suggest homo eretus didnt have a grow spurt
cancers found mostly in adults
= colon, lung, prostate, endothelial
- almost non existant in children
cancers common in children
`1. nervous system tumours - in brain, which has gone fast evo, 3x bigger than apes
2. childhood leukaemia: immune systems have been undergoing continued rapid evo in response to pathogens
arguument for prevelance of childhood cancers
child cancers arent the consequence of exposure or old age, but result of evo changes in morphology as tissue hasnt evolved anti-cancer devices yet
e.g. gut tissue proliferates as much in children as adults but dont see gut or skin cancer in children, sorted out kinks as older in evo time?
animal diversity in body size
differ enormously mammals = 0.02kg dog =20kg human = 75kg whale = 150,000 kg cell size is similar so cell no. must be greater. 6/7 magnitudes between mouse and whale
neoplasia and body size
if risk of neoplasia is constant would expect bigger animals to have more cancers than smaller
all whales should get cancer.
Peto’s paradox
risk of cancer seems constant despite body size changes
wild mice = 46% death by cancer
dogs = 46% death by cancer (US)
humans = 22% death by cancer
nunny theory of cancer resistance
M = expected no. of mutations as function of cell no (c). M = 4(c-1)u M = 4cu-4u (4neU)
- if cell no. or somatic mutation rate increases, expect no. of mutations to increase
proportion of indviduals lacking a mutation
P = e^(-4u(c-1))
P decreases with no. of cells.
P = e^(-4u(c-1))
animal few cells proportion that lack mutation (p) = 1
animal 1 mill cells p = 0 (everyone has a mutation)
selection differential and cancer
if animal has cancer causing muttion which is lethal can estimate selection differential acting against cancer causing mutations S = 1-P, S = 1-e ^-4u(c-1) c = 1000 (c. elegans) u = 10^5 (know from data) selection differential = 0.04
what is required for selection to be effective
S > 1/N
S = 0.04
N = 100
1./ 100 = 0.01
even in small population size of 100 cells there will be selection for cancer resistance
** no. of TS genes increase in evo as animals increase in body size = constant rate of cancer
Tumour suppressor genes
defined as genes in which mutants causing lack of function cause cancer
homo/hetero = responsible for most ases of inherited cancer
inherited cancer example TS
- mouse gets mutation and loses one copy TS in germline = gametes defective breeding produce hetero
mouse protected by single copy, another somatic mutation = gets no protein = neoplastic
commonly mutation TS leading to cancer
NFI - neurofibromatosis
BRCA1 - breast cancer
Rb - retinoblastoma eye
P53 - many cancer
solution to peters paradox
evolution of TS
- to get cancer need multiple losses of TS genes
- some cancers caused by mutations in single gene Rb, but others requrie sereis of mutations in multiple genes. - e.g. colon cancer
colon cancer need to have many mutations in many genes - suggest big animal have evolved more TS genes
tumour resistance due to TS
multiplicative
- probability of getting new mutation in any one copy of TS = P
probablility og getting two mutations [ p^2
more TS = more resitance
TS and body size
gaining one extra TS protects for a considerably larger body size until size increases again and need more.
cancer evolution and suppression fish
mexican fish
X. maculatus: platy = has spots for camoflage against cichlid predator
X. helleri = sword tail
- can hybridise to produce fertile F1 and F2
X. maculatus and X hellari cross phenotypes
F1 = intermediate
F2 = diversity of phenotypes
- some no spots, some some, some huge ones that develop cancer
** spots caused by melanocytes which have tendancy to cause tumours
X. maculatus and X. hellari cross genotypes causing cancer
interaction between two loci cause cancer
Tu-m = causes spots, cancer in hellari
Tu h = doesnt priduce spots or cancer
Diff -m = suppreses spots and cancer
Diff h = doesnt suppress cancer or spot
=== epistatic interaction, so F2 with tum and diffh get cancer = dissociated alleless
selection in x. maculatus
if hellari genotypes are ancestral
then maculatus has been under selection for cancer suppression due to spots.
dynamic begins leading to larger spots, greater suppression
homology of tu and diff
tu = homologous to EGF-1 = mammalian oncogene diff = homologous to CD2 = mamamlaian TS
why do large long lived animals not have a n increase risk of cancer relative to small?
cancer resistance mechs
- reduced rate of somatic mutation
- increased no. of selective barriers to mutations = TS
- reduced selective advantage of mutation
do large animals have relatively reduced rate of somatic mutation
humans = 5x10^11 bp/division mice = 1.8x10-10 humans = slower mutation rate.
what could mutation rate be related to
basal metabolic rate
- if mutations are caused by free radicals which are product of metabolism, a higher metabolic rate would produce more mutations.
although large animals have lower metabolic rate relative to body size
BMR increases with body size across species linear
reduced rate of oncogenic mutation
selection works on reducing oncogene mutation specifically? e.g. via oncogene deletion.
- little evidence, if oncogene missing could be sequence error, plus they are important
** teleomerase activity decrease relative to body size, humans little activity = tightly controlled potenitally to reduce risk of upreg that causes cancer
increasing no of TS
in mice
extra copies of p53 = tumour free for longer than WT, increased longevity
probs a cost to this
deep evo of TS
phylogeny of TS - no. of tumour suppressors spikes around origin o metazoa
dont seem to increase in more elaborate body plans
most TS seem to be ancient
elephant TS
19 copies of p53 hyrax = only 1 evidence that elephant cells undergo PCD more readily than humans perhaps due to DNA damage, more copies of p53 high expression in cells harder to make elephant cells neoplastic - requires more p53 KOs
naked mole rat
eusocial, burrowing, live for up to 35 years cancers never seen
naked mole rat and cancer
skin fibroblast produced hyluronan - composed of repeated disacchariddes of glucoronic acid and acetyl glucosamines
- - molecule also confers cancer resistance by altering contanct inhibition of cells.
if take cells and inhibit p53 and rb dont become neoplastic
Ko hyluronan by overepxression of breakdown enzyme they do.
