cancer biology Flashcards
what can you see when you look at cancer tumour
-different layers of cells
how does cancer occur
-disease of aberrant cell proliferation & differentiation
cancer incidences in the west
-high levels of cancers in oral cavity and pharynx, digestive organs, respiratory system, breast, reproductive tract, urinary system, blood and skin melanoma
-lower levels in nervous system, endocrine and thyroid system, bones
cancer incidences across the world
-lots of Japanese -> Hawaii migration showing cases in Japan to hawaii
-they have low levels of prostate, colon and breast cancer, but high levels of colon cancer in Japan
-caucasians have much higher levels of prostate cancer and much lower levels of colon cancer
what are the environmental influences of cancer
-Infection
-Diet
-Noxious agents
how does infection cause cancer
-viruses integrate into the genome frequency
-Src= master regulator in signal pathway for cell adhesion and proliferation and mobility
-Scr stands for sarcoma
-Peyton Roux:
=chicken with sarcoma in breast muscle
=remove sarcoma and break up into small chunks of tissue
= grind up sarcoma with sand
=collect filtrate that has passed through the fine pore filter
=inject filtrate into young chicken
=observe sarcoma in injected chicken
-Cancer arises because the virus encodes a hyperactive form of a human tyrosine kinase gene
-other examples ;
=Nasopharyngeal carcinoma (caused by Epstein-Barr virus)
=Cervical carcinoma (caused by human papillomvirus)
=Kaposi’s sarcoma (caused by human herpesvirus 8)
=Helicobacter pylorii can turn into gastric carincoma
-viruses
how does diet lead to cancer
-Aspergillus oryzae (koji mold – rice , peanuts) leads to hepatocellular carcinoma
-diet, overweight, lack of exercise, alcohol
how does noxious substances lead to cancer
-Asbestos (naturally occurring silicate) leads to mesothelioma- Diffuse pleural
mesothelioma (fatal)
-uv and ionising radiation
-occupational carcinogens
what else can cause cancer except environmental factors
-genetics
-Retinoblastoma
-Li-Fraumeni Syndrome
-Wilm’s Tumour
-Gorlin’s Syndrome
-Breast Cancer Syndrome
-Familial adenomatous polyposis coli (FAP
what can cancer be a consequence of
-chromosomal changes
-CML for example
what underlies CML
-chromosomal translocation (swapping of genes)
-Fluorescent In Situ Hybridisation
Why does this chromosomal translocation have such a devastating effect
-Fusion of two genes:
=ABL (9q34)
=BCR (22q11)
-kinase (phosphorylates other things) and a target protein which is turned off and (the kinase) a positive regulator of cell growth
-When fused to BCR, it cannot switch itself off
-ADP->ATP
-target protein switched on-> constant proliferation
what an oncogene
-A gene with the potential to cause cancer by transforming cellular behaviour
how do oncogenes come about
-Oncogenes are genetically DOMINANT
-arise from normal genes in cells regulating proliferation
-proto-oncogene ->
=deletion point mutation in coding sequence-> hyperactive protein made in normal amounts
=regulatory mutation -> normal protein greatly overproduced
=gene amplification-> normal protein greatly overproduced
=chromosome rearrangement-> nearby regulatory DNA sequences causes normal protein to be overproduced OR fusion to acovly transcribed genes produces hyperactive fusion protein
what was the first human oncogene
-Ras
-binds to GTP
-the last phosphate that binds in GTP is very close to 2 AA - glycine 12 and glutamine 51
whats Ras
- a protein called Sos that exists in 2 conformational shapes
-depedening whether it binds GTP or GDP
-when its bound to GTP its on, off for GDP
-a proto-oncogene
how can you change Ras from being off-> on
-nucleotide exchange
-another protein goes to approach Raw, reaches in a grasp GDP and pulls it out of the protein
-bc there’s lots of GTP floating around in cell, GTP then binds, and its switched on
-extrinsic
how does Ras get turned off
-Ras is an enzyme
-catalyse hydrolysis of GTP-> GDP to turn Ras off
-Ras isn’t good at doing this toug- bad enzyme
-intrinsic
whats The importance of ras in growth factor-induced growth
-EC queues to IC effects
-receptor tyrosine kinase in plasma membrane
-growth factor binds to receptor in tyrosine kinase causing them to dimerise
how does Ras get turned into an oncogene
-if mutation occur in the 2 AA, then there is an abolishment of GTPase activity meaning Ras can’t turn off ever
hypothesis for cell fusion experiment
-Normal cells express tumour suppressor genes that are lost during oncogenesis
-says hybrid cells are non-tumerogenic
Might tumour suppressor genes exist
yes- loss of growth suppressor gene more likely than gain-of-function oncogene mutations
no- loss of both alleles of putative growth suppressor genes unlikely
whats Retinoblastoma
-arises sporadically as well as in families
-usually only affects one eye- unilateral
Knudsen’s one/two-hit hypothesis: why was it important
provides evidence that:
- for tumour suppressor gene hypothesis
-that cancer requires loss of both wild-type alleles
-for the basis of inherited predisposition to cancer
what does Cytogenetics provides evidence for
-a Chr13 deletion in inherited retinoblastoma
-Allow people to design probes that would sequence your way through this chromosome to figure out what was missing in that one
Identification of tumour suppressor genes in familial cancer syndromes
-Retinoblastoma
-Li-Fraumeni Syndrome
-Wilm’s Tumour
-Gorlin’s Syndrome
-Breast Cancer Syndrome
-Familial adenomatous polyposis coli (FAP)
Comparison between oncogenes and tumour suppressor genes
-oncogenes:
=effect on mutation=Activating Gain of function Dominant
=number of alleles mutated to exert effect= one
=Effect on function of the protein product= enhanced
-TSG:
=effect on mutation= Inactivating Loss of function Recessive
=number of alleles mutated to exert effect= 2
-effect on function of the protein product= reduced
whats required for tumorigenesis
-More than one mutation
-increase in age= increase in cancer chances
