Causes of cancer Flashcards
What is the risk assessment for carcinogens?
Definate carcinogens Probable carcinogens Possible carcinogens -potency -type of exposure -dose response
Describe the agents of outdoor pollution
Particulate matter Nitrogen dioxide Sulphur dioxide Ozone gas Carbon monoxide Polycyclic aromatic hydrocarbons (PAHs)
What is the significance of asbestos?
Almost exclusively causes pleural mesothelioma
List some water contaminants
Arsenic- bladder, skin, lung
Nitrates- stomach, non-hodgkin lymphoma
Radium- leukaemia
Chlorination by products- bladder
List groups of people with risk of cancer from radioactive sources
Japanese atomic bomb survivors Underground minors Radiologists Luminous dial painters Generally public- from solar radiation
Name the cancer causing viruses
Epstein-Barr virus (EBV)
Hepatitis B (HBV)
Human T cell lymphotrophic virus type 1 (HTLV1)
High-risk human papilloma virus (HPV16, 18, 45)
Hepatitis C (HCV)
Kaposi’s sarcoma herpes virus (KSHV)
Merkel cell polyomavirus (MPV)
Describe Epstein Barr virus and cancer
Endemic Burkitt lymphoma- 4-7 yrs Sporadic Burkitt lymphoma 11 and 30yrs Hodgkin lymphoma 20-24 70-80yrs Nasopharyngeal carcinoma Gastric carcinoma
Describe the causes of Burkitt lymphoma
EBV
Malaria
C-much translocation to the Ig heavy or light chain
Describe the causes of Kaposi’s sarcoma
KSHV
- classical- v rare
- iatrogenic (immunosuppression)
- HIV/AIDS patients
Describe the causes of skin cancer in EV
HPV5, HPV8
UV light
Epidermodysplasia verruciformis gene mutation
Describe the causes of hepatocellular carcinoma
HBV and Aflatoxin
How do viruses act as carcinogens?
Direct- introduction of a vital oncogene into host cell, activates an endogenous oncogene, inhibits a tumour suppressor gene
Indirect- causes chronic inflammation, prevention of apoptosis, virus induced immunosuppression (HIV)
They prolong cell cycling allowing the cell to live longer and squire more genetic mutations and promote cell survival making cancer more likely
Same some protein targets of virus that cause cancer
HPV encodes E7 which binds RB so it releases E2F-1 that activates transcription of S phase genes
And encodes E6 which binds p53, which is activated in response to uncontrolled cell cycling, and promotes its ubiquitination and therefore degradation so it cannot initiate transcription of apoptosis eg. p21
Describe HPV vaccination
HPV1) and 18 most prevalent HPV type in cancers
Cervical cancer arises at the “squamocolumnar” junction of the cervix
Vaccine is the proteins that make up the virus particle that assemble into the native 3D structure when in cells and so initiates a good antibody response
Describe the function of the retinoblastoma protein
Tumour suppressor
Unless hyperphosphorylated, prevents progression through the restrictions point in G1 to S phase
When hypophosphorylated, bound to E2F, DP, GDAC and p300
Phosphorylation of pRB by cycD and cdk4/6 removes HDAC
Phosphorylation by cycD and cdk2 removes RB from the complex activating transcription
p16(ink4a) is a cdk inhibitor and promotes cell senescence
Describe the role of p53
Activated by ATM, CHK2 as apart of the DNA damage response
Regulated by mdm2 a E3 ubiquitin kinase
Activated by CBP, TRAF, PCAF P300 ASPP1
Promotes anti-angiogenesis (tsp1), growth arrest (p21), DNA repair (p48) and apoptosis (DRS, Fas)
When are the cell cycle checkpoints?
R point in G1 G1/S Replication point in S phase G2/M Antephase checkpoint before mitosis Spindle checkpoint in M phase
What is the DNA damage response to checkpoint arrest?
DSB- MRN➡ ATM➡ BRCA1/53BP1➡ Chk2/p53- effectors
SSB- RPA➡ ATR/ATRIP➡ TopBP1/Claspin➡ Chk1- effector
Facilitated and amplified by Rad17 and H2AX
Describe telomeres
Nucleoprotein structures that protect chromosome ends- 10-15kb in humans
Maintained by telomerase (hTERT) and an RNA template (TERC)
Telomere length is maintained in cancer to immortalise the cell
Telomere DNA is associated with the proteins TRF1 and 2
With a 3’ overhang of 250-200nt
Forms a D loop of ssDNA protected by Pot1 and a T loop of dsDNA, this is so out does not look like a DSB
Describe senescence
STress and Abberent Signalling Induced Senescence (STASIS)
Inhibitors of cdks- p21 and p16
Describe TRF
Telomere repeat binding factors-Shelterin
TRF1 Contains TANK, TRF1, TRF2, POT1, PTOP, RAP1, TIN2
TRF2 contains ERCC2, TRF2, ORP1, WRN, BLM, KU86, ATM, MRE11/NBS1/RAD50
What is the significance of histone methylation of telomeres?
RB regulates H4K20Me3
SUV3aH2 regulates H3K9Me3
Loss of either results in the extension of telomeres and opening of chromatin
What induces M1 senescence?
DNA damage➡ ATM➡ p53➡ p21➡ growth arrest
In cells that bypass M1 senescence, telomeres continue to erode so that cannot protect the chromosome and crisis is triggered- apoptosis
What induces M2 senescence?
Many short telomeres induce the DNA damage response
ATM/ATRIP dependent- components of TRF2-shelterin complex
Dicenteic chromosomes trigger apoptosis
Describe cell immortalization
Mutations in critical genes and maintainence of telomeres via telomerase or ALT pathways
What is ALT?
Alternative lengthening of telomeres
Strand invasion of the template molecule and formation of HR intermediate
Copying
Dissolution of HR intermediate
Possible filling of complementary strands
Describe telomerase as a possible cancer therapy
Oligonucleotides complementary to the TERC template
Telomerase targeted immunotherapy
Targeting telomerase- expressing cells with suicide gene or oncolytic viruses
Describe the PI3-kinase pathway
Receptor tyrosine kinase➡ PI3-kinase➡ PI(3,4,5)P3➡ PDK1➡ Akt➡ mTOR
Cell survival and proliferation
What is the action of Akt?
Phosphorylates a variety of targets like Bad
Upon phosphorylation Bad releases active apoptosis-inhibitory protein which promotes cell survival
mTOR complex 1 (complex two helps to activate Akt)- contains the protein raptor, sensitive to rapamycin
Stimulates cell growth by promoting ribosome production and protein synthesis and inhibiting protein degradation
Akt inhibits the action of Tsc2 a GAP that inactivates the molecular switch Rheb, so Rheb remains GTP bound and can activate mTOR
How do you turn the growth and survival signal off?
Removal of receptor ligand
Switching the activated RTK off using protein tyrosine phosphatases (PTPs- SHP1, SHP2)
Dephosphorylation of target proteins by serine/threonine phosphatatases
PTEN- inositol lipid phosphatase- removes s phosphate from PI(3,4,5)P3 spo jit is no longer a docking site for PDK1 or Akt
Describe the importance of the EGF receptor family in cancer
EGFR1 activated by ligands such as EGF and TGFalpha
HER2 heterodimerises with EGFR1
Over expression and amplification of EGFR family members are implicated in 30% cancers
Describe the treatment of cancer with monoclonal antibodies
Cetuximab- humanised anti-EGFR1 antibody
Only approved is patients with wildtype Ras
Used to treat colon, lung, head, neck and pancreas cancer
Trastuzumab (herceptin)- humanised anti-HER2 antibody
Used in patients over expressing HET2
Used in breast cancer
Imatinib- blocks the ATP binding site in the tyrosine kinase domain in the BCR-ABL fusion protein so it cannot phosphorylate target proteins and stimulate proliferation
How were oncogenes first identified?
Sarcomna in chickens can be transfered to previously undiseased chickens
Caused by a virus
Virus contains homologous genes to those found in the target species that cause the cancer- one must have been derived from the other- viral oncogene is a ‘pirated copy’ of the cellular gene
(Using a radioactively labeled ssDNA copy of the v-src from Rous Sarcoma- annealed to melted chicken DNA)
What is the significance of Avian Leukosis virus (ALV) in oncogene discovery?
Infection can lead to bursal lymphomas
Lag in tumour development as the virus needs to be randomly inserted in to the genome close to the c-myc gene
Provirus integration allows the strong enhancer in the LTR to induce deregulated transcription of the c-myc gene
How can oncogenes be amplified to cause cancer?
Chromosomal translocation eg. 8:14/2/22 in Burkitts lymphoma
The c-myc gene is placed near the immunoglobulin genes which are highly expressed in B cells and the expression of the c-myc gene is then constitutively increased
Gene replication
Double minute chromosomes
What is myc?
A transcription factor
Heterodimerises with max to activate transcription of S phase genes
Max homodimerises to suppress gene transcription in the absense of myc
What is the importance of tyrosine kinase in cancer?
Amino acid changes or over expression can lead to contituative activation or constant phosphorylation and cell growth cascades
Eg. Pp60c-src a non-receptor tyrosine kinase- often over expressed in colon, liver, lung, breast and pancreas tumours binds to phosphorylkated receptors and the kinase domain becomes active leading to survival and proliferation
Describe Ras
Commonest oncogene mutated in human tumours
Common cancer causeoing mutations at codons 12,13 or 61
Is a molecular switch-inactive Ras-GDP➡ active ras-GTP (GEF)
Ras-GTP➡ ras-GDP (GAP- Ra’s has intrinsic GTPase)
Reduced GTPase activity results in a constant ‘on’ leading to constitutive signalling
➡raf➡ mek➡ erk
What is the significance of the retinoblastoma protein?
Classical example for a genetic predisposition to cancer
Recessive at the cellular level
Almost inevitable that after all the necessary cell divisions that one retinal cell with acquire the mutation to inactivate the remaining RB1 gene in the heterozygote- therefore the cancer shows dominant inheritance
Also shows increased incidence in other cancers- loss of heterozygosity
RB is a master controller of the cell cycle controlling S-phase entry- when hyper-phosphorylated dissociates from E2F at R-point allowing the transcription of genes for S-phase
What are some mechanisms for loss of function of tumour suppressor genes
Deletion of chromosome region
Whole chromosome loss
Transcriptional silencing- aberrant methylation of promoter region
Virus targeting
Lists some other tumour suppressor genes involved in pathways controlling cell proliferation
NF1- Ras-GAP- associated with Neurofibromatosis type 1 and colon carcinoma, astrocytoma, AML
APC- beta-catenin degradation- associated with familial adenomatous polyposis coli and colorectal, pancreatic, gastric and prostate carcinoma
PTEN- PIP3 phosphatase- associated with Cowden’s disease, breast and GI tumours and glioblastomas, breast, prostate, thyroid carcinomas
What is the significance of p53?
It is the ‘Guardian of the Genome’
Regulates cell cycle arrest, DNA repair, block of angiogenesis and apoptosis in response to lack of nucleotides, UV, IR, oncogenic signalling, hypoxia, blockage of transcription
Unlike most tumour suppressor a p53 mutations are predominately Mis-sense and a single allelic loss confers predisposition to cancer alone
DNA damage stabilises p53 via phosphorylation so it is not ubiquitinated by MDM2
Mutations in the DNA binding domains prevent the transcription of cell cycle arrest proteins like p21
List other tumour suppressor genes that are involved in maintaining the integrity of the genome
BRCA 1+2- DSB repair- associated with familial breast and ovarian cancers and breast, ovarian, prostate and pancreas
ATM- DSB repair- associated with ataxia Telangiectasia, leukaemias, lymphomas and breast cancers
