Biology of Cancer

What are 5 ways cancer cells different to normal cells?
Loss of: Anchorage dependence, GF dependence, Contact inhibition, density inhibition, replicative senescence.
1 of 158
What is the relationship between the dosage of a carcinogen and the delay in tumour formation
Inversely proportional, meaning the greater the dose the shorter the delay
2 of 158
What is a possible explanation for the reason there is a delay between tumour formation and carcinogen exposure?
It suggests multiple independent hits genetically are required to produce a tumour (this is also seen in viral tumour viruses and the need for co-factors)
3 of 158
What is the function of telomeres
During DNA replication they fix the ‘end replication defect’, however limited replication is also a result of telomere shortening.
4 of 158
How does telomere shortening cause limited replication in normal cells & what is the result of this shortening
With each replication telomeres get shorter, at a certain length DNA is flagged as damaged and senescence and apoptosis occur via tumour suppressor networks
5 of 158
What are the tumour suppressor networks involved in telomere induced senescence / apoptosis?
p16INK4a / Rb and p53 / p21cip1
6 of 158
What is the name of the enzyme that maintains telomere length
Telomerase / TERT reverse transcriptase. Synthesis telomere repeats from a short RNA template
7 of 158
What % of human tumours express telomerase and what is the significance of this?
~85%. Meaning these tumour are able to constantly add telomere repeats and lose this senescence / apoptotic pathway of telomere shortening
8 of 158
Tumour cells achieve telomerase activity by reactivating expression, however a minority of tumour cells achieve long telomeres without reactivating this enzyme, what is the name of this pathway?
ALT pathway
9 of 158
Name for a gene that contributes to cancer and is derived from a cellular protocol-oncogene
10 of 158
Do oncogenes have a dominant or recessive effect
11 of 158
Name 4 ways in which oncogenes create cancer whereas proto-oncogenes do not
1. Overexpression. 2. Inappropriate expression. 3. Deregulation of protein product. 4. Altered specificity / function (translocations can create a whole new protein altogether which has a different function to the original pronto-oncogene)
12 of 158
What are the normal functions of protooncogenes
Cell growth / proliferation, regulation of apoptosis, differentiation and cellular life span
13 of 158
PDGF = and is released by what cell type
Platelet derived GF, platelets
14 of 158
How many different genes are there for PDGF
4 (A->D increasing in size)
15 of 158
Which of the 4 PDGFs are ubiquitous
A, B and C
16 of 158
What is the expression pattern of PDGF-D
Highest expression in: heart, pancreas and ovary. None is seen in brain, lung and muscle
17 of 158
All PDGFs have a conserved region of how many amino acids? And what residues do they all contain
100aa, cysteine residues allowing them to form disulphide bonds
18 of 158
PDGF form dimers to be ligands, how many isoforms of PDGF ligand are there?
19 of 158
Which two PDGF genes only form homodimers
C and D
20 of 158
What are the biological functions of PDGF? (3)
Embryonic development (kidney, blood vessels, lung, CNS), Adult blood vessels, Wound healing (fibroblasts, WBCs, SMCs)
21 of 158
Sis oncogene derives from a PDGF chain / gene. Which PDGF chain
22 of 158
Sis oncogene is an example of what type of expression?
23 of 158
EGF genres all contain a same core motif of how many amino acids, how many cysteine residues do they all have and how many peptide loops does this develop?
100aa, 6 cysteine, 3 loops (through the formation of disulphide bonds)
24 of 158
Are EGF proteins transmembrane?
25 of 158
What are the biological functions of EGF (2)
Wound healing (fibroblasts, regeneration of epidermis), in viva involved in embryonic development
26 of 158
TGF-Beta =
Transforming growth factor Beta
27 of 158
Are TGF-beta and TGF-alpha in the same family?
No, TGF-alpha is part of the EGF family
28 of 158
What are three proteins that are part of the TGF-beta family?
TGF-beta, Activin A, BMPs
29 of 158
How many TGF-beta isoforms are there and which is the most ubiquitous
5 and B1
30 of 158
Describe the steps of biosynthesis of TGF-beta
1. Complex of TGF-beta, signalling sequence and latency-associated protein. 2. The signal sequence is removed in the Golgi apparatus. 3. LAP-TGF-beta complex forms a homodimer with another complex via disulphide bonds. Homodimer is released into ECM
31 of 158
What are the two methods of activating TGF-B from its inactive form sequestered by LAP and held in the matrix at LAPs ECM binding sites?
1. Plasmin cleaves TGF-b from LAP. 2. LAP has an RGD sequence that binds to integrin (transmembrane protein that anchors cells to ECM). As the cell moves there is a mechanical pull that frees TGF-b
32 of 158
What is the significance of the mechanical activation of TGF-beta in tumorigenesis?
Matrix surrounding tumours is different to that of normal cells, and the mechanical activation opportunity presents much more widely in tumour cells.
33 of 158
What effect does TGF-beta have on cell proliferation?
Can be both pro or anti (but mostly anti), dependent on the growth environment. Slows down in fibroblasts but promotes NK cells
34 of 158
As well as cell proliferation what are other biological activities of TGF-beta
Cell adhesion (increased integrin, ECM proteins and inhibition of ECM degradation), cell differentiation, tissue repair
35 of 158
Fibroblast growth factor
36 of 158
How many FGF genes are there in humans and how many families are they divided into
22 genes, 7 families
37 of 158
What are the two favourable integration sites of MMTV (mouse mammary tumour virus)
Wnt-1 and FGF3
38 of 158
Once a ligand has activated a receptor, signalling is then regulated by (4)?
Affinity of ligand to receptor, duration of interaction, internalisation of receptor, receptor degradation (turn off) or cycling back (sustained)
39 of 158
What is a receptor tyrosine kinase (RTKs)
A catalytic receptor that has an enzymatic region (which is a tyrosine kinase) that is activated upon a ligand binding. Has extra cellular, transmembrane and intracellular domains.
40 of 158
From ligand binding to Sh2 domain containing protein recruitment, what are the steps that occur on an RTK?
1. Ligand binding promotes receptor dimerisation. 2. Dimerisation and therefore conformational change -> kinase activity which trans/autophosphorylates leading to activation. 3. Proteins which contain Sh2 domains bind to phosphorylated tyrosine
41 of 158
Name 4 groups of RTKs
42 of 158
How many known RTKs and oncogenes are there known in humans
58 RTKs, 29 oncogenes
43 of 158
What was the first discovered RTK
44 of 158
EGFR is also known as
Erb and HER
45 of 158
How many types of EGFR are there?
46 of 158
EGF forms homo or heterodimers, what are the most common?
Homodimer of 1, 1:4, 2:3, 2;4
47 of 158
Which EGFR lacks an extra cellular domain and which lacks an intracellular domain?
2 - extracellular, 3 - intracellular
48 of 158
HER2 mutations you do not see truncations / mutations like other EGFR receptors, what do you see?
Over expression / amplification
49 of 158
Ertibux / cetuximab block what region of the EGFR
The receptor site (extracellular)
50 of 158
Gefitinib, erlotinib, lapatinib target what region of the EGFR receptor
Kinase terminal
51 of 158
Herceptin is what?
Monoclonal Ab that selectively targets the extracellular domain of HER2
52 of 158
How many subunits of a PDGFR are there and what are they called?
2, alpha and beta. (There are differences in the downstream signalling of each receptor) can form homo or heterodimers
53 of 158
Which PDGFs bind to alpha PDGFR
A, B, C
54 of 158
Which PDGFs bind to beta receptor
B and D
55 of 158
Which PDGF ligand dimer can interact with all PDGF receptors
56 of 158
What would be the effect of an activating point mutation in a kinase domain of an RTK
Receptor will be able to phosphorylate without an external signal -> constant phosphorylation
57 of 158
Amplification of PDGFR alpha is seen in which cancers
58 of 158
Activating point mutation of PDGF alpha R is seen in which cancer
GIT, stromal tumours
59 of 158
Translocation involving the PDGFBR is seen in which cancers
Chronic myelomonocytic leukaemia
60 of 158
Translocation involved the PDGFB ligand is seen in which cancers
61 of 158
How many FGFR genes are there?
62 of 158
What is required for FGF binding to the FGFR
Heparin / heparin sulphate (this is also required for the dimerisation of FGFR)
63 of 158
Name of a drug that has been shown to reduce tumour growth and metastasis by its action on FGF
64 of 158
What GF binds with strong affinity to a receptor encoded by the c-met oncogene
65 of 158
What intrinsic kinase activity does TGFbR have
Serine / threonine therefore a RSTK
66 of 158
How many high affinity TGFbR are there and which two have an intracellular Serine threonine domain
3, 1 and 2 have kinase domains, 3 is a proteoglycan
67 of 158
What are the steps of ligand binding to TGFbR receptor -> intracellular signalling
1. TGFb binds to TGFbR3 which then presents TGFb to TGFbR2. Or 1b. TGFb binds to TGFbR2 directly. 1. Binding induces TGFbr2 to recruit TGFbR1. 3. R2 then phosphorylates and activates R1. 4. R1 then phosphorylase intracellular proteins
68 of 158
TGFb inhibits epithelial, endothelial and haematopoietic cell proliferation, therefore what would you expect to see in tumour cell
Virtually all epithelial derived tumours become resistant to growth inhibition by TGFb
69 of 158
TbRII gene is downregulated in what two cancer types
Breast and Lung
70 of 158
TbRII is mutated in what two cancer types?
Colon and pancreas
71 of 158
TbRII protein is not expressed in what cancer type?
72 of 158
V-src has several mutations including the deletion of Tyr527, what is the relevance of this?
Phosphorylation of Tyr527 inhibits kinase Src activity, no terminal = no inhibition
73 of 158
Src family of tyrosine kinases share how many homologous domains and what does each domain recognise
3. 2 = phosphotyrosine binding site, 3 - prolin-rich motif binding site
74 of 158
SH2 has two recognition domains to allow for specificity. What are these?
1 - phosphotyrosine binding domain, 2 - binding site for amino acid side chain
75 of 158
Fos, jun and myc are ‘immediate early’ genes as they are switched on by GF even in the presence of what?
Protein synthesis inhibitor cycloheximide
76 of 158
SH2 domain binds to
Phosphorylated tyrosines
77 of 158
SH3 domains bind to
PXXP - proline rich motifs
78 of 158
What are the three major MAPK in animals
Erk, Jnk, p38
79 of 158
What do MAPK regulate (4)
Proliferation, apoptosis, differentiation, migration
80 of 158
To become activate MAPK need phosphorylation of what residues?
Serine and threonine and therefore need a dual specificity kinase
81 of 158
Describe the steps from EGF binding to R to SOS recruitment?
EGF binds to EGFR - dimerisation, activation, phosphorylation of tyrosine. Tyrosine-P recruits SH2 domain protein Shc. Shc is phosphorylated and recruits Grb2 SH3 domain. Grb2 binds PPP domain on SOS. SOS is a GEF for Ras
82 of 158
What is a GEF
Guanine exchange factor. Catalyses conversion of GDP -> GTP
83 of 158
What is Ras, what is it’s active form
An oncogenic protein that is bound to the plasma membrane with intrinsic GTPase activity. Active form is when GTP bound
84 of 158
What % of pancreatic tumours have a Ras mutation
85 of 158
To switch of Ras what enzyme is required
GAPs (GTPase activating proteins) Ras will then hydrolyse GTP back to GDP
86 of 158
What is the key effector protein of Ras
87 of 158
What is Raf
A kinase
88 of 158
What are the 3 closely related proto-oncogenes of Ras
H-ras, K-ras (4a, 4b) N-ras
89 of 158
What are the two domains that make up Raf
Ras binding domain and a serine/threonine kinase domain
90 of 158
How many isoforms are there of Raf
91 of 158
What is the structure of inactive Raf
Raf folded in the cytoplasm with 14-3-3 protein bound to phosphorylated shrines in both the kinase and Ras domain
92 of 158
How is Raf activated?
GTP-Ras recruits Raf to plasma membrane, Ras binds to ras binding domain, De-phosphorylation of Ras binding domain. Raf then becomes phosphorylated at additional residues (by PAL, SRC of Raf), leading to activation of kinase domain.
93 of 158
What protein is Rafs target and what is its function
MEK, which is a dual specificity kinase
94 of 158
What is MEKs target
95 of 158
What happens after the phosphorylation of Erk
Erk translocates the nucleus where it acts as a s/t kinase for >50 substrates including cyclin d1
96 of 158
As well as growth factor signalling, what other mechanism leads to Erk activation
Downstream of integrin engagement. Following a focal adhesion, proteins are recruited inside the cell into an adhesion plaque, some proteins in this plaque are kinases which can phosphorylate Raf...
97 of 158
Without either GF and integrin mediated adhesion, what occurs in a normal cell
The signalling of Erk is not strong or sustained enough that the cell does not progress into G1
98 of 158
Some non-receptor tyrosine kinases can be bound to what kinase
99 of 158
Describe the steps of JAK-STAT signalling
Cytokine binding to receptor triggers activation of JAKs through conformational changes, JAKS then trans/auto phosphorylate and then phos the R at a tyrosine residue. Phos-(y) recruits sH2 domain protein STAT. STAT then phosphorylted by JAK
100 of 158
What is the unique response element for STAT1 homdimer
101 of 158
What is the URE for STAT3 homodimer
102 of 158
What is the URE for Stat1:2 heterodimer
103 of 158
How do SOCs suppress cytokines signalling
They are unregulated in response to STAT:DNA binding, they bind to activated JAKs and inhibit catalytic effect via -ve feedback
104 of 158
P38 and Jnk are activated following what kind of signal
Stress (Rac (also a GTPase) -> PAK -> MEKK1...)
105 of 158
How many genes and isoforms are there of Jnk
3 genes, 10 isoforms
106 of 158
What does Jnk phosphorylate
AP-1 complex (made up of c-jun and c-fos, jun is what’s phosphorylated)
107 of 158
What does p38 phosphorylate
MEF2 and dimer of ATF-2 and c-jun
108 of 158
Strong ATF-2 expression is seen in what tumour typw
109 of 158
What is R-SMAD
Regulatory SMAD, sits at the TGFbR either SMAD2 or SMAD3
110 of 158
What is co-SMAD
111 of 158
Describe TGFb signalling
Once the R has been activated. R-Smad and co-sad form an oligomer which migrates to the nucleus and recruits other gene proteins to activate transcription
112 of 158
What are some examples of DNA binding factors for r-smad:co-sad complexes
FAST and OAZ which can target TF such as AP-1
113 of 158
What are target genes for the TGFbeta signalling
Fibronectin, collagen type 1, MMP-2
114 of 158
Ras mutations are present in what % of human cancers
115 of 158
Raf mutations are present in what % of melanomas
116 of 158
What codons are most Ras mutants recognised
12, 13 and 61 (GTP binding sites of ras) - these tend to prevent Ras from hydrolysing GTP and therefore is constantly on
117 of 158
B-raf is frequently mutated in 60% melanomas, what is one hotspot
V600E (majority of mutations are in the kinase domain rather than regulatory). Allows RAF to be always active even as a monomer
118 of 158
Why are tumour cells with RAF or Ras mutations Anchorage independent
Normal cells require both GF and integrin signalling. However with sustained GF signalling, this produces enough Erk that Anchorage isn’t required. WHy transformed cells can grow on soft agar and normal cannot
119 of 158
What is meant by oncogene addiction
The observation that a tumour cell, despite multiple genetic alterations will exhibit dependence on a single oncogenic pathway
120 of 158
What are the three popular methods for inhibiting kinases (in order of most popular to least)
ATP competitive inhibition, substrate competitive inhibition, non-competitive inhibition
121 of 158
What is the target for Imatinib/Gleevec
BCR-Abl, substrate binding
122 of 158
What are 4 mechanisms in which cancers cells develop resistance to biologics
Over express PDGFRB, promote WT raf diners, n-ras mutates, cancer cells reactivated by stromal HGF
123 of 158
What is the target for PLX4032 / vemurafenib
RAF - interaction inhibitor
124 of 158
Resistance emerges to which EGFR inhibitor due to a mutation at T790M
125 of 158
What is the name of a promising drug in mutated Ras targeting
126 of 158
Outcome of shh signalling is dependent on what?
Concentration and duration of signal
127 of 158
Describe signalling pathway of Shh in presence of Shh
Shh binds to PtcR (co-receptors Cdo/boo), Shh inhibits Ptc binding to Smo, Smo is liberated, proteins of intracellular complex are no longer proteolytically cleaved and GliA are able to translocations the nucleus
128 of 158
What are Shh target genes e.g.
Bcl-2, cyclind1, Snail, Gli1
129 of 158
Activation of Shh occurs in the
Primary cilia
130 of 158
How many Gli transcription factors are there and which are activating which are repressive
3, Gli1 = A, Gli2 and 3 = R
131 of 158
Mutations in Ptc are seen in what diseases?
BCC, Gorlin-gotz syndrome (nevoid BCC), medulloblastoma, rhabdomyosarcomas
132 of 158
What is SUFU
Protein involved in the cleavage of Glis
133 of 158
What % of BCC are due to LOF ptch 1 and GOF smo
90% - Ptch1, 10% - smo
134 of 158
What are the effects of Shh signalling within the developing cancer cell
Proliferation (cyclinD1,D2, Myc, wnt, hes 1), survival (Bol-2), EMT
135 of 158
What are the effects of hh signalling in tumour environment?
Angiogenesis (vegf), immune escape, stromatolites myofibroblasts (cancer promoting fibroblasts that encourage metastasis)
136 of 158
What is juxtacrine signalling?
Both ligand and receptor are membrane bound, seen in notch signalling
137 of 158
How many notch receptors are there in mammals
138 of 158
What are the intracellular domains of Notch
PEST sequence (ICD stability), TAD (transcriptional active domain), NLS (nuclear localisation signals)
139 of 158
What are the mammalian ligands in notch
DLL 1,4,3 and JAG 1 and 2
140 of 158
Steps of notch signalling to formation of NICD
DLL ligand binds to receptor, cleavage by TACE and gamma secretase, liberate NICD, NICD enters nucleus and modulates transcription
141 of 158
How does NICD modulate transcription
No NICD, proteins part of this signalling CSL complex on dNA bind bound to co-repress or. NICD displaces co-depressor and binds to cSL recruit CoAa and mastermind like 1. This activates target genes including Hes repression genes
142 of 158
What are the three modes of notch signalling
Lateral inhibition, lineage decision, inductive signalling
143 of 158
Lateral inhibition occurs in the ear, do the hair cells produce the ligand or receptor
Ligand, support cells have > receptor
144 of 158
In lineage / binary signalling - what does a daughter cell inherit to inhibit notch signalling
145 of 158
Notch signalling is a tumour promoter in what cancers and what is the effect
T-all and melanoma (proliferation and survival), breast and colon (snail and slug)
146 of 158
Notch signalling is a tumour suppressor for what type of cancer
147 of 158
What % of T-all patients have notch mutations
148 of 158
T-all is the result of what translocation
T(7;9) truncated notch from 9 moves to C7 TCRb promoter -> increased NICD
149 of 158
What mutations are seen in notch signalling (4)
Heterodimerisation domain (increased NICD activity), PEST inactivity (no degradation of NICD), Ikaros (lymphoid normally inhibits notch R), FBW7 (normally removes nicd from nucleus)
150 of 158
Notch signalling increases levels of what TF that drive EMT
Twist, snail, slug, ZEB1/2
151 of 158
Mutations in wnt is the leading cause of what type of cancer
Colon (mutations in tumour suppressor APC)
152 of 158
How many Wnts and how many FzR are there
19wnts, 10 frizzled receptor
153 of 158
What are the three key pathways in Wnt signalling
1. Canonical (wnt-beta catenin), JNK (planar polarity), wnt/ca2+
154 of 158
Describe the steps of the Wnt-b catenin pathway
Wnt bind to Fz (with co-factors LRP5/6, lgr5 and rspondin), binding modulates Dsh. Dsh inhibits destruction complex. Destruction complex normally target b-catenin for ubiquitination meaning inhibition of this complex allows beta-c to enter the nucleu
155 of 158
What does the canonical pathway regulate
Cell proliferation, survival and fate
156 of 158
JNK pathway regulates what?
Cell shape, orientation and migration
157 of 158
Is wnt signalling outcome more dependent on the Wnt or the fzR
158 of 158

Other cards in this set

Card 2


What is the relationship between the dosage of a carcinogen and the delay in tumour formation


Inversely proportional, meaning the greater the dose the shorter the delay

Card 3


What is a possible explanation for the reason there is a delay between tumour formation and carcinogen exposure?


Preview of the front of card 3

Card 4


What is the function of telomeres


Preview of the front of card 4

Card 5


How does telomere shortening cause limited replication in normal cells & what is the result of this shortening


Preview of the front of card 5
View more cards


No comments have yet been made

Similar Biology resources:

See all Biology resources »See all Genetics resources »