Cancer Flashcards
(73 cards)
1
Q
challenges with cancer
A
a. early onset cancer is on the rise (and early onset cancer deaths)
b. 200+ histologically different cancers
c. Average cancer cell ~5000 mutations (5 “driver mutations, rest are “passenger mutations”)
d. get rid of cancer scam drugs
2
Q
driver mutations
A
the ones that cause cancer
3
Q
passenger mutations
A
just along for the ride
4
Q
model organism to study cancer
A
zebra fish used to study defective genes that cause melanoma
5
Q
tumors
A
much smaller than normal cells
- the nuclear:cytoplasmic ratio is smaller in normal cells
6
Q
normal cells
A
- don’t grow in semisolid medium (apoptosis)
- typical karyotype: 23 sets=46
- normal set of miRNAs
- few extracellular proteases
- 10-15 micrometers in vivo
- lower nuc/cyto ratio
- organized cytoskeleton
- ECM is normal
- single layer in vitro (contact inhibition)
- can’t generate tumor in SCID mouse
- serum dependent growth in vitro
- secrete few growth factors
- cell division # 25-50 x–> apoptosis
- few genetic defects
- normal glycolysis
- cell membrane permeability
- no angiogenesis
- normal RTK pathway
- Apoptosis normal
7
Q
cancer cells
A
- grow in semi solid medium
- aneuploidy
- aberrant set of miRNA (abnormal)
- secrete proteases
- 3-5 micrometers in vivo
- higher nuc/cyt ratio
- disorganized cytoskeleton
- ECM: little–> don’t synthesize fibronectin
- in vitro= multilayer
- generates a tumor
- can be grown in serum-free medium–> can take advantage of autocrine system
- some can make their own growth factors
- unlimited cell divisions
- lots of mutations
- Warburg effect
- 10x more permeable cell membrane
- can secrete VEGF (angiogenesis factor)
- mutations in RTK
- block apoptosis
8
Q
aneuploidy
A
abnormal number of chromosomes in a cell
9
Q
miRNAs
A
- play crucial role in cancer biology by regulating oncogenes and tumor suppressor genes
- when abnormal, can worsen cancer progression, cause drug resistance…etc.
10
Q
evolutionary progression of cancer
A
- can’t pinpoint a singular genetic event, mutation usually suspected
- precancerous cells acquire mutations that dysregulate growth-control pathways, causing inappropriate cell proliferation
- also acquire mutations that cause genome instability and propensity to acquire more mutations, mainly by loss of DNA damage checkpoint
- need to acquire additional somatic mutations that allow them to evade cancer cell elimination
- angiogenesis
- metastasis
11
Q
metastasis
A
- cancer cells leave main tumor and attack the basement membrane, using ECM fibers to reach the blood vessels
- cancer cells can be attracted by signals such as epidermal growth factor (EGF)
- at blood vessels, they penetrate the layer of endothelial cells that forms the vessel walls and enter the bloodstream
- carcinoma cells penetrate the extracellular matrix and blood vessel wall by extending invadopodia (actin-rich protrusions of the plasma membrane), which produce proteases to open up a path
12
Q
cell divisions in senescent cell
A
<25
13
Q
cell divisions in cell
A
25-50x
14
Q
cell divisions in stem cells
A
100-200+
15
Q
viruses causing cancer
A
- 1911- Peyton Rous- worked with Rous Sarcoma virus (retroviral)
- later, V-SRC was discovered–> oncogene (causes cancer)
- 1970s: C-Src= proto-oncogene (doesn’t cause cancer, similar effects
16
Q
SV40
A
- DNA virus
- produces a protein called Large T-antigen–> interacts with and inactivates tumor suppressor proteins like p53 and Rb–> uncontrolled cell division
17
Q
HPV
A
cervical cancer
- Gardasil= vaccine
18
Q
Gardasil
A
- first cancer vaccine now for both boys and girls to prevent up to 90% HPV infections that can cause cervical and other cancers
- Rick Perry mandated vaccination in 2007 for girls and then reversed position due to public opposition (former governor of Texas, Merck donated money to his campaign)
19
Q
UV light
A
- causes Thymine dimers
- cause a kink in DNA–> damages DNA–> can divide and grow in an uncontrolled way–> forms tumor
20
Q
what causes cancer
A
- viruses
- radiation
- chemical mutagens
- defective cell cycle
- defective tumor suppressor genes (p53, Rb, BRCA1)
- defective care taker genes
- defects in apoptotic pathway
- defects in RTK pathway
- defective telomeres/telomerase
- cancer stem cells
- chromosomal translocation
- DNA Amplification
- Overexpression os MYC (C-MYC) and Fos (C-Fos)
21
Q
chemical mutagens
A
- tobacco smoke= 60 chemical mutagens
22
Q
defective cell cycle
A
- cyclins
- ex: defective cyclin D1–> 50% of breast tumors
- if checkpoint controls are defective= Cyclin-CDKs aren’t inhibited–> cancer
23
Q
Defects in RTKs
A
- defects in Ras= present in about 30% of all cancers
- includes Ha-Ras, K-Ras, others
- leads to continuous cell growth
24
Q
defective telomeres/telomerase
A
- telomeres that don’t shorten is a requirement of cancer
25
cancer stem cells
- arise from normal cells
- every solid tumor
- 1% of total cell population in tumor
- Metric: CD133--> cancer stem cell
- responsible for metastasis and re-emergence after remission
- influenced by micro-environment
- resistant to chemo and radiation
26
Burkitt's lymphoma
- caused by chromosomal translocation
27
DNA Amplification
- ex: HER 2+ cancer
- normal= 20,000 HER cells
- HER 2+ = 1-2 million
28
BCR-Abl protein kinase
- when this gene is present, it causes "Philadelphia chromosome"
- philadelphia chromosome= abnormal chromosome 22 (part of chromosome 9 is transferred to it--> they break off and trade places)--> forms a new gene called BCR-ABL
- can cause development of leukemis
Philadelphia chromosome produces an abnormal tyrosine kinase--> cancer cells grow uncontrollably
29
Imatinib
- blocks Philadelphia chromosome
- targets proteins in cancer cells and stops cancer cells from growing (kinase inhibitor)
- blocks the abnormal protein signals that cause cancer cells to multiply--> stops spread of cancer cells
30
Overexpression of C-MYC and C-FOS
- transcription factors
- C-MYC causes increased cell proliferation (diagnostic; if increased= poor outlook)
- C-MYC is a proto-oncogene (normally involved in healthy cell growth), when overexpressed, becomes oncogene (promotes cancer)--> turns on cells that promote entry into S phase--> makes cells continue dividing
- C-FOS causes increase drug resistance and increases cancer stem cell activity
31
oncogene
- not species specific
- causes cancer (come from proto-oncogenes)
32
Robert Weinburg
- isolated first tumor suppressor gene
- Rb
- showed that genes cause cancer and it is not tissue or species specific
- also showed that microenvironment for tumors is important
33
why is cancer age dependent
accumulation of mutations over time
34
Model for Cancer induction
- multi-hit model
- several errors
- cooperative effects of multiple mutations in cancer induction
35
Do cancer cells originate from one cell
- yes
- data from women prove it due to X-chromosome inactivation
36
oncogenes associated with RTK Pathway
- proteins that act positively in the RTK pathway (ex: receptor protein or intracellular signaling protein) can become oncogenes by acquiring a gain-of-function mutation
- negative regulator of pathway may activate the pathway because of loss-of-function mutation--> corresponding gene would be a tumor suppressor gene
37
chimeric oncogene
- formed from fusion of two different genes, often due to chromosomal translocation, inversion, or deletion
- the fused oncogene produces abnormal/hyperactive function that can lead to uncontrolled cell growth and cancer
38
SFFV
- some oncogenes are due to interactions with virus glycoproteins
- SFFV (spleen focus-forming virus)
- results in excessive number of RBCs
- SFFV--> gp55--> erythroleukemia
39
tumor suppressor genes
1. Rb
2. p53
3. BRCA tumor suppressor
40
Rb
- retinoblastoma
- a tumor of the neural retina
- 1/200,000 60% not inherited; 40% are inherited
- bilateral
41
hereditary retinoblastoma
- somatic retinal cell--> loss of functional Rb allele--> homozygous cell gives rise to tumors in retina
42
sporadic retinoblastoma
somatic retinal cell--> loss of 1st functional Rb allele--> loss of second functional Rb allele--> homozygous cell gives rise to tumors in retina
43
Li-Fraumeni syndrome
- caused by a p53 mutation
- inherit defective p53
- 25x more susceptible to cancer
44
BRCA1 tumor suppressor
- when function normally, keeps tumors from forming
- when not functioning normally, it can lead to an accumulation of genetic mutations and an increased risk of developing breast cancer
45
carcinogens
can be direct or indirect (procarcinogens)
46
indirect carcinogen
- Aflatoxin= peanut fungus= mutates p53
- benzo (a) pyrene= tobacco smoke
47
Xeroderma pigmentation
- caused by gene mutation that affects Nucleotide excision repair
- causes sensitivity to UV radiation, point mutation
- susceptible to skin carcinomas, lymphomas
- symptoms= skin and eye photosensitivity, keratoses
48
Camp Sundown and Midnight Sun
- camp for children who have UV sensitivity disorders
- Midnight Sun is a 2018 movie focused on a real life story about XP
49
Galleri Blood test
- developed by Grail
- recommended for use in adults with an elevated risk for cancer, such as those aged 50 or older
- intended to be used in addition to and not replace other cancer screening tests
- all cells in your body release DNA into bloodstream, but DNA from cancer cells is different from healthy cells
- Galleri test looks for signals present in the blood that may be associated with cancer at the time of your blood draw
50
Cancer treatment categories
- Radiation (Brachytherapy, EBRT)
- surgical ablation (resection)
- Chemotherapy using non-biologics (drugs)
- Biologics (mAbs and conjugated mAbs)
- Immunotherapy (CAR-T therapy)
51
Radiation
| Brachytherapy, Cyberknife
- oldest treatment for cancer
- 1895: discovered X-rays
- Brachytherapy: injected radioisotope to tumor (ex: radioactive seeds) that release radiation if placed next to tumor--> Radium
- Cyberknife is an example of EBRT (External Beam Radiation Therapy)--> delivers high-energy x-rays to treat cancerous tumors
52
Tardigrades and radiation
- tardigrades are known to survive harsh conditions that would otherwise be lethal to other animals
- code for Dsup(damage suppressor gene that protects DNA from radiation-induced breaks)
- mRNA vaccine for this protein showed that it could protect injected targets against radiation damage but in the noninjected tumor, there was no protection
53
Da Vinci Robotic System
- prostate cancer
- minimally invasive surgical approach
- uses robotics to remove all or part of a man's prostate gland
54
SCN and PSN systems
- designed to treat a variety of cancers using cryoablation
- uses cold to treat cancer (insert thin needle into cancerous tissue and freeze it)--> shrinks and kills cancer cells while sparing healthy tissue
55
chemotherapy
| taxol, taxotere
- taxol (natural product)
- taxotere (semi-synthetic)
- target microtubules--> disrupts cell division in cancer cells
56
5-Fluorouracil
- 5-FU
- targets DNA and RNA in cancer cells
57
Imatinib
- inhibits the bcr-abl fusion protein
- $100k/yr to treat CML
- tyrosine kinase inhibitor
- stops signaling pathways that promote cancer cell proliferation--> slows/halts the growth of certain types of cancer
58
Tamoxifen
- competitive antagonist of the estrogen receptor (blocks estrogen receptors= prevents estrogen from promoting cancer cell growth)
- 8/10 breast cancers are hormone receptor positive that means they need estrogen or progesterone to divide
59
Monoclonal and synthetic bispecific antibodies as cancer treatment modalities
- biologics
- bispecific antibodies are trifunctional and generated using "quadroma" cell lines
- two Fab ends
- used for treating cancer
- bind both tumor cells and immune system cells simultaneously--> trigger antitumor immune response--> destroys cancer cells
60
Herceptin
- gentech
- first introduced in 1988 to treat HER2+ cencers
- 20-30% of all cancers have an overproduction of HER2+ receptor
- normal= 20,000 HER receptors per cell
- HER 2+= 1-2 million--> breast cancer
61
Kadcyla
- modified antibody
- herceptin with a killer molecule (DM1) attached
- DM1= toxic to microtubules
62
problem with Herceptin and Kadcyla
- bind to all HER receptors
- some HER 2+ cancers are due to HER 2 mutations-- not overabundance
- developed a HER2 antibody that does not bind to normal HER2 receptors but does bind to a HER2 receptor that differs from the normal one by one amino acid
63
conjugated antibodies
| mAB L-DOS47
- mAB L-DOS47 conjugated antibody with urease kills by increasing the extracellular pH--> enhances response to immunotherapy
64
Avastin
- Anti-VEGF (vascular endothelian growth factor) mAb blocks growth of blood vessels
65
Immunotherapy
a treatment regime that directs an individuals immune system to fight cancer by either stimulating it to attack cancer cells or by introducing manufactured immune system components to augment immunce function
- some cancer patients with Strep infections experienced spontaneous remission of their cancers--> T cells can recognize and eradicate the cencer cells
66
Provenge
- immunotherapy designed to treat prostate cancer
67
Dr. Honjo and Dr. Allison
- a number of approaches to immunotherapies
- stimulate overall immune response of patients
- introduce engineered T cells harvested from the patient with CAR-modified T-cells (CAR= chimeric antigen receptor)= CAR-T therapy
68
Chronic Lymphocytic Leukemia
cured by Cell Therapy using Car-T cells
69
problems with CAR-T
- CAR-T triggered secondary malignancies such as CAR-positive lymphoma
- tumor cells can express multiple inhibitory ligands to repress T-cell function and thereby evade being targeted by the immune system
- challenge is to design a CAR T-cell that targets ONLY the target tumor and not similar or surrounding tissue
- severe toxicity can occur leading to death
- CAR-T is very effective with liquid tumors but not solid tumors but 90% of adult and 40% of child cancers are solid
70
Natural Killer cells
- optogenetically triggered with blue light to burrow into tissue engineered solid tumor spheroids and kill them via small 3 micrometer holes in the spheroids
- if the same technology can be used in CAR-T cells, this might allow the CAR-T cells to burrow into tumors
71
Diffuse Intrinsic Pontine Glioma
- first success reported with CAR-T cells treating solid tumors
72
Keytruda
- immunotherapy mAb that blocks the PD-L1 "don't kill me" signal on tumor cells--> T cell can bind to tumor and kill it
73
Nature Communications
wearable CTC filter system
