Integrity: Cancer Pathology Flashcards
(81 cards)
1
Q
Definitiion of atrophy
A
- Atrophy
- Shrunken tissue with reduced cell size (± number)
2
Q
Definition of hypertrophy
A
Hypertrophy
* Enlargement of a tissue with increased cell size
3
Q
Definition of hyperplasia
A
Hyperplasia
* Increased number of otherwise normal cells in a tissue
4
Q
Definition of transdifferentiation
A
Transdifferentiation
* A switch of differentiation direct from one mature lineage to
another which is normally present in that tissue
5
Q
Definition of metaplasia
A
Metaplasia
* A switch of differentiation from one mature phenotype to
another which is not normally present in that tissue,
in response to an environmental change.
6
Q
Definition of dysplasia
A
Dysplasia
* Disordered microscopic appearance and maturation of cells,
implying neoplasia.
7
Q
Definition of a tumour
A
Tumour
* Abnormal lump of no specific cause (often presumptively a neoplasm)
8
Q
Definition of a cyst
A
Cyst
* Abnormal fluid-filled lesion lined with epithelium
9
Q
Definition of a hamartoma
A
Hamartoma
* Disorganised but mature normal tissue elements, lacking autonomous growth
10
Q
Definition of neoplasm
A
Neoplasm
* Abnormal accumulation of cells derived from a mutated ancestor ‘seed’ cell
* growth is autonomous of environmental restraining signals
11
Q
Deinition of cancer
A
Cancer = a malignant neoplasm
- Invasion: crosses tissue boundaries
- Metastasis: discontinuous spread to survive & grow at remote sites
- carriage in: blood / lymph / serous cavity fluid / CSF (cerebrospinal fluid)
12
Q
How is the craniospinal venous system relevent in metastasis?
A
- 2-way venous flow (no valves)
- Links cranial + vertebral circulation
with intercostal, abdominal & pelvic
venous plexuses - Direct ’back-door’ route for metastasis
to spine and brain - skips lungs, lymphatics
- e.g. from prostate, breast, thyroid.
13
Q
6 appearances of surface neoplasms
A
14
Q
Definition of carcinoma
A
Carcinoma is cancer that forms in epithelial tissue
15
Q
What is a sarcoma?
A
Sarcoma is the general term for a broad group of cancers that begin in the bones and in the soft (also called connective) tissues (soft tissue sarcoma)
16
Q
What is Cachexia
A
progressive muscle dysfunction + lean muscle wasting (+/- adipose loss), not reversible with nutritional support
17
Q
What is paraneoplastic?
A
Paraneoplastic = a problem caused by a neoplasm but not attributable to cancer invasion or secretion of indigenous tissue hormone aka it’s directly, physically or anatomically affecting an organ
18
Q
What is clonal expansion?
A
This is a normal process where you aquire cancer driving mutations (onces that encourage growth) but they don’t progress further, if these fill a neish well they will expand and outcompete the surrounding cells
19
Q
What happens with clonal expansion and age?
A
Clonal expansion increases with age and to varying degrees in different sites
20
Q
What is a cancerisation field?
A
Cancerisation field
A tissue with accumulated genetic & epigenetic changes that favour
cancer emergence
21
Q
Field cancerisation:
Mutation count & clonal patch sizes increase with…
A
Mutation count & clonal patch sizes increase with
- chronic inflammation (cycles of destruction and regeneration)
- carcinogens: sun exposure, smoking, alcohol
22
Q
Consequence of non-cancerous clonal haematopoiesis
A
clonal haematopoiesis is pro-inflammatory
* Coronary heart disease & stroke (larger risk than hypertension)
23
Q
What has the highest risk of tissue that is
Normal
Hyperplastic
Metaplastic
Dysplastic
A
Dysplastic
Usually means it has gotten much bigger
24
Q
How does cancer arise from clonal expansion: clonal sweep
A
25
What are the hydrodynamics of a tumour and why is it relevent?
The core has a very high interstitial (between cells) pressure resulting in an area with poor diffusion, hypoxia, acidic and ripe for ischemia.
This hypoxia produces a strong selection bias for angiogenesis in growing cancers (through HIF - hypoxia driven gene expression and angiogenic factors)
The flow of fluid is also radially outward from the core and then towards the lymphatic drains.
This makes it hard for drugs to diffuse into the core and promotes cells migration towards the lymphatics
Key points:
* High core pressure
* Hypoxia in core which promotes angiogenesis selection bias
* Prevents drugs from reaching core and promotes spread outward towards lymphatics
26
WHat is angiogenesis?
The creation of new blood vessels
27
What's happening here?
Competition for blood in cancer creates dissorganised angiogenesis
This results in non-hierarchical unstable haemodynamics
* pooling, eddies, flow reversals
* pO2 varies in “waves & tides”
28
What is a cancer driver gene?
Most human cancers have 2-8 mutant drivers
>500 total but most early cancers have mutations in the same 9 genes
Typically they affect multiple cancer hallmarks, suppressing some and promoting others
29
How are do key drivers differ after treatment?
Key driver mutations are often ubiquitous in untreated cancer + its metastases
* New mutations often have no selective impact: neutral passenger mutations in ‘subclones’
After treatment you are applying new pressures which unmask previously neutral or minority but resistant subclones
30
Key cancer mutation hallmarks
4 Early
4 Late
Early
1. Promotes proliferation genes
2. Surpresses anti-proliferation genes
3. Unlimited copying - removes caps that normal cells have whereby they can only be copies so many times before the quality becomes worse
4. Metabolic reprogramming for energy
Late
1. Evasion of immune system
2. Resisting aopoptitic mechanisms
3. Invasion and metastasis
4. Angiogenesis
31
What do we mean by plasticity when it comes to cancer cells
Many have an ability to change state, whether this is a speciality state or a stem state.
This means they can often adapt to differing pressures
32
What does epithelial-mesenchymal plasticity (EMP) mean?
Some cancer cells can switch between being epithelial and mesenchymal
33
How do cancer cells subvert immune activation
* release immunosuppressive factors
* TGFb, IL-10, PG
* repress antigen processing & presentation
* Small cell lung cancer
* reduce MHC I; display immune inhibitors (PDL1, CTLA4)
The first is by creating the space of metabolic stress this makes it had to immune cells to survive. Cancer cells can competitively steal glucose from T cells.
Aditionally:
* release immunosuppressive factors TGFb, IL-10, PG
* repress antigen processing & presentation
* reduce MHC I; display immune inhibitors (PDL1, CTLA4)
34
Why is relapse quite common?
Risidual cells are often left behind after treatment (these can be a handful of subclones)
These are then treatment resistant and spread making a second treatment less successful
35
What is enhancer switching?
Enhancer switching is where cells can activate different enhancers to promote the same survival genes. Multiple different routes to the same end. This gives heritable and reversible resistance to targeted cancer therapy
36
Three types of carcinogen
chemical - natural or synthetic
physical - UV or ionising radiation
biological - bacteria, viruses, parasites
37
What is Replicative Senescence and what is used to overcome replicative senescence in germ and stem cells
Replicative senescence is the phenomenom where cells can only divide so many times.
The end of chromosomes are clipped with repetitive sequences called telomeres. These shorten with every division eventually resulting in apoptosis.
Telomerase is present in stem cells and germ cells in order to maintain telomere ends which results in unlimited replication.
Telomerase is abnormally upregulated in cancer cells
38
What are the loops on the ends of chromosome designed to cap unlimited cell replication called?
Telomeres
39
What substance can maintain telomeres during replication?
Telomerase
40
What happens to telomerase in cancer cells?
Abnormally upregulated
41
What is the cap on the number of times a cell can divide called?
Replicative senescence
42
What is inherited predisposition to cancer in humans
In rare instances tumour mutations can be inherited in the germ line giving rise to an inherited predisposition to a particular cancer.
43
What is Retinoblastoma?
Retinoblastoma is a rare childhood cancer of retinoblasts, with a peak
incidence at 3-4 years of age
44
What is the difference between an inherited retinoblastoma and a sporadic one?
You need a loss of both RB1 genes.
In the inherited version one is lost in every cell already hence if the other spontaineously mutates in any cell it results in the retinoblastoma. Bilateral likely.
In spontaineous if one cell mutates loss of one RB1 gene then the mutation would have ot happen in the same cell therefore it would likely only be in one eye. Unilateral.
45
What gene is involved in a retinoblastoma?
Rb
46
What is an allele
One of two or more alternative forms of a gene that arise by mutation and found in the same part of the chromosome
47
What is a zygote?
Fertilized egg
Pre-zygotic: before fertilization
Post-zygotic: after fertilization
48
What does Heterozygous mean?
Posessing two different alleles of the same gene
An example of a heterozygous condition is inheriting different genes for eye colour from both biological parents. If there are two different versions, it is a heterozygous genotype for that particular gene.
49
Gene involved in Familial adenomatous polyposis coli (FAP)
APC - regulates signal transduction
50
What is Familial adenomatous polyposis coli
An inherited colon cancer, hundred of polyps through colon or rectum
51
What is Li Fraumeni sydrome?
A heriditary condition that predisposes people to several forms of cancer
52
Gene involved in Li Fraumeni
p53 or TP53 - Cell cycle control/DNA damage
53
What is Lynch / Hereditary
non polyposis colon cancer
Another heriditary colon cancer
54
Gene involved in Lynch syndrome?
MLH1, MSH2 - DNA Mismatch repair
55
Gene involved in Familial breast and ovarian
cancer
BRCA-1, BRCA-2
- DNA repair (d/s break repair)
56
What is Basal cell naevus
A condition with multiple complications but a big one is numerous basal cell carcinomas
Basal cells are the cells at the bottom of the epidermis that make new skin cells
57
Gene involved in basal cell naevus?
Ptch - Signal transduction
58
Syndromes in which the heterozygotes express the tumour phenotype
(one mutation inherited form one parent however there will be one unmutated allele)
59
Syndromes in which the homozygotes
have an increased risk of cancer
(you need to inherit two of the same in order to have an increased risk of cancer?)
60
Common carcinogen for gastric carcinoma
Helicobacter pylori
61
Parasitic cause of infection and carcinoma of the bladder
Schistosoma haematobium
62
Virus linked to carcinoma of the cervix
HPV
human papillomavirus
63
Viruses linked to hepatocellular carcinoma
hepatitis B virus, hepatitis C virus
64
Virus linked to Nasopharyngeal carcinoma
EBV
Epstein Barr virus
65
Virus linked to Adult T cell leukaemia
HTLV 1
Human T cell lymphotropic virus
type 1
66
What is naphthylamine
Involved in the dye industry
Bladder cancer in workers exposed to naphthylamine
67
What is a proto-oncogene?
This is a normal gene involved in regulating cell function that has to potential to become mutated and become an oncogene
68
In terms of oncogene activation, what is a point mutation?
This is where the mutation occurs by one part of a codon switching
69
In terms of oncogene activation, what is amplification
This is where one gene get copied over and over thus amplifying it's effect
70
In terms of oncogene activation, what is innapropriate regulation
This is where a promotor is present where it shouldn't be thus activating a gene where it shouldn't be activated
71
Are oncogenes considered dominant or recessive?
Oncogenes activate tumour promoting factors therefor if one is switched on it has an effect hence they are considered dominant
72
Are tumour suppressor genes considered dominant or recessive?
With a tumour suppressor genes these are genes whic work to surpress tumour function. You only need one to function in order to suppress the tumour hence both need to mutate in order for suppression to fail so they are considered recessive
73
What is p53 protein?
This is a protein which is released in response to DNA damage which arrests the cell and stops it proliferating.
The p53 gene is therefore a tumour suppressing gene
74
How do mutations in mismatch repair genes (MLH1, MSH2) encourage cancer?
By inhibiting missmatch repair the chance of DNA mutation will be greatly increased thus increasing the chance of cancer
75
How does damage to exision repair encourage cancer?
DNA repair by exision of mutation is key to maining DNA. If this is inhibited mutation are more likely to stick
76
How does damage to DNA strand break repair cause cancer?
BRCA1 & BRCA2 involved in d/s break repair. If the genes producing BRCA1 & BRCA2 are mutated then DNA is less likely to able to repair itself
77
Three things invasion requires
Change and/or loss in cell-cell and
cell-matrix adhesion
Changes in adhesion are essential for motility
Focal proteolysis of the matrix
Movement to occupy the space
78
78
What are integrin receptors?
These are responsible for cell-matrix adhesion & signaling for cell survival
& proliferation.
There are often lost and rearranged in cancer cells to allow for invasion
79
Things that determine where metastatic spread goes
Anatomy
nature of lymphatic and venous drainage
eg breast cancer -> local axilla nodes,
colorectal cancer -> local mesenteric nodes & liver
Organ specificity
adhesion molecules on the cancer that permit preferential attachment to different capillary beds
Different organs have different chemokine receptors
Common metastatic sites: liver, lung, bone, brain
80
Blood markers of cancer
* PSA- Prostate Ca
* CA 125- Ovarian Ca
* CEA- Colorectal Ca
* AFP- Hepatocellular Ca
* CA-15-3- Breast Ca
* CA19-9- Pancreatic Ca
Potential: cell-free DNA in blood – tumour mutations
