Cancer pathology Flashcards
1
Q
Give examples of benign tumours
A
Papilloma Gliomata Adenoma Leiomyoma Lipoma
2
Q
Possible damaging effects of benign tumours
A
Bleeding Pressure (on other structures) Endocrine toxicity (large amounts of hormones in a non-feedback type manner) Possible progression into malignancy
3
Q
Examples of malignant tumours
A
Squamous cell carcinoma
Adenocarcinoma
4
Q
What are leiomyomas? Discuss their growth
A
Smooth muscle tumours of the uterus
Increase rapidly in size during pregnancy
Cease growing or atrophy and become largely fibrocalcific after menopause
5
Q
What is an adenoma?
A
A benign tumour of epithelial tissue with glandular origin, glandular characteristics, or both (e.g. can grow from adrenal glands, pituitary, thyroid, etc or growing from non-glandular tissue with glandular properties e.g. familial polyposis coli)
6
Q
What are adenomas called when they transform and become benign?
A
Adenocarcinomas (most do not transform)
7
Q
What is a papilloma? Describe it.
A
A benign epithelial tumour
- grows in a ‘nipple-like’ way
8
Q
What is a gliomata?
A
- can be malignant or benign
- tumour of glial tissue of nervous system
9
Q
What is a lipoma? Describe
A
Benign. tumour of adipose tissue
- not necessarily hereditary, although hereditary conditions, such as familial multiple lipomatosis, may induce development
10
Q
What are sarcomas? Give some examples
A
Malignant neoplasms arising in mesenchymal tissue
- fibrosarcoma - cancer of fibrous origin
- chrondrosarcoma - malignant neoplasm composed of chondrocytes
11
Q
What are carcinomas? Give examples
A
Malignant neoplasms of epithelial cell origin (can be derived from all germ layers):
- squamous cell carcinoma - tumour cells resemble stratified squamous cell epithelium
- adenocarcinoma - starts in mucus-producing glandular cells of the body
12
Q
Example of adenoma
A
Colonic polyps
13
Q
What are the characteristics of malignant tumours?
A
- invasion
- metastasis
- progression
- aberrent differentiation
- pleomorphism (different types of cell)
- anaplasia (poor differentiation)
14
Q
What are the 6 original Hallmarks?
A
- Evasion of apoptosis
- Self-sufficiency in growth signals
- insensitivity to anti-growth signals
- sustained angiogenesis
- limitless replicative potential
- tissue evasion and metastasis
15
Q
What two new hallmarks of cancer were added in 2011?
A
- deregulating cellular energetics
- avoiding immune destruction
16
Q
What two new enabling characteristics were added in 2011 to the hallmarks?
A
- Genome instability
- Tumour-promoting inflammation
17
Q
What does the 2011 Hallmarks of cancer review focus a lot on?
A
- role of non-tumour stromal cells in determining the tumour microenvironment
18
Q
What are the steps of metastasis?
A
- EMT
- Invasion - breakdown of the ECM and migration
- Establishment of pre-metastatic niche
- Extravasation
- Angiogenesis
19
Q
What does EMT result in?
A
Spindle-shaped cells with a strong migratory potential
20
Q
Give an example of how EMT may occur
A
- Activation of Snail and Slug occurs via Ras-MAPK pathway
- Activation of any of this pathway leads to loss of E-cad and EMT
21
Q
What occurs after the cells have acquired the ability to migrate?
A
- invasion of surround tissue
- breakdown the basement membrane and access blood vessels
22
Q
What is one of the mechanisms allowing invasiveness? Explain it
A
Reciprocal interactions between the tumour cells and the surrounding stromal cells
- tumour cells drive stromal proliferation through production of substances (such as CSF1 which drives macrophages)
- The macrophages the produce substances that act on tumour cells (e.g. EGF) → stimulates tumour cell proliferation
23
Q
What do interactions between stromal cells and tumour cells produce?
A
A local inflammatory environment → results in the production of enzymes that cause breakdown of ECM and basement membrane
- e.g. matrix metalloproteinase 2
24
Q
What is the second mechanism that allows invasesiveness?
A
Active locomotion
25
Describe active locomotion
- involves manipulation of the internal machinery of their cytoskeleton
- this can be altered by interactions on the cell surface
- MMP cleavage of certain substances in the ECM can generate fragments that bind to cell surface receptors which in turn promote migration
26
Describe the establishment of pre-metastatic niche
- once the tumour cells have migrated through the tissue & basement membrane, the can enter the blood of lymph vessels and establish new tumour sites
- often depends on blood flow patterns, although it cannot depend solely on this (e.g. kidney is a large recipient of blood but an uncommon site of metastasis)
27
Describe the 'seed and soil' theory
Paget hypothesized it:
- metastatic spread is determined not only by viable tumour cells accessing the site (the seed) but also by a 'fertile environment' at the site (the soil) which enables the tumour cell to grow
28
What is a pre-metastatic niche?
A tumour can create its own 'soil' to colonise
29
How may a primary tumour form a pre-metastatic niche?
- secretion of cytokines to recruit non-cancerious cells to the future metastatic site (incl. endothelial progenitors and haematopoetic cells) → these can form an environment of survivak molecules
- secrete exosomes → these express integrins
30
What is extravasion?
LEAVING the circulation
31
Describe non-molecular mechanism of extravasion
- initially does not involve any molecular mechanisms → impact of tumour cells lodging in a capillary bed = damage to the endothelium = exposes basement membrane and allows cells to adhere = access to tissue
32
Describe molecular mechanisms of extravasion
- important in homing to their correct metastatic site though selection expression of ligands only on target organs
- chemokine action
33
Are tumour cells good at colonising distant organs?
no
- only cancer stem cells can metastasise (1-2% of cells))
- these can be dormant
34
What does angiogenesis involve?
Increases production of angiogenic factors (VEGF) and/or loss of angiogenesis inhibition (thrombospondin-1)
35
Two routes for invasion
infiltration (directly through tissue) and permeation (lymphatic spread - seen in skin tumours)
36
Differences between epithelial and mesenchymal cells
columnar vs spindle
apico-basolateral polarisation vs anteror-posterior
strong cell-cell adhesion
no migration
markers=E-cad, occludin, claudin, vs N-cad, fibronectin
37
Draw diagram of preffered sites of metastasis
OneNote
38
Local effects of malignant tumours
- pressure (e.g. ICP)
- occupation of space (e.g. intra-thoracic or intra-cranial)
- obstruction of vessels or ducts
- intussusception of the gut (a part of the intestine invaginates (folds into)
into another section of intestine)
- haemorrhage
- infection
39
Systemic effects of malignant tumours
- Cachexia (weight loss, nausea, anorexia, lethargy)
- Hormonal effects (over-secretion, ectopic secretion or destruction of endocrine tissue)
- Marrow destruction in leukaemias leading to infection (neutropenia), bleeding (thrombocytopenia). or anaemi
40
Discuss incidence of cancer in populations that are immunocompromised
It is higher
- however, individuals with these conditions do not become susceptible to severe common human cancers such as breast, prostate lung etc
- instead there is a many-fold increase in cancers associated with oncogenic viral infections due to patients'. incompetent immune systems, which cannot suppress the latent infections or fight new infections
41
Which cancers have a particularly high incidence in immunocompromised hosts?
Kaposi's sarcoma and B-cell non-Hodgkins lymphoma (linked to HHV-8) and EBV
42
What are some factors that limit tumour cell proliferation?
- many cells in a tumour are no actively proliferating
- cellular differentiation
- death (ischaemic lysis or apoptosis)
- cell loss (e.g. from skin and gut, or shedding into the circulation)
43
Examples of oncogenes
- RAS (maintained in GTP bound configuration)
| - HER2 (EGFR)
44
Example of TSG
- RB
- TP53 (normally promotes apoptosis)
- VHL
45
Main sites of metastasis from the breast
Lung
liver
bones
46
Main sites of metastasis from the kidney
lung
liver
bones
47
Main sites of metastasis from the lung
adrenal gland
liver
lung
48
Main sites of metastasis from melanoma
skin, muscle liver
49
Main sites of metastasis from the pancreas
lung, liver, peritoneum
50
What are the oncogenic viruses?
1) EBV
2) HBV
3) HPV
4) HHV8
5) Merkel cell polyomavirus
6) HCV
7) HTLV-1
51
What can EBV cause?
Burkitt lymphoma, Hodgkin lymphoma and post-transplant lymphoproliferative disorder
- some T cell disorders
- some epithelial malignancies
52
Whats the most common cause of cervical cancer?
HPV16
53
What cancer can HCV cause?
Hepatocellular carcinoma
54
What microorganism may cause gastric cancer?
H.pylori
55
In which conditions does cellular proliferation, repair of damaged tissue and ongoing inflammation lead to a greater likelihood of mutation?
- liver cirrhosis
- chronic ulcerative collitis
- atrophic gastritis
- epidermal actinic keratosis
- oral leukoplakia
56
What does Rb do?
See notes
57
Mechanism of p53
See notes
58
What are the 3 main approaches to treating established cancer?
Surgical excision
Irradiation
Chemotherapy (drug therapy)
59
What is first order cell kill theory?
Describes the actions of chemotherapeutics → the given dose kills a proportion of the tumour cell population, rather than a constant number of cells
60
Describe radiotherapy
Uses ionising radiation to damage the DNA of cancer cells and so kill them - not selective for cancer cells
Has important acute and late side-effects:
- Acute → includes nausea, vomiting, mouth, throat and stomach sores, infertility if gonads are exposed
- Late → fibrosis, lymphedema, creation of new mutations leading to cancer
61
Describe surgery for cancer treatment
- Used to resect tumour
- Normally a significant amount of healthy tissue is remove to, to minimise the cancer cells that remain
- Lymph nodes in the vicinity may also be removed to reduce risk of metastasis
62
What may chemotherapy drugs be divided into?
```
Cytotoxic drugs:
- Alkylating agents
- Antimetabolites
- Cytotoxic antibodies
- Anti-mitotic agents
- Topoisomerase inhibitors
Targetted therapy:
- Hormones and antagonists
- Small molecules - e.g. protein kinase inhibitors
- mAbs
```
63
What do alkylating agents do?
Form covalent bonds with nucleic acids in DNA
They can also lead to other effects:
- misreading of DNA code
- single strand breaks
- double strand breaks
Their principal effects occurs during DNA synthesis and the resulting damage triggers apoptosis
64
Describe some important alkylating agents
1) Cyclophosphamide → oxidised in vivo to form phosphoramide mustard. It undergoes release of a chloride ion, which allows covalent cross-linking between N7 nitrogens of guanine bases
2) Platinum analogues (e.g. cisplatin) → displacement of choline by water allows cross linking of DNA bases by platinum - intra-strand crosslinks account largely for its cytotoxicity
3) Nitrosureas → highly lipid-soluble, and so are frequently used against tumours of the meninges and the brain
65
Describe antimetabolites. Give examples
Block or subvert pathways of DNA synthesis:
1) Folate antagonists, e.g. methotrexate - inhibits dihydrofolate reductase, preventing generation of tetrahydrofolate, interfering with thymidylate synthesis, which is in turn essential for DNA synthesis and cell division
2) Pyrimidine analogues, e.g. fluuorouracil - converted into a fraufulent nucleotide and inhibts thymidylate synthase and hence thymidylate synthesis
3) Purine analogues
66
Give examples of cytotoxic antibodies
Anthracyclines - e.g. Doxorubicin → inhibits DNA and RNA synthesis
The DNA effect is mainly through interference with DNA topoisomerase II and activation of protein kinase C, leading to intercalation of DNA pairs
It also results in generation of reactive oxygen species, stimulating apoptosis
67
Describe anti-microtubule agents
Several natural occuring plant products exert potent cytotoxic effects through inhibition of mitosis, including:
1) vinca alkaloids, e.g. vincristine - inhibit mitosis at metaphase by binding to tubulin
68
List side effects of cytotoxic drugs
- alopecia
- bone marrow toxicity (neutropenia and thrombocytopenia)
- extravasion of cytotoxic drugs - local skin reaction when escapes
- GI distress (nausea, vomiting, diarrhoea)
- depression of growth in children
- infertility
- nephrotoxicity
- neurotoxicity
- cardiotoxicity
- pulmonary toxicity
- therapy-induced tumorigenesis
69
Strategies for avoidance of resistance to chemo
- use of maximum tolerated dose
| - use of combination therapies
70
Examples of hormones or antagonists used for cancer therapy
1) Tamoxifen - to treat breast tumours, metabolised to hydrotamoxifen, oestrogen receptor antagonist, binds ER, recruits co-repressor proteins and inhibits ER-dependent transcription , arrests growth of ER-positive breast cancer
2) Glucocorticoids - for lymphomas and leukemias - e.g. prednisolone - inhibitory effect on lymphocyte proliferation
3) Anti-androgens - for prostate cancer - e.g. bicalutamide
71
What are molecular targetted cancer therapies good?
Lower toxicity c.f. cytotoxic drugs
72
What do aromatase inhibitors do?
```
Block peripheral (extra-ovarian) oestrogen synthesis in post-menopausal women
- for breast cancer
```
73
How are mAbs for cancer produced?
produced by hybridoma cells in culture - target specific antigens
- they are expensive
74
How may mAbs for cancer function?
1 - binding of antibody to target activates host's immune system (e.g. rituximab for lymphomas)
2 - attach to and inactivate growth factor receptors
75
Give an example of a mAb that attaches to and inactivates GF receptors
Trastuzumab
- HER2 overexpressed in ~25% of breast cancers
- against extracellular domain of HER2
76
Given an example of a small molecule targetted therapy
Imatinib
- t(9;22) - Philadelphia chromosome - BCR-ABL fusion gene
- drives CML
- BCR-ABL fusion protein has deregulated tyrosine kinase activity
- Imatinib → inhibitor of tyrosine kinase activity
77
What is the anti-tumour antibiotic?
Doxorubicin
78
What is the anti-tumour metabolite?
Methotrexate
79
Adverse of chemotherapy drugs?
Reversible (bone marrow, lymphoid, GI epithelium hair) and irreversible injury in organs with little/no growth (kidney, nerves, heart & lungs)
80
Treatment of prostate tumours?
Reduction of testosterone
