WEEK 8 Flashcards
What are the differences between tumour cells and their surrounding stroma?
Tumour cells are neoplastic cells and is autonomous (i.e. response to physiological stimulus is lost/abnormal, allowing unregulated growth)
- have self sufficiency in growth signals
- are insensitive to anti-growth signals
- invade tissue & metastasise
- have limitless replicative potential
- sustained angiogenesis
- avoid apoptosis
Their surrounding stroma is anything that is not a cancerous cell
- e.g. connective tissue, blood vessels, inflammatory cells.
What are the general characteristics of benign and malignant tumours?
BENIGN:
- well circumscribed
- slow growth
- no necrosis
- non-invasive
- no metastasis
MALIGNANT:
- poorly circumscribed
- rapid growth
- often necrotic
- invasive
- metastasises
What are the four ways in which malignant tumours spread?
- Directly invade locally
- Via the lymphatics
- Via the bloodstream (haematological)
- Through body cavities (transcoelomic)
Why is a benign tumour not always clinically benign?
- Have space occupying effects
- obstruction
- epilepsy
- conduction abnormalities - Cause haemorrhage
- pulmonary
- GI - Cause hormone production
- pituitary
- adrenal
- endocrine production
The seed and soil hypothesis explains that not all tumours behave the sae. What are some of the common areas that certain tumours metastasise to? (HINT: there’s 4 examples)
- Prostate (tends to metastasise to) -> bones
- Lung -> brain, adrenals
- Breast -> lung, liver, bone, brain
- Ovary -> peritoneal cavity
What are the macroscopic features of benign and malignant tumours?
BENIGN:
- intact surface
- exophytic growth
- homogenous cut surface
- circumscribed/encapsulated edge
MALIGNANT:
- alterated surface
- endophytic growth
- heterogenous cut surface due to necrosis
- irregular infiltrative edge
- endophytic growth
What are the microscopic features of benign and malignant tumours?
BENIGN:
- resemble tissue fo origin
- well circumscribed
- well differentiated
- minimal nuclear polymorphism
- mitotic figures normal
- no necrosis
MALIGNANT:
- variable resemblance
- poorly circumscribed
- variable differentiation
- variable pleomorphism (may be anaplastic)
- mitotic figures abnormal
- necrotic
What do the terms grade and stage mean in relation to tumours? Give examples of how staging is used clinically.
GRADE = the degree of resemblance to the tissue of origin
- correlates broadly with clinical behaviour
- e.g. a grade 1 malignant neoplasm = well differentiated whereas a grade 4 malignant neoplasm = nearly anaplastic
STAGING = the extent to which a cancer has developed by spreading
- e.g. TNM staging : T = tumour size
N = degree of lymph node involvement
M = extent of distant metastases
- e.g. Dukes’ staging system for colorectal cancer (A, B, C, D)
How are benign and malignant tumours named? (for both epithelial and connective tissue tumours)
BENIGN:
- epithelial = papillomas or adenomas
- connective tissue = begin with the term denoting the cell of origin e.g. lipoma
MALIGNANT:
- epithelial = carcinomas
- connective tissue = sarcomas
Give examples of (i) epithelial (ii) mesenchymal (iii) miscellaneous tumours.
(i) Benign = squamous cell papilloma, transitional cell papilloma, adenoma
Malignant = squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma
NOTE: epithelial tumours may be associated with a non-invasive precursor (e.g. carcinoma in situ, intraepithelial neoplasia)
(ii) Benign = lipoma, haemangioma etc
Malignant = liposarcoma, haemangiosarcoma
NOTE: not usually associated with a non-invasive prescursor
(iii) melanoma, teratoma, lymphoma, blastomas, carcinoid tumours, cysts
What is a teratoma?
- contains elements of all three embryonic germ cell areas
- is of germ cell origin
- is both benign and malignant forms
- ovarian = almost always benign
- testicular = almost always malignant
What are tumour stem cells?
- the cells which can repopulate the tumour
example = basal and squamous cell carcinoma
What does the statement “many tumours have a clonal origin” mean?
- gene coded for by the X chromosome
=> in females one X is randomly switched off - The enzyme G-6PD can be separated by chromotography into an A and a B form
- normal tissue = a 50:50 ratio of A and B enzyme markers
- If the tumour arises from a single cell (i.e. clonal) then all the cells have the same enzyme marker (all A or all B)
What are the changes in bone structure and function that occur with osteoporosis?
- decreased size of osteons
- thinning of trabeculae
- enlargement of haversian and marrow spaces
What is the incidence of osteoporosis in the UK?
Affects 3 million people in the UK
Affects 1 in 3 women and 1 in 12 men
- at the age of 50, the chances of fragility fractures are: In woman all fractures = 40% chance, for hip fractures in woman = 18% and in men = 6% chance.
What are the risk factors for osteoporosis?
- GENETIC/GENDER: females more prone than men due to menopause (change in oestrogen regulation)
- LIFESTYLE & NUTRITIONAL: smoking, excess alcohol, prolonged immobilisation, sedentary
- MEDICAL CONDITIONS: many are related to hormone imbalances. Examples include; anorexia nervosa, rheumatoid arthritis, early menopause, hyperthyroidism
- DRUGS that lead to OP: chronic corticosteroid therapy, excessive thyroid therapy, anticoags, anticonvulsants, chemotherapy, gonadotrophin releasing hormone agonist OR antagonist
- RISK OF ANOTHER FRACTURE AFTER A PREV FRAGILITY FRACTURE: Fragility fracture = low energy trauma - mechanical forces that wouldn’t normally cause a fracture
A previous wrist fracture: doubles risk of future hip fracture & triples risk of future vertebral fracture
What are the most common sites for osteoporotic fractures ? Appreciate the morbidity associated
Distal radius, neck of femur, vertebral body, spine, proximal humerus
- hip fractures are: fatal in 20-30% of cases
only 30% fully recover
permanently disables 50%
List the modifiable and non modifiable risk factors for osteoporosis.
MODIFIABLE: NON MODIFIABLE
- oestrogen deficiency - gender
- smoking - age
- alcohol - previous fracture
- low calcium - family history
- low BMI - long term steroids
- vit D deficiency - race
- inacitvity
How is osteoporosis diagnosed?
- blood tests, FBC, serum biochemistry, bone profile
- thyroid function tests
- testosterone & gonadotrophin levels (men)
- x-ray of lumbar and thoracic spine ( BUT >30% bone loss is required to be visible)
- BMD measurement using DEXA
How is osteoporosis treated?
- BIPHOSPHONATES: e.g. alendronate, risedronate
- disrupt the activity of osteoclasts => OC end up dying as they inhibit part of the mevalonate pathway
- potential side effects = oesophagitis, mandibular necrosis - ANABOLIC AGENTS e.g. strontium ranelate, intermittent PTH.
- stimulate bone production (OB activity increase)
- this may be more effective than the above as it’s replacing wasted bone rather than simply halting the wasting - Ca2+ supplements
- HRT - this carries an increased risk of breast cancer
- INCREASE EXERCISE
What are the types of osteoporosis?
TYPE 1: POST MENOPAUSAL - affects cancellous bone - vertebral & distal radius fractures common - related to oestrogen loss - F:M = 6:1 TYPE 2: AGE RELATED IN >75 y.o - affects cancellous AND cortical bone - hip & pelvic fractures common - related to poor calcium absorption - F:M = 2:1 DISUSE OSTEOPOROSIS - resulting from conditions resulting in prolonged immobilisation, typically in neurological or muscle disease
Explain the scoring for DEXA.
T-SCORE: comparison with a young adult of the same gender who has peak bone mass
>-1 = normal
-1 to -2.5 = osteopenia
less than -2.5 = osteoporosis
Z-SCORE: comparison of pt with data from the same age/sex/size
What is X-chromosome inactivation? Give an example.
Because females = XX and males = XY
- females need to silence one X chromosome (= chromosome inactivation)
- mechanism of silencing is initiated by Xist
{ X inactive specific transcript “marks” the inactive X, it is only expressed from inactive x-chromosome & codes for RNA. No protein product or RNA remains in the nucleus}
- this is then followed by DNA methylation
E.g. Calico cats; whether paternal or paternal X depends whether express orange or black coat (white = autosomal)
What is the difference between heterochromatin and euchromatin?
HETEROCHROMATIN:
- highly condensed in interphase
- transcriptionally inactive (contains few genes)
- replicates LATE in S phase
EUCHROMATIN:
- organised in 30nm fibre during interphase
- transcriptionally active
- replicates EARLY in S phase
What is DNA methylation?
- inhibits gene transcription
- prevents binding of transcription factors to promoter & inhibits transcription by converging chromatin from an open to a closed conformation
- methyl CpG proteins contain a methyl binding domain that specifically recognises methylated CpGs
- it recruits other proteins (e.g. histone deacetylases) that remove acetyl groups and => favouring compact chromatin
What are the two ways in which the methyl tags can silence genes?
- Can block transcription machinery from binding to the DNA
2. Can recruit proteins that bind to methylated DNA, which then block the transcription machinery from binding
What is uniparental disomy? Name and explain certain diseases which result from uniparental disomy.
Chromosome imbalances
- both chromosomal copies are inherited from the same parent
Meiosis I = uniparental heterodisomy
Meiosis II = uniparental isodisomy
chr 11 = Wilms’ tumour
chr 15 = PWS/AS
PWS and AS are 2 v. different disorders but are both linked to the same imprinted region of chr 15. Some of the genes in this region are silenced in the egg & at least one is silenced in the sperm => someone who inherits a defect on 15 is missing different active genes, depending on whether the chromosome came from mum OR dad
What is genomic imprinting? State the mechanism and the evidence for imprinting.
Imprinted genes only expressed from one allele, dependent on parental origin
- imprinting resets on passage through germline
MECHANISM: must be somatically stable
must be reversible during gametogenesis
=> DNA methylation = best candidate
EVIDENCE: human tumours: hydatidiform mole (2xF) ovarian teratoma (2xM)
Mouse chimeras: normal + androgenetic (2xM) = growth enchanced. normal + gynogenetic (2xF) = growth retarded
Give examples of diseases arising from abnormal epigenetic regulation. (HINT: there’s 6)
Beckwith-Wiedmann (BWS) Syndrome [overgrowth] Fragile X Syndrome Myotonic Dystrophy (congenital) Prader-Willi Syndrome Angelman Syndrome Wilms' Tumour [overgrowth]
What is the epidemiological time triad?
= Time - place - person
Time:
- long term = secular
- epidemic = temporary increase
- periodic = cyclical
- seasonal
Place:
- geographical, local, workplace, community, home, social gatherings
Person:
INTRINSIC = genetics, sex, age, marital status, ethnic group
EXTRINSIC = lifestyle, behaviour, occupation, migration, socio-economic
