Growth, Cell Death and Neoplasia Flashcards
define apoptosis
programmed cell death
define necrosis
traumatic cell death - unintended cell death in response to cellular injury
why do we need apoptosis?
for continuous renewal of cells, working alongside mitosis
name some inhibitors of apoptosis
growth factors
extracellular cell matrix
sex steroids
some viral proteins
name some inducers of apoptosis
growth factor withdrawal loss of attachment of ECM glucocorticoids some viruses free radicals ionising radiation DNA damage
give some examples of when apoptosis is crucial for normal growth - and what occurs if apoptosis fails
separating of fingers - interdigital cell death - syndactyl (webbed fingers)
removal of redundant epithelium on fusion of palatine processes in roof of mouth - cleft palate
what is coagulative necrosis?
most common.
dead tissue is swollen and firm, then later becomes soft - digestion of macrophages
what is colliquative (liquefactive) necrosis?
occurs in brain due to lack of supporting stroma - necrotic tissue liquefies
what is caseous necrosis?
dead tissue is completely structureless. histology shows amorphous eosinophilic area with haematoxyphilic nuclear debris.
seen in TB.
what is gangrene?
necrosis with putrefaction of tissues. tissues appear black.
what is fibrinoid necrosis?
occurs in malignant hypertension - increased arterial pressure results in necrosis of SM wall.
eosinophilic and fibrinous deposits seen.
what is fat necrosis?
focal adipose tissue destruction due to direct trauma, or enzymatic lipolysis (seen in acute pancreatitis)
define hypertrophy
increase in size of a tissue caused by increase in SIZE of the constituent cells
define hyperplasia
increase in size of a tissue caused by an increase in NUMBER of constituent cells - decrease in apoptosis
define atrophy
decrease in size of a tissue caused by a decrease in NUMBER or SIZE of constituent cells - apoptosis
define metaplasia
change in differentiation of a cell from one fully-differentiated type to another
define dysplasia
morphological changes seen in cells in the progression to becoming cancer
give some examples of physiological hypertrophy/hyperplasia
muscle hypertrophy in athletes - in limbs and LV of heart.
hyperplasia of breast tissue at puberty and in pregnancy/lactation.
hypertrophy and hyperplasia of uterine smooth muscle at puberty/pregnancy.
give some examples of conditions involving pathological hypertrophy/hyperplasia
RVH/LVH.
gynaecomastia.
prostate hyperplasia.
follicular epithelial hyperplasia e.g. in Graves’ disease (thyroid)
define congenital
present at birth - not necessarily inherited, foetus is affected by environmental factors in womb (eg FAS)
give some examples of changes to the body that are typical of ageing
loss of dermal elastosis osteoporosis cataracts senile dementia sarcopaenia (loss of skeletal muscle mass/strength) deafness
define carcinogenesis
transformation of normal cells to neoplastic cells through permanent genetic alterations or mututations
- malignant tumours
define oncogenesis
formation of benign and malignant tumours
define carcinogen
agents known/suspected to cause cancer - malignant tumours.
act on DNA - mutagenic
define oncogenic
agents known/suspected to cause tumours - benign or malignant
what problems are presented by attempts to identify carcinogens?
latent interval may be decades.
environment is complex - difficult to isolate one factor.
ethical constraints - can’t deliberately give people a suspected carcinogen as part of a study
list the classes of carcinogen
chemical viral ionising/non-ionising radiation hormones, parasites and mycotoxins misc.
define neoplasm
lesion resulting from autonomous (or relatively autonomous) abnormal growth of cells which persists after the initiating stimulus has been removed
A NEW GROWTH
what are the features of neoplasia?
autonomous
abnormal
persistent
new growth
what makes a neoplasm malignant?
if they invade surrounding tissues, and are able to metastasise/spread to other tissues
describe the structure of solid tumours
neoplastic cells + stroma
what induces stroma formation in a tumour?
connective tissue fibroblast proliferation is induced by growth factors produced by tumour cells
why is angiogenesis needed in tumours?
to perfuse the tumour, allowing it to grow - without angiogenesis, tumour may only grow to 1-2mm diameter
what induces angiogenesis in tumours?
vascular endothelial growth factor (VEGF) - secreted by tumour cells
describe the features of a neoplastic cell
derived from nucleated cells, usually monoclonal.
growth pattern relates to parent cell.
synthetic activity relates to parent cell - production of collagen/mucin/keratin/hormones etc
describe the features of a benign neoplasm
localised, non invasive.
slow growth rate, low mitotic activity.
closely resembles normal tissue.
necrosis/ulceration rare.
how might benign neoplasms cause problems?
pressure on adjacent structures. obstruction of flow. production of hormones. transformation to malignant neoplasm. anxiety.
describe the features of a malignant neoplasm
invasive.
metastases.
rapid growth rate.
variable resemblance to normal tissue - closer resemblance = better prognosis.
poorly defined/irregular border.
hyperchromatic nuclei, increased mitotic activity.
necrosis/ulceration common.
how might malignant neoplasms cause problems?
destruction of adjacent tissue. metastases. blood loss from ulcers. obstruction of flow. hormone production. paraneoplastic effects. anxiety.
what is a papilloma?
benign tumour of non-glandular, non-secretory epithelium.
prefix with cell type of origin.
what is a squamous cell papilloma?
benign tumour of squamous cell (non-glandular, non-secretory) epithelium
what is an adenoma?
benign tumour of glandular or secretory epithelium.
prefix with cell type of origin.
what is a colonic adenoma?
benign tumour of colonic epithelium
how would you refer to a benign tumour of thyroid epithelium?
thyroid adenoma - benign, secretory/glandular epithelium
what is a carcinoma?
malignant tumour of epithelial cells.
prefix by name of epithelial cell type.
what is an adenocarcinoma?
malignant tumour of glandular epithelium
how are benign connective tissue neoplasms named?
cell of origin, suffix -oma
what is a lipoma?
benign neoplasm of adipocytes
what is a chondroma?
benign neoplasm of cartilage
what is an osteoma?
benign neoplasm of bone
what is an angioma?
benign vascular neoplasm
what is a rhabdomyoma?
benign neoplasm of striated muscle
what is a leiomyoma?
benign neoplasm of smooth muscle
how are malignant connective tissue neoplasms named?
‘sarcoma’ prefixed by cell type of origin
what is a liposarcoma?
malignant tumour of adipose tissue
what is a rhabdomyosarcoma?
malignant tumour of striated muscle
what is a leiomyosarcoma?
malignant tumour of smooth muscle
what is a chondrosarcoma?
malignant tumour of cartilage
what is an osteosarcoma?
malignant tumour of bone
what is an angiosarcoma?
malignant tumour of blood vessels
what does anaplastic mean?
cell-type of origin of a carcinoma/sarcoma is unknown
how are carcinomas/sarcomas further classified, apart from by cell type of origin?
according to degree of differentiation
what is screening?
process of identifying apparently healthy people who may be at risk of a disease or condition - then offering info, tests and/or treatment
what are the four principles of screening to be considered in developing a screening programme?
- knowledge of disease - important condition, recognisable early/latent stage, course of disease understood.
- knowledge of test - suitable and acceptable test. continuous case finding.
- treatment for disease - acceptable, available
- cost considerations - cost of screening balanced by savings
what is meant by the “sensitivity” of a screening test?
how successful was the test at identifying all those with cancer/condition screened for?
true positives divided by true positives + false negatives
what is meant by the “specificity” of a screening test?
how well did the test identify all those without cancer/condition screened for?
true negatives divided by false positives + true negatives
what is meant by the “positive predictive value” of a screening test?
how accurate was the selection of cases believed to have the condition screened for?
true positives divided by sum of true and false positives
i.e. what percentage of positive results were accurate
what is the incidence rate of a disease?
the number of new cases per population at risk in a given time period
what is the mortality rate of a disease?
measure of the number of deaths due to a specific cause in a population, per unit of time
describe some limitations of screening
- reduces risk of developing condition, but doesn’t offer guaranteed protection.
- false positives/negatives
- misinterpretation/false results leading to false sense of security
- cost to society/individuals - funds directed away from other services
what cancers commonly spread to bone?
breast, prostate, lung, thyroid, and kidney
what sort of cancers are treated well by conventional chemotherapy? list some.
fast dividing tumours: germ cell tumours of testis; acute leukaemias; lymphomas; embryonal paediatric tumours; choriocarcinoma
what are the issues with conventional chemotherapy? what side effects does this commonly cause?
not selective for tumour cells.
hits normal cells which are dividing:
myelosuppression; hair loss; diarrhoea
what is targeted chemotherapy?
exploits some difference between cancer cells and normal cells to target drugs specifcally at the cancer cells - more effective, fewer side effects
describe the ‘two-hit hypothesis’ of cancer
first ‘hit’ is inheritance of a defective allele of a tumour suppressor gene, the other allele being normal.
second ‘hit’ is acquired mutational loss of function of normal allele - cell has lost all tumour suppressive function.
what are tumour suppressor genes? how are they classified?
genes that inhibit carcinogenesis.
divided into ‘gate-keepers’ and ‘caretakers’
describe how caretaker tumour suppressor genes act
maintain the integrity of genome by repairing DNA damage
describe how gatekeeper tumour suppressor genes act
inhibit the proliferation of, or promote death of, cells with damaged DNA
name some examples of tumour suppressor genes
gatekeepers - p53, APC
caretakers - BRCA1, BRCA2
what is the p53 gene?
gatekeeper tumour suppressor gene.
transcription factor that responds to DNA damage - mutated in c.50% of human cancers
where is the p53 gene located?
short arm of chromosome 17
what are the normal functions of p53 protein?
enable repair of damaged DNA before S phase in cell cycle, by arresting cycle in G1 until damage is repaired.
enable apoptotic cell death if there is extensive DNA damage.
what is the important consequence of loss of function of p53?
cells with damaged DNA (inc. mutated oncogenes or TSGs) undergo mitosis instead of apoptosis.
how are oncogenes classified? (5 groups)
growth factors;
receptors for growth factors;
signalling mediator with tyrosine kinase activity;
signalling mediator with nucleotide binding activity (disrupting intracellular signalling);
nuclear-binding transcription factor oncoproteins - involved in regulation of cellular proliferation
how may oncogenes be activated?
by mutation;
by excessive production of a normal oncoprotein
list a few oncogene examples and how they function
sis - growth factor (PDGF)
erb-B - receptor (for EGF)
src - intracellular signalling (protein-tyrosine kinase)
define a somatic mutation
mutations that develop after conception in any cell of the body, and are passed down only to daughter cells of that original cell
define a germline mutation
germline mutations are present in the germ cells at birth and are passed down from generation to generation
list factors that influence tumour invasion
decreased cellular adhesion.
secretion of proteolytic enzymes.
abnormal/increased cellular motility.
what is the role of matrix metalloproteinases in neoplastic invasion?
secreted by malignant neoplastic cells, enabling them to digest surrounding connective tissue
what counteracts the action of matrix metalloproteinases?
tissue inhibitors of metalloproteinases (TIMPs) - net effect determined by balance of TIMPs and metalloproteinases.
what is “pagetoid infiltration”?
invasion within epithelium
what is the significance of invasion?
most important criterion for malignancy.
metastases are a consequence of invasion.
what is metastasis?
the process of malignant tumours spreading from the primary tumour to form other, secondary tumours at distant sites
define carcinomatosis
extensive metastatic disease
what are the 6 steps involved in the metastatic sequence?
- detachment of tumour cells from neighbours
- invasion of surrounding connective tissue to reach blood/lymph vessels
- intravasation into lumen of vessels
- evasion of host defences (e.g. NK cells in blood)
- adherence to endothelium at remote location
- extravasation of cells from vessel lumen into surrounding tissue
describe the possible routes of metastasis
- haematogenous - by blood stream
- lymphatic - secondary tumours in regional lymph nodes
- transcoelomic - in pleural/pericardial/peritoneal cavities - neoplastic effusion
- implantation - accidental spillage of tumour cells in surgery
what types of metastatic spread do carcinomas and sarcomas prefer, respectively?
carcinomas = lymphatic sarcomas = haematogenous
describe what the term “tumour grade” means
an assessment of the degree of malignancy or aggressiveness of a tumour -assessed histologically
list the most important features contributing to tumour grade
mitotic activity.
nuclear size, hyperchromasia and pleomorphism.
degree of resemblance to normal tissue (i.e. differentiation)
what does the “tumour stage” describe?
the extent of spread
what do the letters and numbers stand for in the TNM staging system?
T = primary tumour. number indicates tumour size/local extent. number varies with organ harbouring tumour.
N = lymph node status. number indicates number of lymph nodes/groups of nodes containing mets.
M = anatomical extent of distant metastases
TNM is then used to derive a stage score.
what is meant by a “stage 1” or “stage 4” cancer?
varies with type of cancer. derived from TNM status.
stage 1 = confined to organ of origin.
stage 4 = disseminated widely.
