Neoplasia Flashcards
atrophy
an acquired diminution of growth due to a decrease in the size or number of constituent parts (cells) of a tissue eg. decrease in size of ovaries post menopause
Hypertrophy-
increase in the size of individual cells, in response to prolonged demand for increased function eg. pregnant uterus
Hyperplasia-
increase in the number of the component cells- increase proliferation, only lasts as long as the cause eg. lactating breast
competence factor
any factor that causes the cell to enter the cell cycle from G0
commitment factor
factors like polypeptide growth factors & hormones that pushes the cell through G1/S (restriction checkpoint)
2 protein families that affect the entry of cells to the next stage:
- cyclin dependant kinases (CDKs)
- cyclins- concentrations rise and fall regularly throughout cell cycle
points of cell cycle where cyclins are synthesised in the greatest concentration
- G1 cyclins: cyclin Ds
- G1/S: cyclin Es
- S cyclins: cyclin As
- M cyclins: cyclin Bs
3 options a cell can commit itself to in G1:
- recycle and go through the cell cycle another time
- decycle and enter a resting G0 phases where it can re-enter the cycle if conditions demand
- decycle permanently and terminally differentiate
what protein controls the restriction checkpoint?
Rb
E2Fs
transcription factors that bring about own transcription and of the cyclin E- CDK2 complex + regulate other genes that promote entry into the S phase
how does Rb inhibit cell progression and force it into G0?
Rb binds to E2Fs and inhibits them by binding to E2F responsive promoters. Once the Rb-E2F complex is bound, it recruits histone deacetylases and chromatin remodelling complexes. The remodelling and removal of the acetyl groups repress the action of the promoters
why does phosphorylation of Rb allow cells to move onto the S phase?
a certain level of phosphorylation stops Rb from being able to bind to E2Fs
what complex increases the phosphorylation of Rb?
cyclin E-CDK2 complex
purpose of G2/M checkpoint
checking that the cell has replicated all of its DNA and completed any necessary DNA repair
purpose of spindle checkpoint
whether chromosomes are all attached properly so that segregation in anaphase goes correctly
permanent cells
irreversible differentiated, eg. neurones, striated myocytes
constituents of the continuously self renewing population
- Stem cells: self-renewing & slowly proliferating
- Transit amplifying: committed to differentiation and rapid proliferation at same time
- Terminal differentiation: fully differentiated
Metaplasia
replacement of one differentiated cell type by another in response to persistent injury, most commonly involves replacement of a glandular epithelium by a squamous one eg. exposure of bronchial epithelium persistently to tobacco smoke
Dysplasia
part of spectrum of changes of pre-invasive neoplasia, dysplastic changes don’t revert to normal once the injury is removed
morphology in dysplasia
• The regular organised appearance of epithelium is disturbed by variation in shape and size of cells
- Enlargement- increased Nucleus: Cytoplasm ratio
- Irregularity- pleomorphism (variation in nuclear size, shape and chromatin staining)
- Hyperchromatic nuclei (dark nuclei)
- Increased mitosis
• Distortion of the proliferating compartment compared to differentiation compartment
neoplasia
- An abnormal mass of tissue (tumour)
- Growth exceed and is uncoordinated with that of normal tissue
- Persists in same excessive manner after stimulus is removed
- Irreversible
- Composed of living cells
- Cells of a tumour have deregulated or lost the division/ differentiation/death controls which regulate tissue organisation and architecture
invasion
capacity to infiltrate surrounding tissue and organs
Metastasis-
ability to spread to and proliferate in distant parts of body after tumour cells
routes of metastasis
by blood and lymph channels and along body spaces (transcoelomic spread)
Benign neoplasms-
proliferate but do not invade adjacent tissue
Generally, not life threatening but they can cause problems because of position, pressure, obstruction and excess production of hormones.
Malignant neoplasms
proliferate, invade adjacent tissues and/or metastasise, malignant tumours are cancers
morphology of benign tumours
- Slow growing
- Low mitotic rate
- Clearly demarcated from surrounding tissue- encapsulated or pseudo capsule
- Nuclear morphology often near normal, grow outwards
- Clonal mutations or chromosome abnormalities- not aneuploid
morphology of malignant tumours
- Not demarcated (set boundaries) clearly
- Surface often ulcerated and necrotic
- Often grow inwards (endophytic growth)
- Cut surface heterogenous
- Rapid growth
- Nuclei pleomorphic, hyperchromatic
- Abnormal mitoses
- Usually aneuploid
stroma
vascular connective tissue surrounding and supporting the neoplastic cells- very pronounced in carcinomas
why is neovascularisation important?
for growth of tumour
4 most common cancers
breast, lung, colorectal and prostatic cancers
highest levels of mutation
defective DNA repair, UV and smoking
name for preinvasive stage of cervical cancer
cervical intra-epithelial neoplasms (CIN- UK/Europe) or lesions
cytological features of high grade intra-epithelial neoplasms
- Variation in cell size/shape
- Abnormal nuclei (pleomorphism- variability of nuclei & hyperchromasia- excessive pigmentation)
- Abnormal and increased mitoses
- Loss of nuclear polarity
- Loss of differentiation
why have CINs not invaded?
they stay on the epithelial side of the basement membrane- intra-epithelial
breast precursor name
Ductal Carcinoma In Situ (DCIS)
features of ductal carcinoma in situ
excessive numbers of neoplastic epithelial cells (larger than normal with a range of nuclear cytological abnormalities- pleomorphism, hyperchromasia, loss of differentiation- build up within enlarged ducts or groups of small ducts causing them to dilate
in situ
non invasive
large intenstine precursor name
adenoma
adenoma
have dysplastic glandular epithelium, may evolve into an invasive adenocarcinoma (malignant)
polyp
Adenomas of the colon
genes that are target for mutation for neoplasia
genes controlling proliferation, cell death and genomic stability
benign tumours of surface epithelia and glandular epithelia
Surface epithelia- papilloma
Glandular epithelia- adenoma
benign tumours of fat and fibrocytes
- Fat= lipoma
* Fibrocytes= fibroma
benign tumour of cartilage
• Cartilage= chondroma
benign tumours of smooth muscle, skeletal muscle and bone
- Smooth muscle= leiomyoma
- Skeletal muscle= rhabdomyoma
- Bone= osteoma
benign tumours of germ cells/gonads
• Germ cells/gonads= teratoma
malignant tumours of surface epithelia and glandular epithelia
- Surface epithelia= squamous cell carcinoma
* Glandular= adenocarcinoma
malignant tumours of all connective tissue
• All connective= -sarcoma instead of -oma
malignant tumours of germ cells/gonads
• Germ cells/ gonads= teratocarcinoma
malignant tumours of skin
• Skin= melanoma
malignant tumour of lymph nodes and white blood cells
- Lymph nodes= lymphoma
* White blood cells= leukaemia (uniquely exhibit distinctive mutations- no aneuploidy)
malignant tumour of astrocytes
• Astrocytes= glioma
hallmark of cancer- self sufficiency in growth signals
cancerous cell produces its own signals for proliferation (ligands/ECM component interactions/cell-cell adhesion molecules) instead of receiving them from other cells, gains ability of autocrine stimulations.
- Mutated Ras protein is truncated so the GCPR loses its intrinsic GTPase activity and acts like it is receiving growth signals all the time.
- Tyrosine kinase receptors for these may be overexpressed so that the cell is hyper responsive to growth factors
hallmark of cancer- insensitivity to growth inhibition signals
includes genetically inactivated pRb, TGFβ receptor downregulation/ mutation and c-myc overexpression.
C-myc
transcription factor (a proteins that binds to a gene to activate or supress its protein synthesis) so damage will promote proliferation.
hallmark of cancer- evasion of apoptosis
result of decoy death ligands or downregulated/mutated death receptors. Normally changes in ECM signals provoke apoptosis but cancerous cells have lost this ability. Mutated p53 also cannot cause apoptosis in response to damaged DNA, BCL2 is overexpressed
BCL2
Anti-apoptotic BCL2 mitogen provokes cell to start cell cycle
hallmark of cancer- immortality
result of other hallmarks and upregulated, inappropriate telomerase activity
hallmark of cancer- angiogenesis
as tumour enlarges and spreads it requires a greater blood supply for growth, tumour cells and infiltrated macrophages secrete angiogenic factors which switch on the process. ECM breakdown also releases sequestered angiogenic growth factors such as VEGF, Ras oncogene upregulates these factors. The vessels produced are wide and inefficient at exchange, so drugs have difficulty reaching tumour cells to be effective and necrosis develops at centre of tumour.
hallmark of cancer- invasion and metastasis
requires loss of cell-cell adhesion, ECM proteolysis and cell movement. Cadherins and integrins are mutated for this purpose and also to affect cell signalling stimulating proliferation and survival, tumour cells widen spaces by oedema to allow movement. Tumour cells secrete matric metalloproteinases (MMP enzymes) which carry out ECM breakdown and MMP inhibitors (TIMP) are downregulated.
destructive behaviours of cancer
- Blood loss- ulceration and haemorrhage
- Pressure and destruction of adjacent tissue
- Obstruction or constriction of flow in vital organs
- Metabolic effects
- Cachexia (weakness and wasting of body)
- Specific- tumour specific products
- Destruction of vital tissue
- Opportunistic infection cause death
how can colon cancer spread to the liver?
via the hepatic portal venous portal blood or coelom
how can breast cancer spread to bone?
they have similar adhesive molecules- known as the ‘seed and soil’ hypothesis: particular cancer cells require the right tissue/receptor if they are to spread
TNM staging
tumour size, node (lymph), metastasis
oncogenes
normal genes which if mutated, precipitate cancer, often regulatory genes
examples of oncogenes
Ras, c-myc, EGFR (epidermal growth factor receptor)
how can Ras genes become oncogenes?
through a point mutation- the altered amino acid in the protein causes the Ras molecular switch to become constitutively active
organism that can insert oncogenes into the host cell genome?
retroviruses
how can EGFR become overactive?
by either amplification- producing multiple copies of the gene or truncation of the gene causing the receptor produced to become constitutively active, the cell will act like it is constantly receiving growth factor signals and so proliferate excessively
alteration of sis growth factors leads to?
cell proliferating uncontrollably
tumour supressor gene
normal regulatory genes that are protective again neoplastic behaviours
how many TSG alleles must be mutated to produce cancer?
2
how many protooncogene alleles must be mutated to become oncogene?
1
examples of TSGs
p53, APC, Rb
how can Rb cause cancer?
mutation of Rb would allow every cell to progress through the cell cycle by allowing E2F to express S phase entry genes
how can p53 cause cancer?
*only 1 allele needs to be mutated
p21 is a CDK inhibitor and if mutated won’t fix DNA damage or promote apoptosis but instead allows cell to progress
how can APC cause cancer?
regulatory protein in the Went ligand pathway, mutated APC will not bind β- catenin (transcription factor for growth promoting genes) and so growth becomes uncontrolled
how can mutated mismatch repair proteins cause cancer?
mutated proteins are free to be produced from DNA
Mutated nucleotide excision proteins are seen in xeroderma pigmentosum where damaged DNA results in skin cancer
BRCA- altered strand break protein mutation
mutations propagate so patients are more susceptible to cancers
what is aneuploidy a result of?
p53 degradation, common is cold tumours
types of carcinogens/oncogens
- Chemical- natural or synthetic
- Physical- UV or ionising radiation
- Biological- bacteria, viruses, parasites
latent period of carcinogens and tumour appearance
there is a dose dependant time lag between the amount of carcinogen delivered in a single dose and the appearance of macroscopic tumours; high doses reduce time lag while low doses extend it
threshold dose of carcinogen
there is a threshold dose of carcinogen below which no tumours form
imitation in carcinogenesis
alteration of a normal cell to a potentially cancerous cell, carcinogens cause this irreversibly, carcinogens are mutagens
promotion in carcinogenesis
process which permits clonal amplification of initiated cell, promoters are not carcinogens because they induce proliferation, a benign neoplasm forms
progression in carcinogenesis
acquisition of further mutations within neoplastic clone drive progression to a malignant neoplasm and metastasis
activation fo telomerase results in
maintained telomere length, immortalisation of cell
childhood cancer- retinoblastoma
peak incidence of 3-4, can be either sporadic or inherited
carcinogens that can cause neoplasia to occur:
- viral transduction transforming DNA using an oncogene eg. Ras switch
- deletion of a tumour suppressor gene that would inhibit proliferation or promote apoptosis (eg. p53 or pRb) which may in turn activate an oncogene
- defects in DNA repair gene (eg. those coding for mismatch repair proteins)
- Tar metaplasia from smoking
- Radiation eg. UV rays may precipitate DNA strand breaks or thymine dimers which disrupt base pairing
risk factors for cancer
- Increasing age- accumulating mutations and decreasing telomerase
- Smoking- metaplasia due to carcinogens in tar
- Genetic disposition
- Environment, occupation and diet- including carcinogen exposure
- Radiation exposure
- Infectious agents- viruses carrying out transduction
- Parasites- induce chronic irritation which is a promoting agent for tumours
ultimate carcinogens
highly reactive electrophilic molecule, directly damages DNA
Many show tissue, stage and species specificity
synthetic carcinogens
polycyclic hydrocarbons, aromatic amines and Azo dyes
naturally occurring carcinogens
nitrosamines, aflatoxin
how can ionising radiation damage DNA?
DNA by making tracks of free radicals and ions they pass through
infectious agents role in cancer
- Parasites- promoting agent for tumours by inducing chronic inflammation
- Bacteria- infection with helicobacter pylori is a risk factor for the development of gastric carcinoma and gastric lymphoma
- Viruses- both DNA and RNA viruses are known to cause cancer in animals
clonal neoplasia
tumour cells are descendants (progeny) of a single cell
what protein inhibits p53?
mdm2
what inhibits almost all cyclins/cdk complexes?
p21
Transforming Growth Factor β function
inhibits epithelial proliferation
epstein barr virus (EBV) causes
Hodgkin’s lymphoma, nasopharyngeal carcinoma, Burkitt’s lymphoma
Hep B and C cause
liver cancer
HTLV-1 causes
T cell leukaemia
HSV-2 causes
cervical cancer
