Cancer and Signalling Flashcards
3 Pathology specific sampling methods
Cytology sampling: fluid sampling, fine needle aspiration
Tissue sampling: biopsy, resection
Extra tests: immunohistochemistry, genetic profiling
What is neoplasia
An excessive, irreversible and uncrontrolled growth which persists after withdrawl of the stimuli that caused it
Difference between neoplasia and a tumour
Tumour - swelling/lump
Neoplasia - Wider than this as not all neoplasms are guaranteed to cause swelling/lumps e.g. leukaemia
3 types of neoplasms
Benign disease, dysplasia and malignancy
What is hyperplasia
Increase in cell number
What is hypertrophy
Increase in cell size
What is atrophy
Descrease in cell size
What is metaplasia
Change from one cell type to another
(eg, from squamous to glandular epithelium)
Describe hypertrophy
Increase in cell size
Gene activation, protein synthesis, production of cellular organelles
PI3K/AKT pathway important in physiological hypertrophy
Multiple G protein linked signalling pathways important in pathological hypertrophy
Describe Atrophy
decrease in stress -> decrease in cell number or size
decrease in cell number : apoptosis
decrease in cell size: ubiquitin-proteasome degradation of cytoskeleton OR autophagy of cellular components by autophagosomes fused to lysosomes
Describe Metaplasia
Reprogramme of stem cells - different cell type
Can occur across any of the cell categories - commonly epithelium
Can be step on malignany pathway
Example: Barretts oesophagus, Vit A deficiency induced keratomalacia of the conjuctiv, myositis ossificans
What is aplasia
Failure of cell production in embryogenesis, on a spectrum between agenesis and hypoplasia
What is hypoplasia
Decrease in cell production during embryogenesis, which leads to a smaller overall organ size
What is necrosis
uncontrolled cell death
What is apoptosis
programmed cell death
Describe benign disease
Localised
well encapsulated
slow growing
resemble the tissue of origin
regular nuclei
few mitoses
damage at the local level
What is dysplasia
Abnormal/atypical cells due to failure of differentiation
In some areas of the body - intraepithelial neoplasia
The more dysplastic = the higher the chance of future malignancy
2 disordered cellular features of dysplasia
Pleomorphic nuclei - irregular and variable size
Mitotic figures - cells dividing in an irregular way (perhaps pulled to three poles)
Describe malignancy
invasive
can metastasise
grows fast
may not resemble tissue of origin
shows features of dysplasia
damage at local or distant sites
How can cancers spread through metastasis
through lymphatics
through blood
transcoelomic - body cavities
Benign covering epithelia
papilloma
Benign glandular epithelia
Adenoma
Benign solid organ epithelia
Adenoma
malignant covering epithelia
carcinoma
malignant glandular epithelia
adenocarcinoma
malignant solid organ epithelia
[organ] carcinoma
benign smooth muscle
leiomyoma
benign skeletal muscle
rhabdomyoma
benign bone forming tissue
osteoma
benign cartilage
chondroma
benign fibrous tissue
fibroma
benign bllod vessels
agioma
benign adipose tissue
lipoma
malignant smooth muscle
leiomyosarcoma
malignant skeletal muscle
rhabdomyosarcoma
malignant bone forming tissue
osteosarcoma
malignant cartilage
chondrosarcoma
malignant fibrous tissue
fibrosarcoma
malignant blood vessels
angiosarcoma
malignant adipose tissue
liposarcoma
Malignant lymphoid
Lymphoma
Malignant haematopoietic tissue
leukaemia
Malignant primitive nerve cells
Neuroblastoma, retinoblastoma etc
Malignant glial cells
Gliomas (eg astrocytoma)
Malignant melanocyte
malignant melanoma
Benign melanocytes
Pigmented naevi (moles)
malignant mesothelium
malignant mesothelioma
malignant germ cells
teratoma, seminoma
benign germ cells
teratoma
What does immunochemsitry show us in relation to HER2 of breast cancer
Immunochemsistry shows us where certain proteins are expressed within the cell and in roughly what quantity they are expressed (the darker the brown, the more HER2 there is)
Describe Microsatellite instability
occurs when there is a failure of the mechanism to repair damaged DNA in the cell cyle.
tIf there is damage to the MMr system, damaged DNA can be passed down to new cells and this can make them prone to mutations causing cancer.
The higher chance of mutation caused by the failure of the MMR system is called MSI
What is staging
How far has the neoplasm spread through the body
Describe TNM classification
Tumour - measures local invasion
Node - measure spread to lymph nodes
Metastasis - Measures spread to distant tissues
Local effects of neoplasms
Generalised symptoms - pain, lump
Compression of surrounding structures
Ulceration
Bleeding/Anaemia
Obstruction
Metastatic effects of neoplasms
Depends on site
Eg, brain mets cause swelling, raised pressure, stroke, seizures etc
Systemic effects of neoplasms
Weight loss, loss of apetite, cachexia
Fever or feeling non-specifically unwell
Infection
Para-neoplastic effects of neoplasms
Secretion of excess substances, eg. hormones has systemic effects
Raised calcium (leading to confusion) in cencer patients for example
Mental health effects of neoplasms
Depression, anxiety, hopelessness, frustration
Worsening quality of life
What is G0
The pahse when cells are not actively dividing
Also known as quiescenceResponse to external signal/mitogenic
How long is the cell in G1
11 hours
How long is the cell is S phase
8 hours
How long is the cell in G2
4 hours
How long is the cell in M phase
1 hour
What happens in the S phase
Synthesis of DNA
What happens in G1
Growth
Monitoring of environment
RNA and protein synthesis in preparation for S phase
Growth-factor dependent
what happens in G2
Further growth
cell organelle replication
preparation for mitosis
What happens during prophase
The strands of chromatin shorten, thicken and resolve themselves into recognisable chromosomes.
Nuclear envelope dissapears and the spindle microtubules expand into the central region of the cell, attaching to the chromosomes
What makes the mitotic spindle
Parallel microtubules assembled between centriole pairs at opposite poles
What happens in metaphase
Chromosomes assemble along metaphase plate. Each chromsome is attached to a spindle fibre by bundles of microtubules
What happens in Anaphase
Proteolytic cleavage of the proteins that hold the chromatids together, allowing them to be pulled to opposite poles of the spindle.
What happens in telophase
Nuclear envelope reforms and chromsomes decondense, spindles disintegrate.
Describe cyclin dependent kinases
regulate progression through the cell cycle
serine/theorine kinases
activity must be tightly regulated
which CDK is involved in G1
cdk4/6
which CDK is involved in S
cdk2
which CDK is involved in S through to Metaphase
cdk2
which CDK is involved in G2 through to anaphase
cdk1
which cyclin is associated with G1
cyclinD
which cyclin is associated with S
cyclinE
which cyclin is associated with S through to metaphase
cyclinA
which cyclin is associated with G2 through to anaphase
CyclinB
What are cyclins
activator proteins that are up- or down- regulated depending on the phase of the cell cycle
Unstable proteins
different cyclins associated with different cdks
what is cyclin B also known as
Maturation promoting factor (MPF)
Causes of cell injury
Mechanical - Trauma
Radiation
Infection
Chemical
Hypoxia
Genetic - Mutations
Drugs
2 ways in which cells die
Necrosis and apoptosis
Reversible cell injuries
“Cloudy Swelling” - osmotic distrubance
Cytoplasmic blebs, disrupted microvilli, swollen mitochondria
“Fatty change” - accumulation of lipid vacuoles
Cell death by necrosis
injury due to external stimuli
uncontrolled cell death
always pathological
cell contents leak from breakdown of cell membrane
often elixits inflammatory response
cell death by apoptosis
can be physiological or pathological
active controlled or “programmed” cell death
cell contents do not leak due to intact cell membrane
does not elicit inflammatory response
What is karyolysis
Nuclear fading
What is pyknosis
nuclear shrinkage
what is karyorrhexis
nuclear fragmentation
coagulative necrosis
firm, tissue outline retained
haemorrhagic: due to blockage of venous drainage
gangrenous: larger areas (lower leg)
colliquitive necrosis
tissue becomes liquid and its structure is lost
e.g infective abcess, cerebral infarct
caseous necrosis
combination of coagulative and colliquitive, appearing ‘cheese-like’ (caseous)
fat necrosis
due to action of lipases on fatty tissue
effects of necrosis
depends on tissue/organ
inflammation - release of cell contents activates inflammation and causes damage.
physiological fucntions of apoptosis
embryogenesis: deletion of cell populations
cell deletion in proliferating cell populations to maintain constant number of cells
deletion of inflammatory cells after response
deletion of slef-reactive lymphocytes in thymus (auto-immune disease)
pathological targets of apoptosis
viral infection: cytotoxic T-lymphocytes
DNA damage
Hypoxia/ischaemia
Autoimmune disease
Graft vs host disease
apoptosis morphology
cell shrinkage
chromatin condensation
membrans of cell remain intact
cytoplasmic blebs form and break off to form apoptotic bodies which are phagocytosed by macrophages
What are CDKIs
CDK inhibitors
small proteins that block cyclin/CDK activity either by forming an inactive complex or by acting as a competitive CDK ligand
what are the three CDKI families
p21 CIP
p27 KIP
p16 INK
Inactive MPF form
cdk-1 in a phosphorylated state
What does active MPF phosphorylate
Lamins to destroy the nuclear envelope
Histones and condensins for chromosome condensation
Microtubule-associated proteins (MAPs) for spindle formation
What is the restriction point
the checkpoint at G1
after which the cell no longer requires growth factors to complete the cell cycle and commits to cell division.
Dependent on the accumulation of cyclin D.
Retinoblastoma protein acts as the gatekeeper.
Function og epidermal growth factor
EGF
re-epithelialsation
(keratinocyte proliferation and migration)
Function of platelet-derived growth factor
PDGF
matrix formation (increased numbers and activity of fibroblasts)
Remodelling (production of proteases)
Function of vascular endothelial growth factor
VEGF
angiogenesis (endothelial cell proliferation and migration)
What is E2F
Transcription factor that when the cell cycle is active, it transcribes genes necessary for S phase. It is inhibited in G1 by RB
In the presence of growth factors, what does cdk4/6-cyclin D phosphorylate
Retinoblastoma protein. This forces it to dissociate from E2F and allows gene transcription to occur.
Describe tumour suppresor genes
TSGs encode normal cell proteins that inhibit cell proliferation and growth of cell.
They maintain integrity of the genome
Cause cell-arrest in abnormally dividing cells and repair DNA damage
RB - blocks entry to the cell cycle
p53 - detects DNA damage
BRCA1 - DNA repair
Describe p53
Transcription factor
If it detects low levels of DNA damage it will inhibit the cell cycle and express p21 so DNA repair can occur
If it detects high levels of DNA damage it will promote apoptosis.
What occurs at the metaphase checkpoint
Anaphase promoting complex APC is inhibited until all chromosomes are attached to spindles.
Describe morphogen
Cell signalling molecule that travels from one point to another.
Cells near the origin get lots of morphogen and so respond in a particular way that is different to the cells recieving low levels at the second point.
What happens when RAS is mutated
Mutated K-RAS is too active and causes cells to grow/divide/survive in the absence of growth signals.
Describe Herceptin
Drug used agaisnt breast cancer
AKA trastuzumab
Targets cell surface growth factor receptor (HER2)
Stops growth signalling
Describe salbutamol
Asthma reliver
Targets beta-2 receptor in lungs (opens them)
Describe Gleevec
Protein kinase inhibitor used against CML. Inhibits intracellular protein tyrosine kinase (Bcr-Abl)
Describe Avastin
Targets VEGF - signal for angiogenesis (new blood supply for tumour)
Inhibits cancer growth
2 ways to classify biochemical signals
chemical structure
range of action (distance)
3 types of hormones
- Amino-acid derivatives
- Steroid hormones
- Eicosanoids (derived from lipids)
4 terms to classify signals based on range of action
Endocrine - long distance
Paracrine - nearby
Juxtacrine - neighbour cell
autocrine - same cell
3 stages of all signals
- detect signal/stimulus
- Transduce the signal from site of detecction to part of cell that will respond
- Respond - must be coordinated with responses to other signals; and with responses of other cells (tissue/organ/body)
Describe hydrophobic signal molecules
Diffuse directly through plasma membrane into cells
eg. steroid hormones
- bind directly to intracellular receptor proteins
- hormone-receptor complex acts as a transcription factor
- complex binds to DNA and alters gene expression
Describe hydrophillic signalling molecules
Must use a cell surface receptor protein
eg. insulin and adrenaline
binds to a receptor and activates it bringing about a conformational change that results in a cellular response
3 main types of cell surface receptors
- Ion-channel-linked
- G-protein-linked
- Enzyme-linked
describe ion channel linked receptors
e.g. glutamate neurotransmitter
Ion flow into cell changed the electrical properties of the cell
e.g. nerve impulse transmission
describe G protein linked rceptor (GPCR)
e.g. adrenaline, serotonin, glucagon
Activated G-protein activates enzyme that passes on signal into cell
describe enzyme linked receptors
e.g. many growth factors, insulin
Signal binds to the inactive receptor it brings the two parts of the receptor together and brings out about enzyme activity activation within the cell.
2 main methods of transduction
enzyme cascades and second messengers
Describe MAPK cascade
Activated in response to growth factor RTK activation e.g. EGF
Relay proteins Grb/Sos activate Ras
- Ras is a (proto)oncogene
Ras activates a ‘Map Kinase cascade’
Enzymatic casacde ad so amplification as well as transduction
What is a second messenger
Small molecule that is produced in large amounts inside cell after receptor activation
Example of secondary messenger transduction
Adrenaline: GPCR -> cAMP -> PKA activation -> effector proteins phosphorylated
What is a GPCR
G protein coupled receptors
Molecular level responses = changes in…
Gene expression, protein activity, protein binding, protein localisation
Describe role of Receptor Tyrosine Kinases in Cancer
Frowth factor/RTK pathways are often overactive in cancer
- Activating mutation or overexpression of RTK or other pathway proteins
Treatment (anti-cancer drugs) involve inactivating antibodies or small molecule kinase inhibitors.
Describe the use of herceptin
AKA trastuzmab
Targets HER2 (human EGFR2), antibody drug, against HER2+ breast cancer
Describe the use of Avastin
AKA bevacizumab
Targets VEGF, antibody drug, against Colorectal cancer (angiogenesis)
Describe the use of Iressa
AKA gefitinib
Targets EGFR, inhibitor drug, against lung cancer
Describe GPCR activation
- Ligand binding to receptor causes a conformational chnage in cytoplasmic domain.
- Conformational change allows G-protein to bind/be activated by receptor
- Activated G-protein activates intracellular enzymes
What type of receptor does insulin bind to
Receptor tyrosine Kinase
What are the key components of the signalling pathway through which adrenaline causes release of glucose
GPCR -> cAMP second messenger -> PKA
What does the EGF receptor activate
Cell survival, proliferation and invasion via the PI3 Kinase pathway
Proliferation and invasion via the KRAS pathway
Which serine proteins are binded to p53 to induced cell cycle arrest and apoptosis
Mild genotoxic stress - serine 15 - arrest
Severe genotoxic stress - serine 46 (+serine 15 already attached) - apoptosis
Which lymph nodes are most commonly affected by Breast cancer
Axillary LN
Super clavicular LN
Cervical LN
3 breast cancer subtypes
Oestrogen receptor +
Progesterone receptor +
HER2 receptor +
Can be any combination of these
Treatment options for breast cancer
Axillary lymph node removal
breast reconstruction
Radiotherapy
- adjuvant: reduces risk of recurrance
- palliative: treats symptoms, especially pain from bone metastases
Endocrine treatment: hormones +/- ovarian suppression
- tamoxifen, aromatose inhibitors
systemic anti-cancer therapy (SACT)
- chemotherapy (microtubule inhibitors, DNA damaging agents)
- monoclonal antibodies (anti-HER2 drug)
- immunotherapy
- PARP inhibitors, cdk4/6 inhibitors, antibody drug conjugates (ADCs)
Ways to assess treatments for breast cancers
Response rate
Time to progression
Local or distant recurrence rates
Disease-free survival
Overall survival
Future treatment directions for breast cancer
Better targeted treatments
Next generation sequencing to guide treatment options
Better management of side effects
de-escalation of treatment in patients whose cancers respond well
Avoiding uneccessary treatment
More effective surveillance
Define Metastasis
Multi-step process by which tumour cells move from a primary site to colonise a secondary site.
What is cachexia
When the body wastes away due to cancer, despite eating you still lose muslce and fat
7 characteristic of metastasis
- reduced cell-cell adhesion
- altered cell-substratum adhesion
- increased motility
- increased proteolytic ability
- ability to intravasate and extravasate
- angiogenic ability (blood supply)
- ability to proliferate (locally and etopic sites)
What is the epethilial-mesenchyme transition
EMT
process in which epithelial cells lose their characteristic polarity, diassemble cell-cell junctions and become more migratory
Function of e-cadherin
decreased expression in cancers as it is involved in cell-cell junctions. binds cadherins across jucntion and to the actin cytoskeleton via alpha and beta catenon
calcium dependent
Function of integrin
mediate cell adhesion to the ECM
found in hemi-desmosomes and focal adhesions
altered integrin expression is frequently detected in tumours
examples of integrins
avB3 & a5B1 expressed in melanomas
what do proteases expressed by tumours and stroma cells (surrounding tumout) facilitate
- invasion of ECM at primary and secondary sites
- digestion of endothelial BM
- angiogenesis
- activate proteases
example of Matrix metalloproteinases
MMP-2 degrades type IV collagen (found in BM)
example of serine proteases
urokinase plasminogen activator (uPA) turns plasminogen into plasmin
plasmin activates MMPs and degrades ECM
example of Cysteine proteases
cathepsin K collagenolytic activity -> matrix degradation
3 modes of tumpur spread
lymphatic spread
haematogenous spread
transcoelomic spread (across the peritoneal cavity)
describe the steps in intravasation
- attachemnt
- degrade BM
- diapedesis
- New blood vessels are leaky
- assisted by tumour-associated macrophages: chemotactic signals
why do most tumour cells not survive transport
shear stress of blood flow
immune detection
describe the steps in extravasation
- attachment
- degrade BM
- diapedesis
- blood vessels structurally sound
- similar mechanism used by WBCs
define angiogenesis
new vessles are generated from existing vasculature
define vasculogenesis
new vessels are generated from scratch
steps of angiogenesis
- tumour cells detect hypoxia
- transcription factor HIF induced
- this transcribes VEGF
- VEGF secreted and binds to VEGF receptor on endothelial cell
- once bound it signals, resulting in transcription and protein production for new blood vessels.
- Integrin migration, sprout formation (proliferation), protease invasion
define organotropism
when specific cancers tend to metastasise to a preferred secondary site
‘seed and soil’ theory
(secondary growth of cancer cells (seed) is dependent on the microenvironment of the distant organ (soil))
examples of organotropism
Breast carcinoma - bone, lung, brain
Colorectal carcinoma - liver and lung
function of cancer-associated fibroblast (CAF)
within tumour, manipulated by tumour cells to secrete MMPS, cytokines to recruit IL-8 and VEGF
describe pericytes function in cancer
cancer cells manipulate pericytes for poor coverage so that blood vessls arre leaky allowing tumour cell invasion
function of Tumour-associated macrophages
produce growth factors and MMPs to promote angiogenesis, cell invasion and intravasation
Describe precursor lesions fpr cervical cancer
CIN1 = resolves without treatment, patients are monitored
CIN3 = precursor lesion for squamous cell carcinoma
Cervical screening programme is used to detect and treat CIN2 and CIN3
CGIN is much less common and is the precursor lesion for adenocarcinoma
what is dyskaryosis
when abnormal cells have enlarged, irregular shaped nuclei.
cervical cytology
Dyskaryosis is graded as mild, moderate or severe depending on the size of the nucleus
