FoM_PoD Flashcards
what is a tumour
A tumour (or neoplasm) is an abnormal growing mass of tissue Its growth is uncoordinated with that of surrounding normal tissue Its growth continues after the removal of any stimulus which may have caused the tumour It is an irreversible change
what are the different types of tumours
benign
malignant (= cancer)
what is cancer
A fundamental property of cancer (or malignant tumour) is its ability to invade into adjacent tissue and to metastasise (spread) and grow at other sites within the body
what are the most common types of cancer in the uk
prostate breast lung colon melanoma
what is the classification of tumours
Important for understanding tumour behaviour
Important for determining outcome (prognosis) and selecting therapy
Based on tissue of origin -Epithelium -Connective tissue (mesenchyme) -Blood cells -Lymphoid tissue -Melanocytes -Neural tissue -Germ cells (ovary/testis) Benign v malignant
what is the nomenclature of epithelial tumours
glandular:
- benign - adenoma
- malignant - adeno-carcinoma
squamous:
- benign - squamous papilloma
- malignant - squamous carcinoma
what is the nomenclature of connective tissue tumours
bone:
- benign - osteoma
- malignant - osteo-sarcoma
fat:
- benign - lipoma
- malignant - lipo-sarcoma
fibrous tissue:
- benign - fibroma
- malignant - fibro-sarcoma
what is the nomenclature of tumours of blood cells
white blood cells:
- malignant - leukaemia
what is the nomenclature of tumours of lymphoid tissue
lymphoid tissue:
- malignant - lymphoma
what is the nomenclature of tumours of melanocytes
melanocyte:
- benign - naevus
- malignant - melanoma
what is the nomenclature of tumours of neutral tissue
central nervous system:
- astrocytoma
peripheral nervous system:
- schwannoma
what is the nomenclature of germ cell tumours
Teratomas Tumour composed of various tissues Develop in ovary/testis Ovarian teratomas usually benign Testicular teratomas usually malignant
what are the features of benign tumours
- Non-invasive growth pattern
- Usually encapsulated
- No evidence of invasion
- No metastases
- Cells similar to normal
- Benign tumours are “well-differentiated”
- Function similar to normal tissue
- Rarely cause death
what are the features of malignant tumours
- Invasive growth pattern
- No capsule or capsule breached by tumour cells
- Cells abnormal
- Cancers often “poorly differentiated”
- Loss of normal function
- Often evidence of spread of cancer
- Frequently cause death
what are the properties of cancer cells
Loss of tumour suppressor genes
- Adenomatous polyposis (APC)
- Retinoblastoma (Rb)
- BRCA1
Gain of function of oncogenes
- B-raf
- Cyclin D1
- ErbB2
- c-Myc
- K-ras, N-ras
Altered cellular function
Abnormal morphology
Cells capable of independent growth
But no single feature is unique to cancer cells
Tumour biomarkers
give examples of tumour biomarkers
Onco-fetal proteins
Oncogenes
Growth factors and receptors
Immune checkpoint inhibitors
what is the clinical use of tumour biomarkers
Screening
Diagnosis
Prognostic
-Identifying patients with a specific outcome
Predictive
-Identifying patients who will respond to a particular therapy
Alpha-fetoprotein -Teratoma of testis -Hepatocellular carcinoma Carcino-embryonic antigen (CEA) -Colorectal cancer Oestrogen receptor -Breast cancer Prostate specific antigen -Prostate cancer
what is tumour growth
Tumour growth is balance between cell growth and cell death
- Angiogenesis
- Apoptosis
what is tumour angiogenesis
New blood vessel formation by tumours
Required to sustain tumour growth
But provides route for release of tumour cells into circulation
More blood vessels in a tumour equals poorer prognosis
what is apoptosis
Mechanism of programmed single cell death
Active cell process
Regulates tumour growth
Involved in response to chemotherapy and radiotherapy
spread of cancer
Fundamental property of cancer
Invasion and metastasis
Major clinical problem of cancer is formation of metastatic (secondary) tumours
Prognosis depends on extent of cancer spread
process of tumour spread
normal -> tumour -> metastasis
modes of spread of cancer
Local spread
Lymphatic spread
Blood spread
Trans-coelomic spread
tumour invasion
malignant tumour -> invasion into connective tissue -> invasion into lymph/blood vessels
Tumour Metastasis Via Lymphatics
Adherence of tumour cells
to lymph vessels
-> Invasion from
lymphatics -> Invasion into lymph node -> Formation of metastasis in lymph node -> Clinical evidence of metastasis
tumour trans-coelomic spread
Special form of local spread
Spread of tumour cells across body cavities e.g. pleural or peritoneal cavities
Tumours of lung, stomach, colon and ovary show trans-coelomic spread
tumour metastasis
Tumour metastasis is major clinical problem
Sites of metastasis not related to tissue blood flow
Depends on both tumour and tissue related factors
Metastatic niche
uncommon sites of metastasis
spleen
kidney
skeletal muscle
heart
common sites of metastasis
tumour: breast prostate colorectal ovary
tissue:
bone
liver
omentum/peritoneum
what are the local effects of benign tumours
pressure
obstruction
what are the local effects of malignant tumours
Pressure Obstruction Tissue destruction -Ulceration/infection Bleeding -Anaemia -Haemorrhage Pain -Pressure on nerves -Perineural infiltration -Bone pain from pathological fractures Effects of treatment
what are the systemic effects of malignant tumours
Weight loss-cancer cachexia
Secretion of hormones
“Normal” - (produced by tumours of endocrine organ - but abnormal control of hormone production/secretion)
“Abnormal”/inappropriate - (produced by tumour from an organ that does not normally produce hormone)
Paraneoplastic syndromes - (Cannot be explained by local or metastatic effects of tumours e.g. neuropathy, myopathy)
Effects of treatment
early detection of cancer
Important to detect cancer at early stage Reduce/prevent morbidity/mortality Detection at pre-invasive stage -Identification of dysplasia/intraepithelial neoplasia Requires effective test -Sensitive/specific -Acceptable Cervical cancer screening
dysplasia
Pre-malignant change Earliest change in the process of malignancy that can be visualised Identified in epithelium No invasion But can progress to cancer
what are the features if dysplasia
Disorganisation of cells -Increased nuclear size -Increased mitotic activity -Abnormal mitoses Grading of dysplasia -High grade -Low grade No invasion
cervical cancer screening
Established NHS program
Aims to reduce incidence of squamous carcinoma of cervix
Detection of oncogenic human papilloma virus from squamous epithelium of cervix
what is cell division
mechanism of cellular replication
nuclear division plus cytokinesis
generates two genetically identical daughter cells
Cell Cycle = ordered series of events between mitotic divisions
consists of the interphase and the mitotic phase
what does the interphase involve
during which the cell grows and accumulates nutrients needed for mitosis; the cell is synthesizing RNA, producing protein and growing in size
G1, a growth phase,
S phase, during which the DNA is replicated,
and G2, a further growth phase
what does the mitotic phase involve
mitosis - phase during which the cell splits itself into two distinct cells
cytokinesis - new cell is completely divided
how is the cell controlled
The molecular events that regulate the cycle are ordered and directional- it is impossible to reverse the cycle
Cycle phases must be in correct sequence
DNA synthesis and mitosis must occur sequentially
Quality control
-each daughter cell must receive a full chromosome complement
-detection and repair of genetic damage
mutations in DNA sequences must not pass on
Division is coordinated and tightly controlled
Regulation of the cell cycle allows detection and repair of genetic damage as well as the prevention of uncontrolled cell division
genome replicated only once; daughter cells missing all or part of crucial genes die
Errors in mitosis can either kill a cell or cause mutations
possession of extra copies of certain genes also deleterious
ensures genetic fidelity
25 x 106 cell divisions sec-1 in humans
> 1013 cells in the body
Monitor and regulate progress
Prevent progression at specific points
G1/S restriction point
control is achieved by checkpoints in the cycle: G1/S transition is a rate-limiting step in the cell cycle and is also known as Restriction point; Cells that progress through this point are committed to enter S phase
prior to restriction point progress through G1 depends on external stimuli after restriction point progression becomes autonomous
progress can be arrested if certain molecular events are incomplete; The cell cannot proceed to the next phase until checkpoint requirements have been met.
Several checkpoints are designed to ensure that damaged or incomplete DNA is not passed on to daughter cells. Two main checkpoints exist: the G1/S checkpoint and the G2/M checkpoint.
Inadequate nutrient supply - G1 arrest
External stimulus lacking - G1 arrest
Abnormal cell size - G1 or G2 arrest
DNA not replicated - S arrest
DNA damage detected - G1 or G2 arrest
Chromosome misalignment - M-phase arrest
External factors
Hormones, growth factors, cytokines
Intrinsic factors
critical checkpoints - Restriction point (R) in G1
cell cycle checkpoint activators
System of cyclically active and inactive enzyme switches
Catalytic sub-unit cyclin-dependent kinases (CDKs) (determines a cell’s progress through the cell cycle) activated by a regulatory sub-unit cyclins
The active enzyme complex = CDK/cyclin complex
cell cycle checkpoint activators
System of cyclically active and inactive enzyme switches
Catalytic sub-unit cyclin-dependent kinases (CDKs) (determines a cell’s progress through the cell cycle) activated by a regulatory sub-unit cyclins
The active enzyme complex = CDK/cyclin complex
cyclins and cyclin-dependent kinases
Different CDK/cyclin complexes operate at sequential stages of the cycle
Active CDK/cyclin complexes phosphorylate target proteins
Phosphorylation results in activation/inactivation of target proteins
Substrates regulate events in the next cycle phase
When activated by a bound cyclin, CDKs perform a common biochemical reaction - phosphorylation that activates or inactivates target proteins to orchestrate coordinated entry into the next phase of the cell cycle.
Different cyclin-CDK combinations determine the downstream proteins targeted.
A pro-mitotic extracellular signal, induces G1 cyclin-CDK complexes- become active and prepare the cell for S phase, promoting the expression of transcription factors that in turn promote the expression of S cyclins and of enzymes required for DNA replication.
cell cycle inhibitors
CDK inhibitors (CKIs)
-Inhibitor molecules binding to cyclin/CDK complexes
INK4A gene family e.g. p16
CIP/KIP gene family e.g. p21 p27
Two families of genes, the cip/kip family and the INK4a prevent cell cycle progression
The INK4a family includes p16INK4a, which binds to CDK4 and arrests the cell cycle in G1 phase, and p14 which prevents p53 degradation
The cip/kip family includes the genes p21, p27 and p57. They halt cell cycle in G1 phase, by binding to, and inactivating, cyclin-CDK complexes. p21 is activated by p53
retinoblastoma gene
key role in regulating the cell cycle
Encodes a 110 kDa phosphoprotein (pRb) expressed in almost every human cell
Hypophosphorylated pRb is active
cells remain in G1 phase
Active cyclin D/CDK complexes phosphorylate pRb as the cell cycle progresses
Phosphorylated/inactive pRb loses affinity for E2F transcription factor
E2F is a powerful signal for cell cycle activation
In the hypophosphorylated state, pRb is active and carries out its role as tumor suppressor by inhibiting cell cycle progression.
pRb inhibits the cell cycle
Rb gene mutations favour cell proliferation
Mutations in other genes controlling pRb phosphorylation mimic the effect of pRb loss
- Mutational activation of cyclin D or CDK4
- Mutational inactivation of CDKIs also drive proliferation
carcinogenesis
failure of cell cycle control
Balance between proliferation and apoptosis disrupted
Mutations in genes regulating cell division, apoptosis, and DNA repair cause a cell to lose control of proliferation
Uncontrolled proliferation of cells forms tumours
Two frequently disrupted regulatory pathways -
1. The cyclin D-pRb-E2F pathway
2. p53 pathway
Environmental agents
- Chemicals
- Radiation
- Oncogenic viruses
Inherited factors
p53
maintains the integrity of the genome
Cells with mutated p53 do not G1 arrest or repair damaged DNA
Genetically damaged cells proliferate and form malignant neoplasms
cancer relating to the cell cycle
Virtually all cancers are dysregulated at G1-S
mutated cell cycle regulating genes:
cyclin D CDK4 p16 Rb
Cells with mutated p53 proliferate and form malignant neoplasms
what is the two-hit hypothesis of oncogenes
hypothesis in which both alleles, remember that alleles are the copies for a certain gene. you have two copies of any given gene as you have one copy on the chromosome you got from your mum and another on the chromosome you got from your dad. in the two-hit hypothesis, both alleles must be mutated before the effect is manifested because if only one of the alleles is damaged, you have a “back up” second copy that can still produce the protective protein so you need two hits for each if the alleles that you have
tumour suppressor genes
anti-oncogenes
Genes that protect a cell from forming cancers
Generally follow the “two-hit hypothesis”
- Tumour suppressor alleles are usually recessive
- Loss of both normal allelic copies gives rise to cancer
Mutation causes ‘loss of function’
Normal regulatory genes
-Normal growth-inhibiting genes
Genes negatively regulating mitosis – Rb, INK4A family
Genes regulating apoptosis – p53
-Genes regulating DNA repair
Mutation causes loss of function
inherited cancer syndromes
account for 5-10% of all cancers
genetic predisposition to develop cancer
early onset of multiple tumours
proto-oncogenes
Normal genes coding for normal growth regulating proteins
Growth factors
Growth factor receptors
Signal transduction
oncogenes
cancer causing genes
Derived from proto-oncogenes with ‘gain of function’
Activated by –
Alteration of proto-oncogene structure
point mutation
chromosome rearrangements + translocations
Dysregulation of proto-oncogene expression
gene amplification
over-expression
oncogene activation:
Chromosomal rearrangements: translocations
- Overexpression
Burkitt lymphoma - c-myc moves close to IgH gene
Mantle cell lymphoma cyclin D1 gene-IgH
-Recombination to form chimeric proteins
Chronic myeloid leukaemia
chemical carcinogenesis
Purine and pyrimidine bases in DNA are critically damaged by oxidizing and alkylating agents
Chemical carcinogens react with DNA forming covalently bound products (DNA adducts)
Adduct formation can lead to activation of oncogenes and loss of anti-oncogenes
radiation carcinogenesis
Purine and pyrimidine bases in DNA are critical targets for radiation damage
High-energy radiation is carcinogenic if received in sufficient doses
- ultraviolet radiation (UV-B present in sunlight)
- X-rays
- Gamma radiation
viral carcinogenesis
ONCOVIRUSES
- virus genome inserts near a host proto-oncogene
viral promoter causes proto-oncogene over-expression - virus directly inserts an oncogene into host DNA causing cell division
Viruses known to cause cancer in humans
- HPV (genital, throat and anal cancers)
- Hepatitis B (liver cancer)
- EBV (lymphoma)
multistep carcinogenesis
All sporadic cancers harbour multiple genetic aberrations
Mutations accumulate with time
Activation of several oncogenes and loss of two or more anti-oncogenes occurs in most cancers
what is acute inflammation
fundamental response maintaining integrity of organism
- dynamic homeostatic mechanism
- higher organisms
series of protective changes occurring in living tissue as a response to injury
what are the cardinal signs of inflammation
rubor - redness calor - heat tumor - swelling dolor - pain loss of function all of these explained by the sequence of Pathological events taking place
what are the causes of acute inflammation
micro-organisms - bacteria, fungi, viruses, parasites
-pathogenic organisms cause infection
mechanical - trauma - injury to tissue
-all injuries even sterile (eg surgery)
chemical - upset stable environment
- acid or alkali - upset pH
- bile and urine - irritation when in inappropriate place eg peritoneum
physical - extreme conditions
- heat - sunburn
- cold - frostbite
- ionising radiation
dead tissue
-cell necrosis irritates adjacent tissue
hypersensitivity
-several classes of reaction
what is the process of acute inflammation
series of microscopic events
localised to affected tissue
take place in the microcirculation
result in the clinical symptoms and signs of acute inflammation - the cardinal signs
what is microcirculation
capillary beds, fed by arterioles and drained by venules
extracellular “space” and fluid and molecules within it
lymphatic channels and drainage
Starling forces control flow (fluid flux) across membrane
Q = LpS{(Pc - Pi) - (p - i)}
dynamic balance
hydrostatic and colloid osmotic pressures
compartments and physical constants
what are the steps in acute inflammation (pathogenesis)
changes in vessel radius - flow
change in the permeability of the vessel wall - exudation
movement of neutrophils from the vessel to the extravascular space
Local changes in vessel radius and blood flow
1. transient arteriolar constriction few moments, probably protective 2. local arteriolar dilatation active hyperaemia 3. relaxation of vessel smooth muscle ? autonomic NS or mediator derived called the “Triple Response” - flush, flare, wheal Do this yourself and see the effect
increased radius - why increased flow?
Poiseuille’s law
-Q = P x r4/8L
-flow is proportional to radius to the power of four
-(Q fluid flux, P pressure gradient, r radius, viscosity, L length)
For full details see Cardiovascular System
-increased arteriolar radius causes increased local tissue blood flow
-results in observed redness and heat
what are the effects of exudation
oedema formed
oedema is accumulation of fluid in the extravascular space
explains swelling of tissue in acute inflammation
swelling causes pain - reduce function
what are the phases of neutrophils
margination - neutrophils move to endothelial aspect of lumen
pavementing - neutrophils adhere to endothelium
emigration - neutrophils squeeze between endothelial cells - active process - to extravascular tissues
(note meaning of diapedesis)
what is the resolution of acute inflammation
inciting agent isolated & destroyed macrophages move in from blood and phagocytose debris; then leave epithelial surfaces regenerate inflammatory exudate filters away vascular changes return to normal inflammation resolves
what are the benefits of acute inflammation
rapid response to non-specific insult cardinal signs and loss of function -transient protection of inflamed area neutrophils destroy organisms and denature antigen for macrophages plasma proteins localise process resolution and return to normal
what are the outcomes of acute inflammation
resolution
suppuration
organisation
chronic inflammation
inflammation at various anatomical locations
“structure”-itis
peritoneal cavity -peritonitis
meninges -meningitis
appendix -appendicitis
lungs -pneumonia
pleural cavity -pleurisy
what is the role of neutrophils
mobile phagocytes recognise foreign antigen move towards it - chemotaxis adhere to organism granules possess oxidants (eg H2O2) and enzymes (eg proteases) release granule contents phagocytose & destroy foreign antigen
consequence of neutrophil action
neutophils die when granule contents released
produce a “soup” of fluid, bits of cell, organisms, endogenous proteins - pus
might extend into other tissues, progressing the inflammation
what are the mediators of acute inflammation
molecules on endothelial cell surface membrane
molecules released from cells
molecules in the plasma
molecules inside cells
what is the effect of mediators of acute inflammation
vasodilatation increased permeability neutrophil adhesion chemotaxis itch and pain
what are the systemic effects of acute inflammation
pyrexia - raised temperature -endogenous pyrogens from white cells act centrally feel unwell -malaise, anorexia, nausea -abdominal pain and vomiting in children neutrophilia - raised white cell count -bone marrow releases/produces
what are the outcomes of acute inflammation
resolution suppuration organisation dissemination chronic inflammation
what are the outcomes of acute inflammation - suppuration
pus formation
-dead tissue, organisms, exudate, neutrophils, fibrin, red cells, debris
pyogenic membrane surrounds pus
- capillary sprouts, neutrophils, fibroblasts
- walls off pus
what are the outcomes of acute inflammation - organisation
- granulation tissue characteristic
- healing and repair
- leads to fibrosis and formation of a scar
what are the outcomes of acute inflammation - dissemination
- spread to bloodsteam - patient “septic”
- bacteraemia - bacteria in blood
- septicaemia - growth of bacteria in blood
- toxaemia - toxic products in blood
what is chronic inflammation
inflammation in which the cell population is especially -lymphocytes -plasma cells -macrophages features tissue or organ damage, (necrosis), loss of function healing and repair -granulation tissue -scarring and fibrosis may follow from ongoing acute inflammation -and commonly does -“acute on chronic inflammation” but also arises as primary pathology tends to be long-term
what are the clinical presentations of chronic -inflammation
often no specific “sore bit”
malaise and weight loss
-tuberculosis (lung, lymph node, bone, kidney, skin) – systemic effect
loss of function
- autoimmune thyroiditis (functional gland destruction) – hypothyroidism
- Crohn’s disease (GI tract ulceration and fibrosis) – pain, diarrhoea, gut obstruction
- leprosy (cutaneous nerve destruction) – loss of sensation
when do we see chronic inflammation
arising from acute inflammation
- follows on from acute
- large volume of damage
- inability to remove debris
- fails to resolve – ongoing acute insult
arising as a primary lesion
- no preceding acute phase
- only see chronic changes
what is the outcome of chronic inflammation
granulation tissue is characteristic of organization
involves new vessel formation – angiogenesis
results in healing and repair
leads to fibrosis and formation of a scar
what is angiogenesis
new vessels form- capillary buds
Vascular Endothelial Growth Factor (VEGF) released by hypoxic cells stimulates proliferation
enzyme secretion aids process
enable blood supply to enter damaged tissue
generic nature:
angiogenesis and organisation in thrombosis
limits thrombus propagation
reinstatement of flow
angiogenesis in malignant tumours
angiogenesis occurs as tumour grows
potential for therapeutic control
fibrosis and scarring in atherosclerosis
similarities with chronic inflammation
general nature of angiogenesis
angiogenesis and organisation in thrombosis
limits thrombus propagation
reinstatement of flow
angiogenesis in malignant tumours
angiogenesis occurs as tumour grows
potential for therapeutic control
fibrosis and scarring in atherosclerosis
similarities with chronic inflammation
granulation tissue mechanism and function
capillaries grow into inflammatory mass
access of plasma proteins
macrophages from blood and tissue
fibroblasts lay down collagen to repair damaged tissue
collagen replaces inflammatory exudate
patches tissue defects
replaces dead or necrotic tissue
contracts and pulls together
which cell types are involved in chronic inflammation
macrophage endothelial cell fibroblast pus blood clotting fibrin
what are the special roles in chronic inflammation
distinguish from separate roles of polymorph, mast cells, eosinophil and lymphocyte/plasma cell
what are the causes of chronic inflammation
significance, particularly of fibrosis/scarring
common examples of chronic inflammation
briefly- burns and contractures; cirrhosis of the liver; tubular ulcer/pyloric stenosis; ureter/hydronephrosis. fracture healing
primary chronic inflammation
autoimmune disease
- autoantibodies directed against own cell and tissue components – autoantigens
- damage or destroy organs, tissues, cells, cell components
- thyroiditis, rheumatoid disease, pernicious anaemia (chief/parietal cells), systemic lupus erythematosis (nuclear antigen)
lymphocytes, plasma cells, macrophages, fibrosis
material resistant to digestion
- mycobacteria, Brucella, viruses
- cell wall resistant to enzymes
exogenous substances
- sutures, metal and plastic eg joint replacements, mineral crystals, glass,
- not provoke immune response
endogenous substances
- necrotic tissue, keratin, hair
- cannot easily be phagocytosed
granulomatous inflammation common
pathogenesis of chronic inflammation
cells and their roles
- lymphocytes
- plasma cells
- macrophages
- fibroblasts
tissue components
- granulation tissue
- collagen
what is the role of lymphocytes in chronic inflammation
cells that are part of immune system
small round cells with lots of subtypes and functions
main types of lymphocyte
- T-cell
- B-cell
main functions
- immune response
- immune memory
