Transcript No Slide Title

Cellular Basis of
Cancer
Dr Rosemary Bass
[email protected]
Last session
• Causes of cancer
• History
• Terminology used to discus cancer
• Incidence Rates
• Cancer Types
• How cells change their nature during
cancer progression
Content of this lecture
• Cell Growth / Cell Cycle
• Tumour Growth
• Cancer Progression
• Benign vs Malignant Tumours
• Invasion, Angiogenesis and
Metastasis
• Clinical Symptoms and cancer
staging
• Diagnosis and Treatment
Cancer and Cell Growth
• cancer is a genetic disease
• cancer also a cellular disease
• mechanisms of normal cell growth control
important
• understanding normal cell growth controls may
provide therapeutic targets
• cancer studies have also elucidated normal cell
growth mechanisms
Cell Cycle
Mitosis
G2
G1
S Phase
G0
= major
checkpoints
Cell Cycle Checkpoints
• allow progression to next phase of cell cycle
• cyclins - proteins associated with each phase
of cell cycle
• cyclin-dependent kinases (Cdks) - activate or
regulate proteins critical for each stage of cell
cycle
Control system
co-ordinates cycle
Key control proteins:
Cyclin dependent kinases + cyclins
(CDK or CDC)
Cyclins bind CDKs - affect their ability to phosphorylate
serine & threonine residues of their substrates
7
Checkpoints
G2/M
not completely
understood
Activity and levels
of cyclin/CDK
complexes govern
these checkpoints
8
G1/S progression
Rb, Myc also important
De-regulation of cyclins associated with cancer
Cyclins ctd.
R point
Cyclin B
Cyclin E
Nuclear D1
M
Cyclin A
G1
S
9
G2
M
Restriction or R point
Deregulation of R point decision making machinery
accompanies formation of most types of cancer cells
10
Commitment to replicate
chromosomes, differentiate
or enter apoptosis
General Controls of Cell Growth
• growth Factors (GFs)
eg. epidermal growth factor (EGF)
eg. insulin-like growth factor I (IGF I)
• hormones
eg. thyroid hormones (T3, T4)
• contact / density inhibition
• cell anchorage and adhesion
• nutrient supply (vascularisation)
Tumour Growth Rate
Tumour Diameter (mm)
100
10
1012 cells (patient death)
109 cells (palpable)
108 cells (visible on X-ray)
1
0.1
0
10
20
30
40
Tumour Cell Population Doublings
Clonal Growth of Tumour Cells
Clonal Growth of Tumour Cells (2)
new sub-clones may grow
How do you detect cancer?
Cervical dysplasia (1)
dysplastic
normal
http://medlib.med.utah.edu/WebPath
• normal cervical squamous epithelium with
dysplastic squamous epithelium
Cervical dysplasia (2)
normal
dysplastic
http://medlib.med.utah.edu/WebPath
• normal / dysplastic border in cervical
squamous epithelium - cells become more
disorderly
Cervical neoplasia
Neosplastic infiltration
http://medlib.med.utah.edu/WebPath
• microscopic appearance of cervical neoplasia
• the neoplasm is infiltrating the underlying cervical
stroma
Cancer Progression
• cancer progression occurs in stages
- dependent on cancer promoters
- eg. free radicals / radiation / mutagens
• sub-clones with growth advantage become:
• benign tumours
• malignant tumours
• evidence in some tumours (eg. GI) of progression
from benign to malignant
Cancer Progression - Colon
http://www.eurogene.org/etext/cancgen/img/Fodde2/image003.jpg
Benign vs Malignant - Rapid Growth
• mitoses
Benign
Malignant
few, normal
many, abnormal
• nuclei
normal
large, irregular
• necrosis/
haemorrhage
never
extensive
Benign vs Malignant (2) - Differentiation
Benign
Malignant
• morphology
close to
normal
variable
poor
• function
often
retained
retained, lost
or abnormal
products
Benign vs Malignant (3) - Boundary
Benign
Malignant
• capsule
often intact
• invasion
absent (v. rare)frequent
• metastasis
never
missing
broken
frequent
Invasion
• expanding tumour able to grow into tissue
spaces and cavities
• malignant tumours invade normal tissues
normal
cervix
cervical
carcinoma
invasive
process
beginning
http://www.ma.hw.ac.uk/~jas/researchinterests/cancerinvasion.html
Discovering New Treatments for Cancer
depends upon:
• understanding molecular mechanisms of cancer
initiation
• understanding molecular mechanisms of cancer
progression
most cancer deaths caused by metastatic tumours
• understanding of molecular mechanisms
involved in metastasis important
Invasion and Metastasis
Steps in Metastasis
• most steps are active processes
• tumour cell produces enzymes / growth factors
• similar to normal tissue modelling / wound
healing
growth
factors
inhibitor
proteins
enzymes
Steps in Metastasis
• cell detachment from tumour mass
• invasion of surrounding tissue + invasion of blood
or lymph vessel
Important Proteins in Metastasis
• cell Adhesion Molecules (CAMs)
- lectins
- cadhedrins
• extracellular Matrix (ECM) proteins
- collagen, fibronectin etc interact with
- integrins on cell surface
• all involved in normal tissue organisation /
stability
• interacting proteins must be overcome /
digested by metastatic cancer cell
Steps in Metastasis
• survival of conditions in blood or lymph
• most cells die after a few hours due to:
- mechanical stress
- lack of essential nutrients
- high oxygen toxicity
- destruction by immune cells
Steps in Metastasis
• attachment to endothelial cells in capillaries
at remote site
• extravasation of tumour cell through vessel
wall
Extravasation
Important Proteins in Metastasis (2)
• proteolytic enzymes
- metalloproteinases
- cathepsins etc
• new growth stimulators
- growth factors (+ receptors)
- hormones
• stimulators of vascularisation
- more growth factors (eg. GF stimulates
capillary growth)
Steps in Metastasis
• growth / survival as secondary tumour
• stimulation of new blood supply
Typical Metastatic Spread Patterns
Primary
Tumour
• gastrointestinal
carcinoma
• melanoma
Common Sites of
Metastasis
liver
liver, brain, bowel
• prostatic carcinoma bone
• small-cell lung
carcinoma
• breast
carcinoma
brain, liver,
bone marrow
bone, brain, liver,
adrenal, lung
Angiogenesis
http://www.angio.org/img/cascade_image.jpg
Angiogenesis Steps
1. angiogenic growth factors (GFs) diffuse into
nearby tissues
2. GFs bind to specific receptors on endothelial cells
(EC) of nearby blood vessels
3. & 4. endothelial cells activated - produce enzymes
that dissolve tiny holes in vessel membrane
5 - 10. ECs proliferate through holes towards tumour,
form tubes and loops - become stabilised by
smooth muscle
Tumour Growth Rate
Tumour Diameter (mm)
100
10
1012 cells (patient death)
109 cells (palpable)
108 cells (visible on X-ray)
1
0.1
TUMOUR MARKERS:
aim to detect tumours as
early as possible
0
10
20
30
40
Tumour Cell Population Doublings
Biomarkers
“A biological molecule found in blood, other body fluids, or
tissues that is a sign of a normal or abnormal process, or of
a condition or disease. A biomarker may be used to see
how well the body responds to a treatment for a disease or
condition. Also called molecular marker and signature
molecule”
National Cancer Institute
Tumour Markers
Proteins↑↓ regulated in the progression of cancer
Some specific for one type of cancer, others for >1 type
Potential for screening/prognosis/efficacy of treatment
Blood/saliva/urine vs. biopsy
No routine screening in UK
Classes of Tumour Marker
• Oncofetal proteins
- α-fetoprotein
germ cell tumours
primary liver cancer
- CA-125
ovarian cancer
• Placental Products
- human chorionic
gonadotrophin (hCG)
- placental alkaline
phosphatase
choriocarcinoma
teratoma
ovarian cancer
testicular cancer
Classes of Tumour Marker
• Ectopic Hormones
- adrenocorticotrophic
hormone (ACTH)
bronchus carcinoma
- calcitonin
thyroid cancer
• Tissue-specific Antigens
- prostate-specific
prostate cancer
antigen (PSA)
- thyroglobulin
thyroid cancer
Classes of Tumour Marker
• Enzymes
- alkaline phosphatase
osteosarcoma
- prostatic acid
phosphatase
prostate cancer
- lactic dehydrogenase
neroblastoma
• Immunoglobulins
- IgG IgA IgD IgE
myeloma
- Bence-Jones protein
(free κ and λ chains)
myeloma
Cancer Treatment
• surgery
- principal treatment
- effective local control
- best before tumour
spread
- invasive
http://www.cooperhealth.org/content/MinSurg_Cancer.asp
- may involve risky procedures
Cancer Treatment
• Chemotherapy
- body-wide drug
delivery
- potential to eliminate
metastatic cells
- damaging effects on
healthy cells
http://www.ucsf.edu/dpsl/chemo.html
Cancer Treatment
• Radiotherapy
- effective local
control
- whole body
radiotherapy
possible (eg. for
lymphomas)
- often used to
reduce tumour
size prior to
surgery
http://www.hnsaonline.com/iort.htm
Radiotherapy
• External Beam
- X-rays from linear
accelerator
- γ rays from radio-cobalt
• Radioactive Implants
- pellets or needles of Yttrium-90
- gives very high local dose
http://www.ncrc.ac.yu/onkoeng/odelenja/images/
News Flash!
Effects of Radiotherapy
• both methods use ionising radiation
• doses ~500000 times greater than for
medical imaging
• cause many double-strand breaks in DNA
• cells cannot repair DNA and die
• normal cells often recover more quickly than
tumour cells
100% cure rare - data shown as 5-year survival
Clinical Symptoms of Cancer
• highly variable, vague or none
• early medical attention improves prognosis
• lump detectable if tumour on or near surface
• general symptoms - 1 or more of:
- weakness
- breathlessness
- weight loss
- bleeding
- pain (when tumour presses on nerves,
internal organs or erodes bone)
Clinical Symptoms of Cancer
• clinical investigations:
- physical examination
- imaging:
radiography
CT (computerised tomography)
ultrasound
radioisotope scanning
MRI (magnetic resonance imaging)
lymphography
- biopsy  pathologist
Cancer Staging (TNM) eg. lung cancer
Cancer Staging - Primary Tumour
Tis
in situ, non-invasive
T1 small, minimally invasive within primary
organ site
T2 larger, locally invasive within the primary
organ site
T3 moderate size and/or invasive, spread to
adjacent lymph nodes
T4 very large and/or very invasive,
metastatic spread to distant organs
Cancer Staging - Lymph Nodes and
Metastases
N0 no lymph node involvement
N1 regional lymph node involvement
N2 extensive regional lymph node
involvement
N3 distant lymph node involvement
M0 no distant metastases
M1 distant metastases present