Transcript Cancer

Cellular Basis of
Cancer
Dr Rosemary Bass
[email protected]
Cancer:
Characteristics of cancer cells
Malignant & benign tumours
Oncogenes & tumour suppressor genes (TSG)
Invasion, Metastases, Angiogenesis.
Contents
• Introduction
• Causes
• History
• Terminology
• Incidence Rates
• Cancer Types
• Progressive Nature of Cancer
Introduction to Cancer
• "cancer" from latin for "crab"
• disease of higher, multicellular
organisms
• cell growth is dysregulated (abnormally
controlled)
What is cancer?
www.cancerresearchuk.org
www.mariecurie.org.uk
www.macmillan.org.uk
Cancer is a disease where cells grow out of
control and invade, erode and destroy normal
tissue. The driving forces behind the development
of cancer are damaged genes.
Cancer develops when cells start to divide at the
wrong time and in the wrong place, then continue
to divide and invade nearby tissues and organs. It
is this uncontrolled growth of cells that causes a
swelling or tumour.
Cancer is not one disease but many, all with some
similar features but all with a distinctive
character, which varies according to the cancer's
type and location.
Cancer - Background
• Is cancer a modern disease?
(David & Zimmerman (2010) Nat Rev Can10,728).
• Increased incidence of cancer due to
humans living longer - fewer deaths from
infectious diseases
• Cancer occurs in all
higher animals
• Evidence from ancient
pictures & writings
info.cancerresearchuk.org
• Bone cancers found in Egyptian mummies
• But rare in comparison to modern incidence
Cancer - History
• Percival Pott (1775) - first
scientific investigation of
cancer
• Scrotal cancer in men who
had been boy-sweeps
• Pott suggested soot as
causative agent - carcinogen
iaphomepage.org/ int302/potts
• Advised frequent washing and
changes of clothes
• First epidemiological study on
cancer
iaphomepage.org/ int302/potts
Introduction to Cancer
• Terms "cancer", "neoplasm" and
"tumour" often used interchangeably
• Cancer usually means carcinoma
(malignant tumour of epithelial origin)
• Neoplasm usually means the newlyformed tumour
• Tumour refers to any benign or malignant
growth
Introduction to Cancer (2)
• Cancer is "new growth resulting from
abnormal proliferation of transformed
cells"
• Growth may be rapid, moderate or
slow vs normal cells
• The clinical study of cancer is "oncology"
• Cancer is now the second most
common cause of death in developed
countries (after cardiovascular disease)
Cancer Incidence
One in three people will be diagnosed with cancer
One in four people will die from cancer
Every two minutes someone is diagnosed with cancer in
the UK (<300,000 new cases p.a.)
Cancer affects mainly older people.
Deaths from cancers of the lung, bowel, breast and
prostate together account for 54% of all cancer deaths.
http://info.cancerresearchuk.org/cancerstats/keyfacts/?a=5441
http://info.cancerresearchuk.org/cancerstats/incidence/
•Cancer is a large collection of many
diseases, with many causes
•Cancer kills because the uncontrolled
replication of cells within the tumour
disrupts the structural integrity of the
patient – leading to the spread of the
disease – metastasis
• Cancer rare in young, increased incidence with age
• With demographic shifts in the population, such that
the population in Western countries is increasingly aged,
this will lead to increased prevalence of cancer.
Report from Foresight Ageing
Population Panel ,The Age shift priorities for action,
http://www.education.edean.org/pdf/Intro0
13.pdf
Cancer More Common in Some Tissues
• most common types in men:
- lung
- prostate
- colon  rectum
• most common types in women:
- breast
- cervix
- colon  rectum
- lung
The 20 Most Commonly Diagnosed Cancers, UK 2008
(Excluding Non-Melanoma Skin Cancer)
Non-melanoma skin cancer (NMSC) = very
common condition, BUT it is curable in the vast
majority of cases.
NMSC routinely omitted from the overall total for
new cases of cancer
10 Most Commonly Diagnosed Cancers in Males, UK 2008
(Excluding Non-Melanoma Skin Cancer)
15
10 Most Commonly Diagnosed Cancers in Females, UK 2008
(Excluding Non-Melanoma Skin Cancer)
16
Cancer Survival
Cancer survival figures are usually written as a % or number
of patients alive five years after diagnosis.
This does not necessarily mean that the patient is cured:
No recurrence of cancer
Recurrence of cancer but alive
Recurrence after the five years.
The figures quoted are true for the population but not for an
individual.
http://www.ncsdf.org/
Causes of cancer
•Hereditary (though probably <5%)
•Environmental: radiation
chemical
hazards in workplace
•Lifestyle
diet
smoking
alcohol
sex
•Viruses
http://info.cancerresearchuk.org/cancerstats/causes/lifestyle/tobacco/
• Most cancers are “avoidable” – being due to
environmental and lifestyle factors
• 1/3 of ALL cancers are attributable to SMOKING
http://info.cancerresearchuk.org/cancerstats/causes/lifestyle/tobacco/
http://info.cancerresearchuk.org/
cancerstats/causes/lifestyle/tobacco/
Cancer Research-UK data on
risk of lung cancer in relation to
intensity of smoking and age at
which smoking ceased.
Diet is also a major factor in cancer incidence
• Data above show breast cancer incidence relation to dietary fat.
• Similar relationships hold for prostate & other cancers.
• The importance of diet & lifestyle in cancer incidence is shown
by “epidemiological” studies.
• Early epidemiological studies of Japanese people who moved to
N. America showed that after 1 generation this population had the
same breast cancer risk as the general N. American population.
Origins of Cancer
• There are many connections between embryogenesis & cancer
•Most tumours arise in the cells that come in contact with the
outside world & these are epithelial cells – i.e. the epidermal
keratinocytes of the skin, epithelial cells lining digestive tract,
respiratory system etc.
• Cancers are classified differently based on their cell of origin:
Epithelial cancers = carcinomas
Mesenchymal (ie connective tissue cell types such as
fibroblasts) cancers = sarcomas
Blood/lymphoid tissue = leukaemias/lymphomas
Terminology (2) - Examples
2.
Solid Tumours
• suffix "-oma" defines solid tumour
• prefix defines tissue type eg:
- adenoma = benign tumour of glandular
tissue
- fibroma = benign tumour of connective
tissue
- fibroadenoma = mixed tumour of
glandular + connective tissue
Terminology (3) - Examples
- carcinoma - malignant tumour of
epithelial cells
- sarcoma = malignant tumour of
connective tissue cells
- adenocarcinoma = malignant tumour
of glandular epithelium
others
- lymphoma = tumours of lymph tissue
- teratoma = primitive germ cell tumour
of gonads
Tissue Proliferation Rates
• Rapid Proliferation – bone marrow,
gastrointestinal mucosa, ovary, testis, hair
follicles
• Slow Proliferation – lung, liver, kidney,
endocrine glands, vascular endothelium
• Almost no Proliferation – muscle, bone,
cartilage, nerve
The molecular genetic basis of cancer
•Cancer is a genetic disease
•Cancer arises from mutations in critical genes
Proto-oncogenes- the “accelerators”
Tumour suppressor genes (TSGs) – the
“brakes”
•Cancer is a multistep process involving a series
of genetic 'hits‘
•Cancer is clonal - one cell 'goes wrong‘
•Many factors working both inside and outside
the cell can determine a cell’s likelihood of
sustaining genetic damage
Causes of Cancer - Genetic Factors
Oncogenes
• retroviral cancer-causing genes
• cellular equivalents = proto-oncogenes
• encode growth factors (GFs), GF
receptors or nuclear proteins
First identified Oncogene:
Rous isolated virus from spontaneous
chicken sarcomas = Rous Sarcoma
Virus (RSV) (retrovirus)
WHAT ARE ONCOGENES?
"A gene that causes the transformation of normal cells into
cancerous tumour cells."
"Mutated and/or over-expressed version of normal gene,
that in a dominant fashion releases the cell from normal
growth restraints."
29
GAIN OF FUNCTION
A proto-oncogene is the wild-type allele
(normal gene) of an oncogene.
Activating mutation of proto-oncogene
creates the oncogene
One allele usually only affected =
DOMINANT
WHAT SORTS OF GENES HAVE THE
POTENTIAL TO BE ONCOGENES?
growth factors
growth factor receptors
G proteins
cytoplasmic tyrosine kinases
serine-threonine kinases
other cytoplasmic proteins
nuclear proteins
Oncogene
Function
Growth Factors
int-1
sis
matrix protein
Platelet derived growth factor
Growth-Factor Receptor
(Tyrosine Kinase type)
erb-B
kit
met
ros
ret
Epidermal growth factor receptor
Stem cell growth factor receptor
Hepatic growth factor receptor
Unknown ligand
Glial-derived neurotrophic factor
with GFR-a1-4 receptors
G proteins
H-ras
GTPase
K-ras
GTPase
N-ras
GTPase
Oncogene
Function
Cytoplasmic Tyrosine Kinases
bcr-abl
hck
lck
Tyrosine kinase
Tyrosine kinase
Tyrosine kinase
src
Tyrosine kinase
Serine-Threonine Kinases
raf/mil
Serine-Threonine Kinase
Other cytoplasmic proteins
bcl-2
Prolongs life-span of cell
Nuclear proteins
erb-A
fos
L-myc
myc
Thyroid hormone receptor
Transcription factor
Transcription factor
Transcription factor
33
HOW ARE PROTO-ONCOGENES
ACTIVATED?
Mutation
Amplification
Translocation
ACTIVATION OF PROTO-ONCOGENES
Deletion or point mutation
in coding sequence
Gene Amplification
Chromosome rearrangement
DNA
RNA
hyperactive
protein made in
normal amounts
normal protein greatly
overproduced
nearby strong
enhancer causes
normal protein to
be overproduced
fusion to actively
transcribed gene
greatly overproduces
fusion protein; or fusion
protein is hyperactive
Tumour Suppressor Genes (TSGs)
• 100s recessive genes that normally
regulate or suppress cell growth
• loss of function of TSG can lead to
tumour formation or progression
•first identified in rare, inherited childhood
tumours (retinoblastoma)
• TSG protein functions may be tissuespecific (RB - retina; BRCA1 - breast,
ovary etc.)
HOW CAN TUMOUR SUPPRESSOR
GENES BE LOST?
Mutation
Deletion
Loss of heterozygosity (allelic deletion)
Methylation
Haploinsufficiency
LOSS OF HETEROZYGOSITY (LOH)
Heterozygosity = individual is heterozygote for a
genotype
1 normal gene, 1 mutated gene
When second copy is mutated (doesn't have to be
the same mutation) neither allele will have
functioning gene - homozygous for mutated gene,
hence LOH
Evolving tumour cells can discard the second, still
functional tumour suppressor gene copy
Also occur
recombination
via
missegregation
or
mitotic
PROMOTER METHYLATION
epigenetic
Methyl groups attached to cytosines at CpG
CpG methylation causes repression of
transcription (if present in promoter of gene)
Histone deacetylases (HDACs) recognise
and bind MeCpG
• acetate groups removed from histones
• resulting chromatin configuration
disfavours transcription
39
HAPLOINSUFFICIENCY
Heterozygous for a certain gene mutation or
hemizygous (only one copy) at a particular
locus (often due to a deletion of the
corresponding allele) is clinically affected
because a single copy of the normal gene is
incapable of providing sufficient protein
production as to assure normal function
Human
Rb+/Mouse
Smad4+/tumours in stomach
Mouse
p27Kip1+/Mouse
PTEN+/prostate cancer
40
and Human
develop normally
predisposed to
tumour prone
acceleration of
WHAT SORTS OF GENES CAN BE
TUMOUR SUPPRESSOR GENES?
Signalling
Smad4, DCC, APC
Transcription
WT-1, p53
Gene Expression
VHL
Cell Cycle Control
pRb, p53
Cell Adhesion
E-cadherin
Cytoskeletal Architecture
NF-2
DNA Damage and Repair
p53, ATM
BRCA1, BRCA2
One single oncogene will not cause cancer –
cooperativity
Cooperating oncogenes
in mice-
Land H et al., (1983) Nature 304, 596-602;
Ruley HE (1983) Nature 304, 602-606.
Causes of Cancer - Age
• cumulative effect of carcinogens
• cumulative effect of mutations
• age-related metabolic / hormonal
changes
• reduced ability to repair DNA
Causes of Cancer - Environmental
• viruses
- eg. human papilloma virus 
cervical cancer
• ionising radiation
- eg. 131I  thyroid cancer post-Chernobyl
- eg. UV radiation  skin cancer
• chemicals in food / environment
- eg. arsenic in tobacco smoke  lung
cancer
Cell
Growth
Cell
Death
Normal Cells
Normal tissues balance cell growth with cell
death.
Tumour Cells
In cancer this balance is disrupted.
Acquired Characteristics of Cancer
1. Limitless replication capacity
2. Evasion of apoptosis
3. Self-sufficiency of growth signals
4. Insensitivity to growth inhibitory signals
5. Tissue invasion and metastasis
6. Sustained angiogenesis
From:
Hanahan D and Weinberg RA
(2000) The hallmarks of cancer.
Cell 100:57-70
Is there hope for the future? Yes – definitely!
Cancer Prevention
Novel Therapeutics
Molecular Diagnostics
Cancer Genetics
47
Progressive Nature of Cancer
Normal
Growth
Normal
Cells
Single
transformed
cell
dysregulated growth
Persistent
cell clone
chemicals, viruses,
radiation
Initiation
(tumourigenesis)
Promotion
(smoking, free
radicals, radiation)
Progressive Nature of Cancer (2)
dysregulated growth - progressive mutations, persistence of
tumour cell subclones, enhanced blood supply
Benign
Tumour
Dysplasia
Carcinoma
in situ
further growth - mutations, production of tissuemodelling enzymes, enhanced blood supply
Invasive
Tumour
Metastasis