Download 3rd-years-molecular-mechanisms-of

Molecular Mechanisms of
Malignancy
Prof Orla Sheils
Carcinogenesis
What Causes Cancer?
• Carcinogens
• Age
• genetic make up
• immune system
• diet
• day-to-day environment
• Viruses
Age
Age
Diet
• In addition to chemicals and
radiation,
– viruses also can trigger the
development of cancer.
• HPV
• HBC
• HCV
• EBV
• HHV8
Factors in Carcinogenesis
Trends in Cancer Incidence
Which of the following is
FALSE?
A. Cancer is a genetic disease.
B. Few Cancers can be linked with the
environment.
C. Some genes are protective against
cancer.
D. Several factors may combine to cause
cancer.
E. Rates of incidence remain static for
different cancer types
Environmental triggers
Chernobyl
• Pripyat, Ukraine
• 26th April 1986
• Reactor 4 steam and
hydrogen explosions
• Resultant graphite fire
burned for 10 days
• >400 times more fallout
than Hiroshima
Chernobyl
• An official
exclusion zone
around the plant
remains in place,
extending for 30
kilometres (18
miles).
• It is one of the
most radioactive
spots on Earth.
Chernobyl
Chernobyl today…
Radioisotopes in immediate area
Fallout
Consequences
• Acute radiation deaths
• Reproductive disorders
• Increases in various cancers
–
–
–
–
–
–
–
Breast
Leukaemia
Lung
Stomach
Skin
Prostate
Uterus
• Large increase in thyroid cancer in
children & adolescents
Thyroid Cancer and exposure
to ionising radiation
Background
• Thyroid Cancer
– most frequently occurring endocrine malignancy
– sub-divided into a number of diagnostic
/morphological categories.
– 5 year survival rate >96% depending on subtype
• Papillary thyroid carcinoma (PTC)
– Most common thyroid malignancy
– Ireland~100 cases/yr, U.S.~37,500 cases/yr
– Incidence on the rise - global estimate 0.5 million
new cases this year
Pathological Pathways
Papillary Thyroid Carcinoma
Follicular Epithelial Cell
Follicular Carcinoma
MAPK/ERK pathway (BRAF
V600E)
Melanoma
80%
PTC
30-69%
Colorectal
10%
• Both BRAF and RET/PTC changes
cause cells to grow and divide.
• They impact on the MapK pathway
MAPK/ERK signalling
Proliferation
ret/PTC oncogene
• The DNA mutations that cause some forms of
papillary thyroid cancer are known to involve
over-activation or specific parts of the RET
gene.
• The altered form of this gene, known as the
PTC oncogene is found in 10%-30% of
papillary thyroid cancers overall, and in a
larger percentage of papillary thyroid cancers
occurring in children and/or associated with
radiation exposure.
• These RET mutations usually are acquired
during a person's lifetime rather than being
inherited.
Markers of PTC
 ret/PTC
 To date 15 chimeric mRNAs involving 10
different genes have been described
 Ret/PTC-1 and ret/PTC-3 are the most
common types, accounting for 90%.
RET proto-oncogene
• Located on 10q11.2.
• Transmembrane growth
factor receptor with an
intracellular tyrosine kinase
domain.
• Ligands include members of
the GDNF family.
• Activates a variety of signal
transduction pathways incl.:
MAPK/ERK, PI3K/AKT and
JNK
– Normally expressed in cells of
neural crest origin
– Important in embryogenesis
– Not expressed in mature thyroid
tissues
Ret activation and morphology
 In the setting of radiation induced PTC it is
apparent that specific ret/PTC
rearrangements are associated with specific
tumour morphology
 ret/PTC-1 associated with classic morphology
 ?low dose/long latency
 ret/PTC-3 associated with solid/follicular morphology and
adverse prognosis.
 ?higher dose/short latency
BRAF
BRAF
• Member of the Raf kinase family
–
–
–
–
Serine/threonine kinases
Function in Ras/Raf/MEK/ERK pathway
3 isoforms: A-Braf, B-Raf, C-Raf/Raf-1
BRAF implicated in several cancers
• Most common mutation: T1799A 
V600E
• Mutation mimics phosphorylation
leading to Ras-independent kinase
activity
ret/PTC and BRAF in an Irish PTC cohort
9
8
7
6
5
4
3
2
1
0
ret/PTC
Year
19
94
-9
6
19
97
-9
9
20
00
-0
2
19
82
-8
4
19
85
-8
7
19
88
-9
0
19
91
-9
3
T1799A mutation
ret/PTC and BRAF in an Irish PTC cohort
Sorafenib (Nexavar)
• Inhibits tumour cell proliferation and
angiogenesis by targeting RAF KINASES
and VEGF RECEPTORS;
– Multi-kinase inhibitor that targets
serine/threonine and receptor tyrosine
kinases to decrease tumour growth and
angiogenesis;
– FDA approved orphan drug indication for
hepatocellular carcinoma in 2006.
Sunitinib
• Description: Inhibits VEGF-R2 and
PDGF-Rbeta tyrosine kinase;
– has antineoplastic activity.
• Sunitinib is in a class of medications
called multikinase inhibitors.
– It works by blocking the action of the
abnormal protein that signals cancer cells to
multiply.
– This helps stop or slow the spread of cancer
cells and may help shrink tumours.
MEKi
Melanoma
80%
AZD6244
PTC
30-69%
PD0325901
Colorectal
10%
The discovery that gene expression can be
altered through RNA interference has
stimulated research on the role of RNA
interference in the development of cancer.
The Nobel Prize in Physiology or Medicine 2006
for their discovery of RNA interference - gene silencing by double-stranded RNA"
Andrew Z. Fire
Stanford University School of Medicine
Stanford, CA, USA
Craig C. Mello
University of
Massachusetts
Medical School
Worcester, MA, USA
• The discovery that gene expression can be
altered through RNA interference has
stimulated research on the role of RNA
interference in the development of cancer.
The number of peer-reviewed
publications on miRNA and cancer in
the period from 2001-2007
(Adapted from www.mirnatherapeutics.com)
miRNAs
• emerged as major players in the
complex networks of gene regulation
– implicated in various aspects of human
disease.
– have already significantly improved our
understanding of carcinogenesis.
• As active players in important
human oncogenic signalling
pathways, miRNAs should affect
cancer diagnosis and prognosis
• The main function of
miRNAs appears to
be in gene
regulation.
N Engl J Med 2008;359:2641-50
miRNA production
• Base pairing between the
miRNA and its target
directs RISC to either
destroy the mRNA or
impede its translation into
protein.
• [The initial stem–loop
configuration of the
primary transcript
provides structural clues
that have been used to
guide searches of
genomic sequence for
candidate miRNA genes.]
miRNA expression profiles are
broadly altered in cancers
miRNA and Carcinogenesis
• A. pre-miRNAs are exported from nucleus to the
cytoplasm where they are processed by the enzyme
Dicer to yield mature miRNA. These miRNAs cleave
mRNA’s or inhibit translation in association with RISC.
• B. Overexpression of miRNAs may inhibit expression
of target genes such as tumour suppressors.
• C. Reduced expression of miRNAs may increase
expression of particular oncogenes.