Transcript General-Intro-Cancer-Volkov

Cellular and molecular basics of cancer
Yuri Volkov, Ph.D., M.D.
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Cell: a structural unit of cancer
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Key features of normal cells
• Controlled growth due to regulated replication
(division) and contact inhibition (receptors)
• Progression from basal (stem) cells state into
differentiated state with specialised functions
• Ability to form well organised cell populations,
(e.g. in the blood), tissues and organs
• Life cycle ends in an orderly and programmed
fashion or in apoptosis
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Examples of cancer growth
A, Normal skin tissue
B, Basal cell carcinoma (BCC) shows nodular masses of basaloid
cells (B) extend down into the dermis, with tumour nodules
showing peripheral palisading of nuclei as well as surrounding
stromal elements (S) arranged around tumour masses. The black
arrow indicates palisading nuclei.
C, Squamous cell carcinoma (SCC) shows irregular masses of
atypical epidermal keratinocyte tumour masses (T) invading
downwards through the basement membrane zone (BMZ) and
dermal matrix (D) accompanied by some retained features of
tissue polarity and differentiation in upper layers.
D, Malignant melanoma displays upward 'pagetoid' extension of
melanoma cells into the epidermis (white arrows) combined with
invasion of atypical melanocytic cells and clusters of cells (M)
into the dermis.
Khavari Nature Reviews Cancer 2006
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Normal haematopoesis
http://www.allthingsstemcell.com/wp-content/uploads/2009/02/hematopoiesis_simple1.png
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http://www.healthsystem.virginia.edu/internet/hematology/HessImages/Normal-Peripheral-Blood-50x-website.jpg
Chronic lymphocytic leukemia (CLL)
http://pathwiki.pbworks.com/f/1146144287/blood-23.png
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What keeps the normal cell
“normal” and what can go wrong?
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Nuclei, DNA, chromosomes and genes
• The nucleus is a compartment responsible for the storage
and timely usage of genetic (hereditary) information in
eukariotic cells
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Nuclei, DNA, chromosomes and genes
• Genes reside within chromosomes (large structures within
the nuclei which are composed of DNA molecules and
histone proteins)
http://ec.europa.eu/research/quality-of-life/image/chromosomes.jpg
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http://www.tiricosuave.com/images/chromosome.jpg
Nuclei, DNA, chromosomes and genes
• DNA are biological “macromolecules” composed of two
chemical strands twisted around each other and forming a
"double helix“)
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Nuclei, DNA, chromosomes and genes
• Each DNA strand is constructed from millions of chemical
building blocks represented just by four different “bases”:
adenine, thymine, cytosine, and guanine (A, T, G, and C),
deoxyribose sugars and phosphates.
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http://www.blc.arizona.edu/Molecular_Graphics/DNA_Structure/DNA_12bp_WF.GIF
Nuclei, DNA, chromosomes and genes
• A gene is a segment of DNA (on a specific site on a chromosome) that is
responsible for the physical and inheritable characteristics or phenotype
of an organism. The sequential order of the bases in any given gene
determines the message which is contained in this gene. Genes also
specify the structures of proteins and RNA molecules.
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http://www.biochem.arizona.edu/classes/bioc462/462bh2008/462bhonorsprojects/462bhonors2006/quachg/Images/proteinStructure.gif
Main types of DNA mutations
• Substitution (switch with another base, creating an
irregular sequence):
ABCDEFG  BACDEFG
• Insertion (insertion of an extra base to the sequence):
ABCDEFG  ABHCDEFG
• Deletion (loss of one of the bases in the sequence):
ABCDEFG  ACDEFG
• Frameshift (insertion or deletion of one of the bases,
altering the three bases, or codons completely, creating a
different sequence):
ABC DEF GHI  BCD EFG HI
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Causes of mutations
• Hereditary mutations: contribute to 5-10% of all
cancers
• Acquired (sporadic, somatic) DNA mutations:
cause of most cancers
• Acquired mutations can happen due to a particular
lifestyle (smoking), dietary factors, environment
(e.g. radiation) or toxins
• There are ~ 25,000 genes per cell (the chances are
quite high)
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Lung Cancer
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Normal cell cycle and its phases
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Cancer and the cell cycle
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•
•
•
Cells must replicate exactly chromosomal DNA
DNA duplication occurs in S (synthesis) phase
Cell division proceeds in M phase
“Gap” phases are G1 and G2
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The concept of the
“cell cycle check points”
• Multiple errors can occur
over the entire cell cycle
• Errors must be controlled
• Elaborate machinery of
cyclin proteins acting as
regulatory units for cyclin
dependent kinases (CDKs) is
involved in the process
• Genetic errors in
controlling cell cycle
machinery may be crucial
for cancer development
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DNA mutations and cancer
• Mutations are abnormal changes in the DNA sequence
affecting one or several genes
• As a result, the synthesis of a certain protein by the cell
may be stopped, the produced protein could malfunction or
have structural or folding defects. Some proteins may be
overproduced or undesired ones will be switched on
• DNA mutations can happen in anyone’s life. However,
typically they are either repaired by the internal cell
molecular mechanisms, or the cell goes into programmed
death pathway (apoptosis)
• If the mutation is not fixed on time, it can lead to cancer
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Oncogenes and tumour suppressor genes
• Some genes can contribute to the development of on inherited cancers
(oncogenes)
• Most oncogenes appear as a result of mutations of normal genes called
proto-oncogenes. When a proto-oncogene transforms into an
oncogene, it can become permanently turned on or activated.
Resulting uncontrolled cell growth can lead to cancer
• Inherited mutations of proto-oncogenes:
RET gene mutation  multiple endocrine neoplasia type 2 (medullary
cancer of the thyroid and other cancers, e.g. pheochromocytoma and
nerve tumors)
KIT mutation  hereditary gastrointestinal stromal tumors (GIST)
MET mutation  papillary renal cancer
• Acquired mutations of proto-oncogenes: For example, a chromosome
rearrangement leads to formation of the gene called
BCR-ABL mutation  chronic myeloid leukemia (CML)
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KIT mutation  most cases of (GIST).
Oncogenes and tumour suppressor genes
• A number of genes protect cells from turning into malignant cells
(tumour suppressor genes). When they are mutated (inactivated) ,
cells can start uncontrolled growth leading to cancer
• Tumor suppressor genes are the normal genes dealing with control of
cell division, DNA repair or apoptosis (when a cell has DNA damage
beyond repair). For example, p53 induces transcription of p21 protein,
which forms complexes with G1/S and S cyclin-dependent kinases
(CDK), locking them in the “off position” and preventing further cell
cycle progression. Cells with mutated DNA encoding p53 continue to
grow and divide
• Inherited abnormalities of tumor suppressor genes:
deletion in APC gene  familial adenomatous polyposis (FAP) frequently
leading to cancer
• Acquired tumor suppressor gene mutations:
P53 gene mutations  found in over 50% of human cancers (e.g. lung,
colorectal, breast cancer)
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P53- “guardian of the genome”
• P53 is activated following a
genotoxic insult
• Induced transcription of p21
• P21 locks CDK in the off
position
• P53 defects can block the
function of the whole chain
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Familial adenomatous polyposis (FAP) and cancer
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Main types of DNA mutations
include all of the following, except:
Substitution
Deletion
Elimination
Translocation
Frameshift
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Oncogenes-induced cancer results
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Inactivation of protooncogenes
Activation of protooncogenes
Upregulation of tumour
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Downregulation of tumour
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None of the above
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