Cellular and molecular basics of cancer

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• 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/upload
s/2009/02/hematopoiesis_simple1.png
http//www.healthsystem.virginia.edu/internet/hema
tology/HessImages/Normal-Peripheral-Blood-50x-webs
ite.jpg
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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
http//www.tiricosuave.com/images/chromosome.jpg
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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.

http//www.blc.arizona.edu/Molecular_Graphics/DNA_
Structure/DNA_12bp_WF.GIF
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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.

http//www.biochem.arizona.edu/classes/bioc462/462
bh2008/462bhonorsprojects/462bhonors2006/quachg/Im
ages/proteinStructure.gif
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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

• 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 anyones 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)
• KIT mutation ? most cases of (GIST).

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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

1. Substitution
2. Deletion
3. Elimination
4. Translocation
5. Frameshift

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Oncogenes-induced cancer results from

1. Inactivation of proto-oncogenes
2. Activation of proto-oncogenes
3. Upregulation of tumour suppressor genes
4. Downregulation of tumour suppressor genes
5. None of the above