Role of Inflammation, Genetics, Epigenetics, and Stem Cells in Tumorigenesis
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Transcript of Role of Inflammation, Genetics, Epigenetics, and Stem Cells in Tumorigenesis
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Inflammation
Genetics Epigenetics
Stem Cell Theory of Cancer
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•Definition
•Redness
•Heat
•Pain
•Swelling
•Loss of function (sometimes)
Inflammation
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Inflammation•Your body’s inflammatory response is to:
•Neutralize inflammatory agent
•Remove necrotic material
•Establish groundwork for healing/repair
•HEALING involves making new cells
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Inflammation•Inflammatory response can be
subdivided into the...
•Cellular Response
•Vascular Response
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Inflammation
•V
•Histamine-mediated hyperemia
• Blood vessels dilate
•Fluid moves into tissue
•Platelets/fibrin forms a clot, trapping injurious agent
•Vascular Response
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Inflammation•Cellular Response
•Chemotaxis (Movement of WBCs to site of injury)
• Neutrophils first to arrive
• Neutrophil lifespan -> 24 - 48 hrs
• Bone marrow recruitment, if needed
• Phagocytosis, antimicrobial release, and NETting (neutrophil extracellular trap)
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Inflammation•Cellular Response
•Chemotaxis continued
• Monocyte/Macrophage arrival
• 3 to 7 days after onset
• Phagocytosis of cellular debris
• May form ‘giant-cells’ to eat up larger things (e.g. TB granuloma)
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Inflammation•Cellular Response
•Chemotaxis continued
• Eosinophils
• Usually seen in allergy-mediated inflammation
• Subdue histamine
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Inflammation•Cellular Response
•Chemotaxis continued
• Basophils
• Carry endogenous heparin and histamine
• Both released during acute inflammation
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Inflammation•Chemotaxis continued
• Lymphocytes
• Humoral immunity (antibody-mediated immunity
• Antibodies made by mature B cells (plasma cells) and found in blood
• Cell-mediated immunity
• Cellular response specific to T cells (antibody not necessary)
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Inflammation• Clinical Manifestations
• Local response (redness, swelling, heat, pain)
•Systemic response
• Leukocytosis/Neutrophilia
• Possibly...
• Nausea
• Tachycardia
• Tachypnea
• Fever
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•Stages of the Febrile Response
•Prodromal (nonspecific c/o headache, fatigue, malaise, muscle aches)
•Chill (cutaneous vasoconstriction, ‘goosebumps’, shivering)
•Flush (sensation of warmth)
•Defervescence (sweating, temp reduction)
•Fever
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Inflammation
• Types
• Acute
• Chronic
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Inflammation
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Inflammation...an
increase in the number
of cells resulting
from cellular division.Cells are not
any different from normal, there’s just
more of them.
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Inflammation...a
reversible transformati
on of one cell type
into another.Cells are
different from normal.
Sometimes considered an
attempt to protect.
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Inflammation
...abnormal growth in terms of
size, shape, and
appearance.Potentially reversible, but
also potentially
premalignant
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Inflammation...cell de-
differentiation to a more
immature or embryonic
formCancer often characterized by anaplastic cell growth.
Anaplasia
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GENETICS
• CANCER is a disease of genetics
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GENETICS
You have 23
•Chromosomes that are made
of
•Genes are made of
•DNA is made of...
• Nucleic Acids (nucleotides)
Big to small...
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GENETICS•DNA nucleotides
•Cytosine
•Guanine
•Adenine
•Thymine
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GENETICS
• Allelle - alternative forms of a gene
• Genes can be either dominant or recessive
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Genotype Phenotype
Your genetic
makeup,all
30,000 genes
Your outward
appearance,
a fraction of your 30,000 genes
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GENETICS
• You can be heterozygous or homozygous for any particular gene
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HOMOZYGOUS
Red, recessiveGreen, dominant
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HETEROZYGOUS
Red, recessiveGreen, dominant
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Non-sex linked chromosomes
are called
Autosomes
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Autosomes‘Autosomal dominant’is a term indicating a gene expressing itself in the heterozygous
state.
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Autosomes‘Autosomal recessive’is a term indicating a gene expressing itself
in the homozygous state.
(you need both copies of the gene to express
the trait)
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Sex Chromosomes
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Sex Chromosomes
X-linked recessivetraits express themselves
in males due to no similar/opposingallelle on the Y chromosome
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Understanding cancer involves comprehendinghow and why we get our genes...
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Cancer tissue is known to containstem cells.
Stem cell theory
FACT
(some studies are hesitant to use the ‘stem cell’ terminology, instead using ‘cancer- initiating
cells’.)
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•Idea proposed over 50 yrs ago
•First conclusive stem cell evidence
came in 1997
Stem cell theory
J Egypt Natl Canc Inst. 2008 Sep;20(3):209-15.
Cancer stem cells: from identification to eradication.Kassem NM.Source
The Department of Clinical Oncology; Department of Clinical Pathology; Section of Immunology, Kasr ElAini Oncology Centre (NEMROCK), Cairo University School of Medicine, Egypt.
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Stem cell theory
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• Where do the mutations that lead to cancer occur? In the less-differentiated stem cell or in the more-differentiated end-product cell? (for example, squamous epithelial cells lining the trachea)
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•Totipotent stem cells
•Pluripotent stem cells
•Multipotent stem cells
•Oligopotent stem cells
•Bipotent stem cells
• Unipotent stem cells
Hierarchy
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•Totipotent cells
• Any individual cell could create a new human (e.g. identical twins)
• All genes turned ‘on’ and able to give instructions to the body
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•Pluripotent cells
• Cells with ability to become any germ cell layer (ecto-, endo-, or mesoderm), and - thus - any cell in the body.
• Can not become an adult organism.
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•Multipotent cells
• Cells with ability to become many different cells, but generally only within specific tissue.
• Genes for any other tissues become turned ‘off’.
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•Unipotent cells
• Cells having the ability to become only one lineage.
• Example: Skin stem cells in the basement membrane of the dermis.
...at this point 99% of the cells genes are turned off and the cellis only expressing 1%
of its genes.
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FACT:
Every cell in your body contains a complete copy of your DNA. All 23 chromosomes.
Every last little bit of instruction for every last little protein your body has ever or will ever need.
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EPIGENETICS...the study of inheritable changes in gene expression or cellular
phenotype caused by mechanisms other than changes in the underlying DNA sequence.
(Greek: epi => over, above, outer)
In English: It’s how we turn genes ‘on’ or ‘off’
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‘On’:Transcription factors
‘Off’:DNA methylation
Histone modification
EPIGENETICS
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Transcription factors...proteins (in blue below) that
facilitateDNA transcription into RNA.
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EPIGENETICS1. DNA methylation
2. Histone patterning
Pediatr Endocrinol Rev. 2011 Sep;9 Suppl 1:506-10.How epigenomics brings phenotype into being.
Martín-Subero JI. Department of Anatomic Pathology, Pharmacology and Microbiology, University of Barcelona, Barcelona, Spain. [email protected]
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DNA methylation• Methyl group added to DNA strand (at cytosine)
• ‘Silences’ a portion of DNA
• Blocks transcription factors from accessing portion of the DNA
• Modifications are transferrable to next gen
• Becoming an important process in carcinogenesisBrief Funct Genomics. 2013 Jan 11.
From histones to RNA: role of methylation in cancer.
Xhemalce B
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Histones
Curr Med Chem. 2012 Nov 26. Histone Methyltransferase Inhibitors: Novel Epigenetic Agents for Cancer Treatment.
Zagni C, Chiacchio U, Rescifina A.
•Acetylation
•Methylation
•Phosphorylation
•Ubiquitination
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Histones
Pediatr Endocrinol Rev. 2011 Sep;9 Suppl 1:506-10.How epigenomics brings phenotype into being.
Martín-Subero JI. Department of Anatomic Pathology, Pharmacology and Microbiology, University of Barcelona, Barcelona, Spain. [email protected]
•Histone Acetylation•Performed by the
‘HAT’ enzyme (histone acetyltransferase)
•‘Uncoils’ the DNA from around the
histone, opening it up for transcription
factors to express the gene.
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Histones
Pediatr Endocrinol Rev. 2011 Sep;9 Suppl 1:506-10.How epigenomics brings phenotype into being.
Martín-Subero JI. Department of Anatomic Pathology, Pharmacology and Microbiology, University of Barcelona, Barcelona, Spain. [email protected]
•Histone Decetylation•Performed by the
‘HDAC’ enzyme (histone deacetylase)
•‘Coils’ the DNA around the histone, closing it up from
transcription factors and preventing
expression of the gene
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How does a totipotentstem cell
eventually developinto an ‘end-product’ cell
(skin cell, neuron, cardiac
myocyte)??
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Cancer doesn’t just
involve changes to the GENOME,
it involves changes to theEPIGENOME as
well.