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This is a 2.5 hour presentation on the basic mechanisms of tumorigenesis. It has been used to introduce students to the importance of inflammation, basic concepts/terminology in genetics and epigenetics, and thoughts pertaining to stem cells in tumorigenesis.
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Inflammation
Genetics Epigenetics
Stem Cell Theory of Cancer
•Definition
•Redness
•Heat
•Pain
•Swelling
•Loss of function (sometimes)
Inflammation
Inflammation•Your body’s inflammatory response is to:
•Neutralize inflammatory agent
•Remove necrotic material
•Establish groundwork for healing/repair
•HEALING involves making new cells
Inflammation•Inflammatory response can be
subdivided into the...
•Cellular Response
•Vascular Response
Inflammation
•V
•Histamine-mediated hyperemia
• Blood vessels dilate
•Fluid moves into tissue
•Platelets/fibrin forms a clot, trapping injurious agent
•Vascular Response
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)
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)
Inflammation•Cellular Response
•Chemotaxis continued
• Eosinophils
• Usually seen in allergy-mediated inflammation
• Subdue histamine
Inflammation•Cellular Response
•Chemotaxis continued
• Basophils
• Carry endogenous heparin and histamine
• Both released during acute inflammation
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)
Inflammation• Clinical Manifestations
• Local response (redness, swelling, heat, pain)
•Systemic response
• Leukocytosis/Neutrophilia
• Possibly...
• Nausea
• Tachycardia
• Tachypnea
• Fever
•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
Inflammation
• Types
• Acute
• Chronic
Inflammation
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.
Inflammation...a
reversible transformati
on of one cell type
into another.Cells are
different from normal.
Sometimes considered an
attempt to protect.
Inflammation
...abnormal growth in terms of
size, shape, and
appearance.Potentially reversible, but
also potentially
premalignant
Inflammation...cell de-
differentiation to a more
immature or embryonic
formCancer often characterized by anaplastic cell growth.
Anaplasia
GENETICS
• CANCER is a disease of genetics
GENETICS
You have 23
•Chromosomes that are made
of
•Genes are made of
•DNA is made of...
• Nucleic Acids (nucleotides)
Big to small...
GENETICS•DNA nucleotides
•Cytosine
•Guanine
•Adenine
•Thymine
GENETICS
• Allelle - alternative forms of a gene
• Genes can be either dominant or recessive
Genotype Phenotype
Your genetic
makeup,all
30,000 genes
Your outward
appearance,
a fraction of your 30,000 genes
GENETICS
• You can be heterozygous or homozygous for any particular gene
HOMOZYGOUS
Red, recessiveGreen, dominant
HETEROZYGOUS
Red, recessiveGreen, dominant
Non-sex linked chromosomes
are called
Autosomes
Autosomes‘Autosomal dominant’is a term indicating a gene expressing itself in the heterozygous
state.
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)
Sex Chromosomes
Sex Chromosomes
X-linked recessivetraits express themselves
in males due to no similar/opposingallelle on the Y chromosome
Understanding cancer involves comprehendinghow and why we get our genes...
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’.)
•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.
Stem cell theory
• 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)
•Totipotent stem cells
•Pluripotent stem cells
•Multipotent stem cells
•Oligopotent stem cells
•Bipotent stem cells
• Unipotent stem cells
Hierarchy
•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
•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.
•Multipotent cells
• Cells with ability to become many different cells, but generally only within specific tissue.
• Genes for any other tissues become turned ‘off’.
•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.
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.
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’
‘On’:Transcription factors
‘Off’:DNA methylation
Histone modification
EPIGENETICS
Transcription factors...proteins (in blue below) that
facilitateDNA transcription into RNA.
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]
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
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
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.
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
How does a totipotentstem cell
eventually developinto an ‘end-product’ cell
(skin cell, neuron, cardiac
myocyte)??
Cancer doesn’t just
involve changes to the GENOME,
it involves changes to theEPIGENOME as
well.