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. imartins@clinic.ub.es

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. imartins@clinic.ub.es

•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. imartins@clinic.ub.es

•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.