ZOOL-1073 Cancer Biology

Cancer is a disease of the ___

Cell

Two heritable properties that define cancer cells

Autonomy and anaplasia

Autonomy

• Loss of normal regulatory controls that coordinate cell growth, division and death

• cell acts independently of normal regulatory signals

Anaplasia

• Lack of cellular differentiation

• cells lose their specialized features and revert to an immature form

Cell proliferation

The generation of new daughter cells divided from parent cells

Two types of cell proliferation

• Mitosis

• meiosis

What is needed to maintain body homeostasis

A regulated balance of cell proliferation and cell death

Where are new skin cells generated to replace those who die daily

Stratum basale

How does the liver replace hepatocytes damaged by heavy alcohol intake

Mitosis

Mitosis chromosome count

46 chromosomes in the parent cell → 46 chromosomes in each of the 2 daughter cells

Meiosis chromosome count

46 chromosomes (23 pairs) → 23 chromosomes in each of the 4 new cells

Altered cellular proliferation (autonomy) results in

Overproliferation and crowding of cells due to loss of regulated balance of cell division

Why are cancer cells called autonomous

They grow and reproduce uncontrollably

What happens when a cell undergoes excessive mitosis or meiosis when it is not needed

The tissue those new cells are in can become significantly dysfunctional

Cell differentiation

process of cellular maturation to achieve a specific function

Pluripotent cell

A cell that can mature into a wide variety of different mature cells

Unipotent cell

A cell that can only become one type of mature cell

Direction of differentiation when a stem cell matures

Pluripotent → unipotent

4 controls of cell differentiation

• Genes

• growth factors

• nutrients

• stimulation from the external environment

Genes as a control of differentiation

Certain genes are turned on or off during maturation of a cell

Growth factors that control differentiation (examples)

Hormones such as HGH (human growth hormone), estrogen, testosterone

Nutrient example that controls differentiation

Immature T cells need the amino acid glutamine to differentiate into CD4+ T helper cells

External environment example that controls differentiation

Cutting yourself stimulates production of new skin cells to repair the wound

What balance is needed to maintain homeostasis (differentiation)

A regulated balance of undifferentiated and differentiated cells

Undifferentiated cells are

• Flexible and adaptable

• can mature into whatever the tissue needs

Differentiated cells are

• Not flexible or adaptable

• matured into one cell type and cannot undifferentiate

Altered cellular differentiation (anaplasia) results in

The cell becomes incapable of carrying out its designated function

Why are cancer cells called anaplastic

• They lose cellular differentiation

• lose their ability to carry out their specific functions

• do not die when expected

Neoplasm

Autonomy+ anaplasia

Why do unspecialized (anaplastic) cells matter in a neoplasm

Unspecialized cells multiply much faster

A cell that has lost control of both proliferation and differentiation is considered

A potentially cancerous tumour cell

Can a neoplasm be benign

Yes, a neoplasm can still be benign

Tumour

new growth (neoplasm)

2 types of tumours

benign and malignant

Cancer

A malignant neoplasm

Tumour vs cancer rule

All cancers are tumours, but not all tumours are cancers

Root cause of cancer

DNA damage

Mutations that lead to cancer are called

Carcinogenic

Why are neurons less affected by the base mutation rate

They rarely if ever replicate

Why are epidermal cells more affected by the base mutation rate

They replicate frequently so they can build up many harmful mutations over a lifetime

How metaplasia/dysplasia can lead to anaplasia/autonomy

Stress that triggers metaplasia then dysplasia forces cells to replicate far more than normal, so more mutations build up

Carcinogen

• Any substance, radionuclide or radiation directly involved in causing cancer

• any agent capable of causing genetic mutation

Sunlight causes

Skin cancer

Inhalation carcinogens cause

Lung cancer

Excretory carcinogens cause

Bladder cancer

Human papillomavirus causes

Cervical cancer

Contact carcinogens cause

Skin cancer

How UV radiation causes cancer

Alters DNA sequences and therefore the proteins made from them

How benzene damages DNA

Becomes benzene oxide in the cell, binds to DNA and damages it during DNA replication

How HPV causes cancer

Degrades DNA repair enzymes like P53 and mitosis checkpoint proteins like RB to increase the cell's mitosis so the virus can replicate and spread

UV wavelength that can damage DNA

254.7 nm

How UV damages DNA

Causes cross-linking of neighbouring pyrimidine bases (thymine and cytosine) where the UV photon strikes

When does UV DNA damage lead to skin cancer

When the cross-link hits the gene for the DNA repair enzyme, or the repair enzyme is already damaged (e.g. by HPV), so mutations build up

Skin cancer that results when UV mutations damage proliferation and differentiation proteins

Malignant melanoma

Cancer-causing substance in alcohol

Acetaldehyde, a byproduct of alcohol metabolism

How acetaldehyde causes cancer

When the body can't break it down fast enough it builds up in cells, damages chromosomes and mutates stem cells

Genetic predisposition to cancer

A small percentage of cancer patients have an inherited mutation in their germ cells that predisposes them to certain cancers

BRCA1

• BReast CAncer 1 gene

• normally codes for a DNA repair protein

• mutated form increases DNA mutation buildup and encourages breast and ovarian cancer in women

Retinoblastoma gene

Children who inherit a defective copy are almost certain to develop retinoblastoma, a malignant tumour of the retina

Cancer pathogenesis

The process by which a mutated cell proliferates into an undifferentiated population of cells capable of metastasis

Monoclonal origin theory

Cancer starts from a single mutated cell that builds up mutations in several genes until it becomes autonomous and anaplastic

Most mutations are

• Spontaneous alterations in DNA replication

• most have no consequence because they don't affect genes that regulate cell growth and stability

Which mutations can lead to cancer

Mutations that affect regulatory genes

Carcinogenesis is a ___ process

• Multistep

• no single mutation is enough to produce a neoplasm

Cells become cancerous due to

A cycle of repeated injury and mutation

Smoking example of multistep carcinogenesis

One cigarette is not enough; one pack a day for 35 years is

4 things a single cell needs damaged to become cancer

• Cell cycle stop and go checkpoints

• DNA repair enzymes

• apoptosis-triggering proteins

• growth inhibitors

3 classes of genes that cause cancer when altered

• Mutator genes

• oncogenes

• tumour suppressor genes

Mutator genes

Code for proteins that repair mutated DNA

Oncogenes

Code for proteins involved in cell growth

Tumour suppressor genes

Code for proteins that prevent overproliferation of cells and regulate apoptosis

Loss of function of the 3 cancer gene classes leads to

Autonomy and anaplasia

Classify p53

Tumour suppressor gene

Classify BRCA

Mutator gene

Classify HER2

Oncogene

Classify caspases

Tumour suppressor genes

Classify RB

Tumour suppressor gene

Why are cancer genes often misunderstood

They're named after the cancer they were found in, so people assume only the abnormal gene exists

Proto-oncogenes

• Normal go genes that promote normal cell growth

• become oncogenes when mutated

HER2

• Proto-oncogene that makes human epidermal growth factor 2 for normal growth

• mutant HER2 promotes uncontrolled growth

How tumour suppressor genes work

• Opposite of oncogenes

• stop switches that make proteins that inhibit cell division

• if mutated, cell growth becomes uninhibited

Normal p53 protein function

• Triggers DNA repair

• if damage is too extensive, it stimulates apoptosis of the damaged cell

Most common genetic defect in human cancers

p53 mutation

Fraction of all cancers with a defective p53 gene

half

What happens without functioning p53

Cells with damaged DNA stay alive, can divide indefinitely toward malignancy

Pathogenesis pathway step 1

Normal cell is exposed to acquired (environmental) DNA-damaging agents: chemicals, radiation, viruses

Pathogenesis pathway step 2

DNA damage is either successfully repaired or DNA repair fails

Pathogenesis pathway step 3

Mutations in somatic cell genome: activation of oncogenes, inactivation of tumour suppressor genes, alterations in apoptosis genes

Pathogenesis pathway step 4

Unregulated cell proliferation and decreased apoptosis

Pathogenesis pathway step 5

Clonal expansion (1 cell becomes a huge number of cells; now considered a tumour)

Pathogenesis pathway step 6

Additional mutations, angiogenesis and escape from immunity

Pathogenesis pathway step 7

Tumour progression → malignant neoplasm

Pathogenesis pathway step 8

Invasion and metastasis

Pathogenesis of cancer key fact

Unique for each cancer type and often takes years

When is a cell said to have transformed into a neoplastic cell

When oncogenes are activated and anti-oncogenes are suppressed, giving it autonomous and anaplastic characteristics

Why is cancer more common with age

Over time random chance makes it more likely a mutation hits a critical protein; cells need time for random mutations unless the cancer is hereditary

Initiation-promotion-progression model underscores

The idea of cofactors in cancer etiology

3 stages of carcinogenesis

Initiation → promotion → progression

Initiation

The irreversible alteration of a cancer-related gene

Initiation key points

Initiating event causes the mutation; may eventually be identified but often is not; example: exposure to a carcinogen