Cancer biology

What are the 3 main causes of cancer?

• environmental factors

• hereditary

• pathogenic infection

What does aberrant mean?

diverging from the normal type.

What is observed in all cancers?

chromosomal changes

What is neurofibromatosis?

genetic condition causing tumours to grow along nerves. The tumours are usually non-cancerous (benign) but may cause a range of symptoms.

How does cancer frequency vary within human populations?

depending on geographic location, lifestyle, etc ie nurture

What are examples of environmental influences?

• Infection 

• Diet

• Noxious agents  

How could a sarcoma infection cause cancer?

sarcoma gene contains additional info that can lead for ex. to upregulation of gene coding for tyrosine kinase = cell adhesion, proliferation, mobility

Name some examples of sarcoma genes encoding for proteins that activate kinases in viral infections causing cancers. What do they all lead to ?

• STAT3 = c-Myc = Cyclin D1

• RAS = RAF = MEK/ERK

• P13K = AKT = mTOR or P13K = PDK1

lead to excessive cell proliferation

What are 4 types of viral infections that lead to cancer? Which virus causes each?

• Nasopharyngeal carcinoma - by Epstein-Barr virus

• Cervical carcinoma - by human papillomavirus

• Kaposi’s sarcoma - by human herpesvirus 8

• Breast sarcoma - by Rous sarcoma virus

What types of non-viral infections cause cancers?

Gastric carcinoma by helicobacter pylori (bacteria)

Where is the bacteria aspergillus oryzae found? What type of toxin does it produce and what can this cause?

hot tempered climates, used to saccharify rice, sweet potato + in peanuts

aflatoxin causing hepatocellular carcinoma (liver cancer)

How do aflatoxins cause liver cancer?

once aflatoxin is ingested (produced by mould found in rice, etc), endogenous enzyme cytochrome P-450 catalyses it into aflatoxin 2,3-epoxide which can bind to carcinogens

Name some types of infections, noxious agents and diets that can cause cancers?

• infection: viruses

• noxious agents: smoking, UV and ionising radiation, occupational carcinogens like radiation or asbestos

• diets: alcohol, obesity, lack of exercise

What is mesothelioma and what could cause it?

type of cancer that develops in the lining that covers the outer surface of some of the body's organs from asbestos for ex.

Name cancers not caused by environmental factors

• Retinoblastoma

• Li-Fraumeni Syndrome 

• Wilm’s Tumour

• Gorlin’s Syndrome

• Breast Cancer Syndrome

• Familial adenomatous polyposis coli (FAP)

What is May Grunwald-Giemsa (MGG) stain?

dye used to stain blood cells and other cells in tissue samples

What did Hungerford contribute to cancer research? What type of cancer was this discovered through?

In 1959 discovered the Philadelphia chromosome, the first genetic abnormality associated with cancer showing cancer starts with changes in one or more genes

CML (Chronic Myeloid Leukaemia)

In CML, what causes the cancer?

DNA is "swapped" so translocated between chromosomes 9 and 22 = modification of white blood cells and blood-forming stem cell in the bone marrow

In which stage of mitosis does translocation causing CML occur?

metaphase

Why does chromosomal translocation have such a devastating effect?

leads to the fusion of 2 genes, ABL (9q34) and BCR (22q11) = target protein phosphorylated so ATP to ADP turns it on, when fused to BCR can’t turn off = constant proliferation

What’s an oncogene?

A gene with the potential to cause cancer by transforming cellular behaviour

What makes a proto-oncogene an activated oncogene?

deletion or point mutation in coding sequence

regulatory mutation

gene amplification

chromosome rearrangement = protein overproduction/hyperactive

Are oncogenes dominant or recessive?

dominant

What is a cancer paradigm?

model that explains how cancer develops and how it can be treated

What is virally induced oncogenesis?

Most cancer-causing viruses contain an oncogene by evolutionary capture and mutation of proto-oncogene 

Why were oncogenes evolutionarily selected for viruses?

virus numbers greater from proliferating cells 

What is the first human oncogene to be identified? What type of molecule does it contain?

Ras

small GTPase

How is Ras turned on and off? How does this switch occur?

on: GTP

off: GDP

through phosphorylation induced conformational change

How is Ras involved in growth factor-induced growth?

When Ras is in the presence of growth factor by surrounding cells + there’s space - phosphorylate themselves ie switch themselves on

What’s the role of Grb2, GTPase and Sos in growth factor-induced growth?

Grb2 recognises phosphate on Tyrosine containing the growth factor

Sos allows the exchange of GDP to GTP ie switch on

GTPase allows the exchange between GTP and GDP ie switch off

What are 3 mechanisms through which Ras allows cell growth?

bad inhibition of apoptosis

mTOR stimulation of protein synthesis

GSK-3 beta stimulation of cell proliferation

What are two mechanisms through which Ras modifies cell morphology and movement?

modifying filopodia // lamellipodia

How does a mutant Ras lead to tumours/cancers?

no off is possible so always self phosphorylating. Proto oncogene becomes oncogene 

What information is crucial to understanding cancers along with the dominant nature of oncogenes?

Normal cells express tumour suppressor genes that are lost during oncogenesis

When are tumour suppressor genes lost? Explain the term

oncogenesis: process by which normal cells become cancerous

Through which pathways can Ras modify cell function, growth, morphology and movement?

• PI3K-PIP3, Rho GTPase family

• Raf (MAPKKK)/MEK/ERK - affects transcription,

• Ral-GEF/RalBP1 - cell division control gene (cdc42)

Explain how fusion experiments showed that cancer dominance alone can’t explain cancers?

when combining normal and cancerous cells - one daughter cell led to tumours ie cancer cells are dominant but the other didn’t ie cancer cells are recessive

What is one argument supporting that suppressor genes exist?

loss of growth suppressor gene more likely than gain-of-function oncogene mutations

What is one argument refuting that suppressor genes exist?

loss of both alleles of putative growth suppressor genes unlikely (would have to lose the one from mom AND dad - IOBE, losing two is carelessness ;))

What does sporadic retinoblastoma usually lead to in patients? How does this compare to familial retinoblastoma? Who examined this and over how long was the data collected?

unilateral ie only blindness in one eye /vs/ bi-lateral ie almost always in both eyes = blindness

Knudsen over 1914-1984

What does Knudsen propose after analysis of retinoblastoma data? What does this provide evidence for?

one/two-hit hypothesis

•  for tumour suppressor gene hypothesis

• that cancer requires loss of both 

       wild-type alleles

• for the basis of inherited predisposition 

       to cancer   

What did cytogenetics provide evidence for in the 1980s in relation to inherited retinoblastomas?

single Chr13 deletion responsible for inherited retinoblastoma

Name some cancer genes and which type of cancer they have been found to be responsible for?

• Retinoblastoma - Rb

• Li-Fraumeni Syndrome - p53

• Wilm’s Tumour - WT-1

• Gorlin’s Syndrome - Ptc

• Breast Cancer Syndrome - BRCA-1

• Familial adenomatous polyposis coli (FAP) - APC

What is the effect on mutated genes of oncogenes /vs/ tumour suppressor genes?

activating gain of function // inactivating loss of function

What is the nb of alleles mutated to exert effect of oncogenes /vs/ tumour suppressor genes? What does this mean

one ie dominant /vs/ two ie recessive

What is the effect on function of the protein product oncogenes /vs/ tumour suppressor genes?

enhanced /vs/ reduced

Describe driver mutations

occur in key genes and directly contribute to the initiation and progression of cancer - modifying cell prolifer

Describe passenger mutations

accumulate in cancer cells but don't contribute to cancer development

Describe a mutation landscape

• pattern or distribution of genetic mutations across a particular genome highlighting the frequency, types, and locations of mutations in specific genes.

• X axis is the chr., y is gene position along the chr.

• shows driver and passenger mutations

How many mutations are required for tumorigenesis?

more than one

Do driver mutations need to occur in a specific order to induced tumorigenesis?

in colorectal cancer there’s a specific order, but generally, is just the right combination of driver mutations must occur, regardless of the sequence, to enable cancer cells to gain the ability to grow uncontrollably, evade cell death, and spread

What are two elements that underpin tumour progression? Why’s this called “evolution of the nastiest“?

• successive rounds of random inherited change

• natural selection

the cell best able to multiply, evade cell death and move is going to be the most likely to survive and the most aggressive type of cancer

Describe clonal expansion

initial accidental mutation in epithelia = build-up of mutations over different cell proliferation cycles = proliferation of mutated cells that form tumours

What are 4 types of genomic changes in cancerous cells from normal ones?

• copy number

• amplification of certain regions

• intrachromosomal rearrangement

• interchromosomal rearrangement

What does genetic instability cause? What causes them?

tumorigenic evolution

defects in DNA repair pathways / correction mechanisms for DNA replication errors / correction mechanisms for DNA segregation errors → mainly checkpoint losses

What contributes to tumorigenesis?

• increased cell division

• decreased apoptosis

• genetic instability (defects in DNA repair, replication, segregation, mainly checkpoint loss)

What do increased cell division and decreased apoptosis lead to? why?

tumorigenesis

= uncontrolled/unregulated growth of cells that accumulate and form a tumour

Through which pathway do normal cells respond to cellular stress? What does this lead to in normal cells?

p53 gene = cell cycle arrest/senescence and most likely is apoptosis

Name examples of cellular stressors ? As these increase in a cell, what is likely to happen?

• hyperproliferative signals

• DNA damage

• telomere shortening

• hypoxia

apoptosis

Describe cell arrest, when it can occur and which gene it relies on?

process where a cell stops progressing through the cell cycle

checkpoints G1 (R point), G2, S, M (end)

p53

Which gene is mutated in almost all types of cancers? What does this disrupt?

p53

intrinsic apoptosis

Why can cancer be called an evolutionary disease?

• evolves over time

• through genetic mutations that accumulate in cells

• providing growth advantages, leading to the selection of more aggressive or drug-resistant clones

What is Rb (retinoblastoma protein) and does it cause cancers through loss of function or gain?

controls the progression of the cell cycle by binding to and inhibiting E2F transcription factors, which are necessary for the transition from G1 to S phase

loss = no inhibition of cell division = unregulated proliferation

Are Rb mutations only found in retinoblastomas?

no many other cancers to like breast, lung, GI, bladder, leukaemia, lymphoma etc

How can DNA damage eg cause apoptosis in normal cells?

• cytochrome c released from mitochondrial intermembrane space

• activates Apaf1

• activated Apaf1 proteins assemble to form an apoptosome

• caspase 9 recruited, activated = cleaved and activated executioner caspases

• caspase cascade = apoptosis

How is exon 6 of the BAX gene involved in normal cell apoptosis?

exon 6 allows function of BAX as a mitochondrial pore which allows passage of cytochrome c into the cytoplasm. Without this, apoptosis is not initiated

How is annexin 6 involved in apoptosis?

externalises PS (phosphatidylserine) on the cell surface = recognition of cell for apoptosis