Cancer intoduction

carcinogens, epidemiology, cancers, tumours

Epidemiology definition

study of distribution and determinants of health related statistics or events

Factors effecting incident stats

• detection & reporting.

• Risk factors/causes

Factors effecting mortality stats

• health resources availability

• effective treatment

• risk factors exposure

Childhood cancer risks with Epidemiology

small no.s tumour types

mainly in embryonal tissues and leukaemias

Young adults cancer risks with Epidemiology

tumours uncommon

mainly bone lymphoma and germ cell

Middle to old age cancer risks with Epidemiology

increasing of epithelial neoplasms

Colorectal cancer cause

-lifestyle factors and cancer connections are difficult

-EPIC managed to and they say diet is key factor

Lung cancer becoming a thing of the past?

• increasing in women & decreasing in men

• -increasing rates seen in older generations which relates to carcinogen exposure earlier in life

Cervical cancer graphs

entirely preventable disease

- screening is key

- disease of younger women

- awareness

Carcinogen definition

a substance capable of causing cancer in living tissue

Carcinogen division (3):

1. Physical.

2. Chemical.

3. Biological.

How to classify carcinogens?

1 - definitely

2A - probably

2B - possibly

3 not classifiable

4 prolly not

- not regarding potency

Mode of action of chemical carcinogens

damaging a cells DNA

Example of chemical carcinogen

polycyclic hydrocarbons / vinyl chloride / nitrosamines

Examples of dietary factors as chemical carcinogen factor

red&processed meat / alcohol / dietary fibre

Mode of action of biological carcinogens (virus)

• they cause neoplastic transformation.

• They can inactivate TSGs (p53 &Rb) with cervical cancer (HPV)

Example of viruses as biological carcinogen

Hep B / Hep C / HPV / HIV

Mode of action of biological carcinogens

in relation to hormones and growth factors

- promotion step

Example of biological carcinogens (growth factors)

• Epidermal Growth factor (EGF)

• insulin-like growth factor (IGF)

• Transforming Growth factor - beta (TGF-beta)

Mode of action of physical carcinogen (asbestos)

• asbestos inhalation.

• causes chronic inflammation.

• Wounding response in outer linings of lungs (asbestos bodies).

• Deposition of scar tissue impairs lung func.

• Tissue damage increases risk of mesothelioma

Mode of action of physical carcinogen- ionising radiation:

• DNA damage.

• Leads to mutations in oncogene or TSGs

Examples of ionising radiation carcinogen

• repeated Xray exposure.

• Prolonged UV light exposure.

• Ingestion of radioactive iodine.

• Inhalation of radioactive dust.

Latent period is…

following exposure to a carcinogenic agent but before neoplasia develops

Is cancer a rare disease?

no it affects more than 6/100,000 (600/100,000)

screening for early disease may lead to

increased incidence rates and decreased death rates 

Most common cancers origin?and why?

epithelial bc they undergo cell division throughout their life

Cancer occurs due to changes in (3)

1. cell proliferation.

2. Cell death.

3. Cell differentiation

What is self renewal?

when stem cells divide

- producing progenitors

- which then differentiate to form specialised functional cells of the tissue

-plasia

formatuion/growth

Neo-

new

Dys-

bad/abnormal

Meta-

change

-stasis

place/standing/state

Homeo-

similar

Carcino-

crab/cancer

-genesis

beginning

Ana-

backward

3 step model of cancer development

1. Initiation

2. Promotion.

3. Progression

Initiation is the…

irreversible genome alteration

Promotion is the…

clonal expansion of the initiated cell(growth stimulation)

Progression is the…

stable alteration of an initiated cell (gaining ability to invade and metastasise)

Timing of initiation and promotion

initiator then promotor

- at optimal time intervals

Chemical biological and physical things can cause

initiation and promotion

- by altering the DNA of cells

- in oncogenes +/ TSGs

Oncogene definition

any mutated gene that contributes to neoplastic transformation

proto-oncogenes

oncogenes prior to mutation

Oncogenes during cancer …

are active

Oncogenes promote…

cell growth and survival

2 things mutations can do to oncogenes

1. Alter gene expression levels.

2. Alter the structure of the resulting protein

Constitutive activation

many mutations lead to this during mutations of oncogenes

Many common oncogenes promote what (2)?

1. Mitosis.

2. Progression through cell cycle

Many common oncogenes evade what?

death signals

Oncogenes activated by 4 genetic changes:

1. Point mutations.

2. Deletions.

3. Gene amplification.

4. Chromosomal transactions.

Point mutations…

maybe producing an abnormal functional protein product

Deletions…

anywhere from a few base pairs to an entire chromosome

Gene amplification…

results in an excessive production of oncogene product

Chromosomal translation…

gene is activated inappropriately by the wrong promotor region

Mode of action of oncogenes (4):

1. Increased growth factor produced.

2. Increased expression of growth factor receptors.

3. Mutant transcription factor production.

4. Over-production of factors preventing cell death.

How do oncogenes allow more cells to be produced (2)?

1. They promote cell growth and cell survival.

2. They evade cell death and differentiation.

Overall oncogenes shift the balance

from tissue homeostasis towards neoplasia

TSGs

Tumour Supressor Genes

TSGs definition

growth regulatory genes which-if they lose their function-contribute to neoplastic transformation

TSG fun. During cancer

loss of func.

Knudson’s ‘2 hit hypothesis’

• a cell can only initiate a tumour when it contains 2 mutant alleles

• if one is inherited the other must experience a somatic mutation

• this will then initiate tumorigenesis

Retinoblastoma gene (Rb):

-first suppressor gene to be identified

- discovered in a malignant tumour of the retina in childhood

- inhibits cell progression(mitosis)

- other Rb related cancers : lung/ breast/ bladder

P35 gene (TP53):

-most common genetic abnormality in neoplasia

- deleted/ mutated in most tumours

- regulates cell cycle progression

-key regulator of apoptosis

- “guardian of the genome” (bc of role in DNA damage response

APC gene:

-adenomatous polyposis coli

- multifunc. protein product involved w/ : cell division, signal transduction, apoptosis, cell-cell adhesion, cell motility

- mutated in almost all colorectal cancers

- inheritance of a single inactive copy leads to FAP

FAP:

familial adenomatous polyposis

familial adenomatous polyposis through patient ages:

-early 20s -> 1000s of polyps (benign tumours) in colon

- early 30s -> they progressed to malignant cancer

-by 40 -> almost all FAP patients have malignant cancer

ras oncogene func.

GTP binding

Oncogene ras type

signal transduction

Activation mechanism of oncogene ras

point mutation

Oncogene myc func.

transcription activator

Activation mechanism of oncogene myc

translocation

Oncogene myc type

nuclear regulator

Oncogene bcl2 func.

mitochondrial protein

Oncogene bcl2 type

inhibit apoptosis

Activation mechanism of oncogene bcl2

translocation

OG. 6 Hallmarks of cancer:

-self sufficiency in growth signals

- insensitivity to anti-growth signals

- tissue invasion & metastasis

- limitless potential for replication

- sustained angiogenesis

- evading apoptosis

Hallmarks of cancer acquired by tumour cells due to (3):

-gain of func. Of oncogenes

-loss of func. Of TSGs

-action of selective pressure

Self sufficiency in growth signals:

-growth factors allow continuation of cell cycle

- cancer cells start growing and dividing independently of these signals

Insensitivity to anti-growth signals:

-cancer cells become resistant to the growth factors (that also limit cell growth and division)

- growth inhibitor signals are funnelled through pRB and prevents the inappropriate G1→ S phase transition

Tissue invasion and metastasis:

-malignant tumour invade adjacent normal tissue and continue to spread

- driven by tumour microenvironment

How does cancer metastasis?

-detach from tumour mass

- motility

- move through storm/mesenchyme

-intravasation then extravasation

Limitless replicative potential:

• normal cells reach the “Hayflick limit” (senescence) part of the ageing process

• pRB and P53 TSGs overcome this limit

• many cancers show an unregulation of telomerase

Sustained angiogenesis:

• (vessel)(beginning)

• tumours grow and become hypoxic

• hypoxia induces VEGF production

• allowing new blood vessels to form

VEGF

vascular endothelial growth factor

- stimulates endothelial cell proliferation and migration

Evading apoptosis:

-programmed cell death

- homeostasis between proliferation and apoptosis

- usually cells w/ damaged DNA undergo apoptosis (p53)

Malignant progression:

transition of tumours from benign to malignant (multistep)

Progression of tumours():

-less differentiated & more aggressive

-sub-populations emerge w/ genetic abnormalities

- growth control fails

- cells become invasive

- larger tumours are composed of loads of different cells (tumour heterogeneity)

-natural selection -“evolution in microcosm”

Why don’t metazoic lesions respond to therapy but the primary tumour might?

-clonality

- first clonal expansion may allow for a second mutation

- second clonal expansion allows for multiple independent mutations

- there are multiple parallel clonal expansions

- natural selection creates resistance to therapy

-oma

benign tumours

-carcinoma/ -sarcoma

malignant cancers

Benign vs. Malignant differentiation

well differentiated / become poorly differentiated

Benign vs. Malignant growth rate

slow / rapid rate

Benign vs. Malignant border

proscribed regular border / irregular border

Benign vs. Malignant necrosis

little to none / frequently shows

Benign vs. Malignant surgery

easily removed / difficult

Benign vs. Malignant capsule

usually encapsulated / usually not

Benign vs. Malignant spread

no metazoic spread / possible

Benign vs. Malignant growth pattern

grow by expansion / by infiltration