cancer revision

what is cancer

abnormal growth of cells in an uncontrolled way that can spread or metastasise into other tissues

what are the types of tumours

• benign

• malignant

what are benign tumours

abnormal growths that are no longer under normal regulation

what are malignant tumours

poorly differentiated cells, growing in a rapid, disorganised manner and can invade surrounding tissues and become metastatic, initiating the growth of similar tumours in distant organs

what are the different classifications of cancers based on cell origin

• carcinomas

• sarcomas

• lymphomas

• leukaemia

what is the most common type of cancer

• carcinomas

• 85%

what do carcinomas arise from

arise from the cells that cover external and internal body surfaces

what are the most frequent carcinomas

• lung

• breat

• colon

• including glandular epithelial tissue adenocarcinoma

what is the general principle of carcinomas

• cell with mutation

• hyperplasia

• dysplasia

• in situ cancer

• invasive cancer

what is the percentage that sarcomas make up for in cancer

12%

where do sarcomas originate from

• cells found in the supporting tissues of the body (mesenchymal layer-derived)

• e.g. bone, cartilage, fat, connective tissue, and muscle

sarcoma malignancy

highly malignant

what are the different types of sarcomas

• angiosarcoma

• osteosarcoma

• ewings sarcoma

• chondrosarcoma

• fibrosarcoma

• liposarcoma

• GI stromal tumour

how do lymphoma cancers arise

arise in lymph nodes and tissues of the body’s immune system (B, T, and NK cells) that can spread to intestine, spinal cord, bone, or brain

what type of cancer is leukaemia

cancers of the immature white blood cells that proliferate in the bone marrow and accumulate in the blood stream

what is the staging of cancer based on

1. site of primary tumour

2. size

3. how far it has invaded into local tissues and structures

4. whether it has spread to regional lymph nodes

5. whether it has metastasised to other regions of the body

what does a low number grade refer to

cancers with fewer cell abnormalities than those with higher numbers

what causes cancer

• carcinogenesis

• tumour progression

what is carcinogenesis

a multistep process resulting from the accumulation of mutations

how do normal cells evolve into tumour cells

through a process called tumour progression

what is tumour progression driven by

a series of random mutations and epigenetic alteration of DNA that affects the genes controlling proliferation and survival

when does cancer become more common

as we age

what are the 3 main ways that can result in DNA damage/mutation

1. mistakes in DNA replication- disincorporation of deoxynucleotides during replication

2. nucleotides within DNA molecules undergo chemical changes spontaneously- these changes often alter base sequences of DNA

3. effects of mutagenic agents- molecules generated endogenously by normal cell metabolism (ROS), mutagenic agents (UV) and chemical agents (vinyl chloride)

what causes an incorrect DNA lesion

• removal of altered bases affecting 3’-5’ exonuclease activity

• proofreading of incorrectly incorporated bases

what causes a missing base DNA lesion

• removal of altered bases by DNA glycosylases (Base excision repair)

• removal of purines by aid or spontaneously

what causes a 3’ deoxyribose fragment DNA lesion

by free radicals leading to strand breaks

what causes a DNA lesion in which there is a bulge due to a deletion or insertion of a nucleotide

intercalating agent that cause addition or loss of a nucleotide during recombination or replication

what causes single or double bond break DNA lesions

by ionising radiation or chemical agents

what causes linked pyrimidines DNA lesions

UV radiation

what causes cross-linked strand DNA lesions

covalent linkage of 2 strands alkylating agents

what are human familial cancer syndromes due to

inherited defects in repair e.g. BRCA1 and BRCA2

what can also cause cancer

viruses

what are one of the most important risk factors for developing cancer after smoking

viruses

DNA viruses that can cause cancer

• HHV

• HPV

• EBV

• HBV

what is an episome

circular DNA

what happens to the viral genome in DNA viruses that can cause cancer

• viral genome can persist in the infected cells as an episome

• promoting the expression of proteins that promote proliferation or that inhibit tumour suppressor genes

examples of RNA viruses that can cause cancer

• HCV

• HTLV1

how is RNA transformed into DNA

RNA is retro transcribed into DNA

how can an RNA virus cause cancer

• retro transcribed RNA incorporated into the host genome (provirus)

• replication occurs

what are the ways RNA viruses can cause carcinogenesis

1. providing a gene that alters growth- the RNA viruses can contain an extra gene additional to the sequences needed for viral replication

2. insertional mutagenesis- the virus integrates into the host genome close to a host gene that regulates growth and up regulates its expression

what are the 2 viral mechanisms of carcinogenesis called

• direct

• indirect

what happens in direct mechanisms of viral carcinogenesis

the virus is acting from within the cell that will form the tumour

where are direct-acting carcinogenic agents generally found

• in monoclonal form within the tumour cells

• these agents help to keep the tumour phenotype

what are the 2 direct mechanisms of viral carcinogenesis

• viral genomes can form episomes —> viral oncogene expression

• or integrate into the host genomic DNA —> viral cellular oncogene expression

• after infecting the target cells tumour viruses are persistently maintained as genetic elements

what happens in indirect mechanisms of viral carcinogenesis

the virus is acting from outside the cell that will form the tumour

what are the 2 ways the indirect mechanism of viral carcinogenesis works

• triggering chronic inflammation and oxidative stress that persistently damage local tissues e.g. HBV- major risk to develop hepatocellular carcinoma

• producing immunosuppression that reduces or eliminates anti-tumour immune surveillance mechanisms e.g. HIV- frequent development of lymphomas associated with EBV or KSV infection

what do all tumour viruses probably present

direct and indirect mechanisms

how many mutations are required for cancer

• many

• 3-20 required to develop cancer

what type of process is cancer

a multi-step process

what is hypertrophy

cells are normal but are much bigger

what is atrophy

cells are normal but much smaller

what is hyperplasia

increase in the number of cells but all cells exhibit normal regulatory control mechanisms

what can hyperplasia progress to

dysplasia

what is metaplasia

• where one cell type changes into another

• cells become another less differentiated cell

what is dysplasia

• increase in growth of immature cells

• abnormal and variable appearance

• cell-to-cell interactions broken down

what can progress into neoplasia

• metaplasia

• dysplasia

what is neoplasia

• after dysplasia and metaplasia

• neoplastic growth is rapid and results in a tumour, metastasis, and acquisition of more mutations

what are the phases of carcinogenesis

• initiation

• promotion- long process and reversible

• progression- rapid increase in tumour size

• metastasis- invasive and metastatic mutations

what is tumorigenesis

a step-wise transformation

what is genomic instability

an increased tendency of gene alteration during cell division

what are the different hallmarks of cancer

• sustaining proliferative signalling

• evading growth duppressors

• avoiding immune destruction

• enabling replicative immortality

• tumour-promoting inflammation

• activating invasion and metastasis

• inducing or accessing vasculature

• genome instability and mutation

• resisting cell death

• degranulating cellular metabolism

how do normal cell control their growth

through the cell cycle and growth factor receptor signalling

what happens if there are no growth factors present

cells go into G0/resting

what are some growth factors

• epidermal growth factor

• hepatocyte growth factor

• FGF

• VEGF

which family of receptors are EGFR part of

erbB2 family

explain EGFR signalling

• in presence of ligand (EGF, TGF alpha) EGFR come together and form homodimers or heterodimers

• receptors are then phosphorylated in the intracellular tyrosine kinase domain

• specific adaptor molecules permit Ras/Raf/MAPK and PI3K pathway to proceed and activation of target genes

• PI3K can also bind directly any of of the erbB partners of EGFR heterodimers. cell growth

• activated receptors undergo endocytosis and follow 2 possible routes- lysosomal degradation or imported-mediated nuclear translocation. can act as a transcription factor or as a coregulator of other gene transactivators

• result in nuclear activation of genes related with cell proliferation, survival, invasion, and metastasis

what are proto-oncogenes

• genes that regulate normal cell growth

• these are genes at any point along this cell signalling pathway e.g. was, Raf, ERK, EGFR

what is the product of the ras proto-oncogenes

ras proteins

what are ras proteins

small G-proteins

what are ras proteins involved in

GTPase reaction cycles

what do ras proteins relay

relay a growth signal from a growth factor receptor on the cell membrane to a cascade of tyrosine kinases

how can the function of ras be affected

• mutation of ras proto-oncogene

• point mutation G to T

• just one single amino acid substitution affected the function to convert it form a proto-oncogene to an oncogene

what is the percentage of mutations in the ras gene found in human cancers

30%

what is a mutated proto-oncogene called

an oncogene

what is the functional consequence of the ras mutation

• G protein is stuck on

• constitutive signal

• ras protein will be active with or without the growth factor

• therefore over expression of the protein

• signals on its own

what happens to the cell cycle if there is a mutation in ras

• ras is downstream in the growth factor signalling pathway so if ras is mutated this pathway is activated regardless of presence of ligand

• sustained proliferation

what are the types of mutations that can occur and where are the possible sites of mutations in proto-oncogenes

• gene amplification- too many copies of a gene so too much of a product- site of growth factor, site of receptor, and in nucleus

• gene rearrangements- promoter in the wrong place so normally a weakly expressed gene can be expressed at high levels- in nucleus

• large structural deletions- deletions in receptors sequences- at site of receptor

• subtle mutations- a single nucleotide change- at site of G protein

what are some cancers caused by

mutations in the proto-oncogene

what are some examples of cancers caused by mutations in a proto-oncogene

• breast cancer

• non-small cell lung cancer

• colorectal cancer

• pancreatic cancer

• melanoma

• papillary thyroid cancer

• glioblastoma

what are the common mutations of EGFR signal transduction pathways in cancer

• EGFR extracellular and intracellular domain mutations e.g. glioblastoma

• EGFR cytoplasmic domain mutations e.g. non small cell lung cancer

what happens in truncated ectodomain EGFR

receptors dimerise in the absence of ligand

what is a EGFR a member of

the HER family of receptors that includes HER1/EGFR, HER/NEU receptors

what occurs in 25% of breast cancer patients

HER2 is amplified and over expressed

what are some examples of targeted chemotherapies

• trastuzumab- humanised monoclonal antibody, blocks HER2 activity

• cetuximab and panitumumab- monoclonal antibodies that block EGFR activity in colorectal cancer

• erlotinib and gefitinib- inhibit tyrosine kinase portion of EGFR and prevent the receptor-mediated signalling pathway from being activated in non-small cell lung cancer

how do normal cells control their proliferation

1. through checkpoints or external signals- favourable environment, proto-oncogenes, nutrients, enough GF

2. by internal signals- DNA damage e.g. tumour suppressor genes

how many known tumour suppressor genes are there

200

what are the 3 main tumour suppressor genes

1. cyclin/cyclin dependent kinases and cyclin dependent kinase inhibitors

2. retinoblastoma protein

3. p53

where are cyclins expressed

different cyclins are expressed in different phases of the cell cycle and combine with different cdks

what does each of the activated cdk complexes do

phosphorylates a different set of target proteins in the cell

what is common in tumours

mutations of G1 checkpoint genes

what do retinoblastoma proteins act as

acts as a brake keeping the cell in G1

what do retinoblastoma proteins inhibit

inhibits the genes necessary for progression into S phase

what does phosphorylation of retinoblastoma proteins do

releases the brake

what does a mutation in retinoblastoma proteins cause

consitutive activation of the cell cycle

what happens in normal physiology of retinoblastoma proteins

1. active G1-Cdk phosphorylates and inactivates Rb

2. phosphorylated Rb releases E2F transcription factor

3. E2F activates transcription of genes that encode proteins required for S phase like G1/S cyclins and S cyclins

4. cell enters S phase

where were tumour suppressor genes discovered

in retinoblastoma

what is retinoblastoma

• cancer of the eye

• common in children aged 1-2

what happens if retinoblastoma is left untreated

almost all patients die of intracranial extension and disseminated disease within 2 years

what happens to the Rb gene in cancer

it is inactivated

what happens in some patients with cancer

they have a deletion of Rb1 gene or point mutation