Cancer Cells Flashcards
Give an overview of cancer cells?
A tumour can be benign if it hasn’t invade other cells but if it metastasises then it is cancerous and is considered malignant
Metastases are secondary tumours forming at other sites in the body
They develop gradually from increasingly aberrant cells - through varying stages
There are often successive rounds of random mutations leading to natural selection of ‘favourable’ mutations causing increasingly worse cancer
Most cancers derive from a single abnormal cell - primary cell
Cancer cells contain somatic mutations and they need more than a single mutation to cause cancer
They are genetically unstable - accumulating gross abnormalities in the karyotype
What can cancer cells be defined by?
- They reproduce in defiance of normal restraints of cell growth/division
- They invade/colonise territories of other cells
How do we classify cancer cells?
This depends on the tissue it invades:
Carcinoma - arise in epithelial cells (most common)
Sarcomas - arise from connective tissue/muscle cells
Leukaemia/lymphoma - derived from white blood cells and cells of the nervous system
What are the hallmarks of cancer?
Self-sufficiency in growth signals Insensitivity to anti-growth signals Tissue invasion and metastasis Limitless replicative potential Sustained angiogenesis Evading apoptosis
What are the major processes affected in cancer developement?
- Cell cycle - excessive cell proliferation
- Programmed cell death (apoptosis) is reduced resulting in a greater rate of cell survival
- Cell adhesion is impaired - allowing tumour cells to detach from the tissue of origin
- Angiogenesis - formation of new blood vessel which deliver oxygen and nutrients for tumour growth
What is the mammalian cell cycle and how is it involved in cancer cells?
S phase - where DNA is synthesised
Mitosis
G1 and G2 - gap phases (preparation for S phase or mitosis)
There are checkpoints in the cell cycle to make sure everything is favourable to move onto the next phase
If not favourable the cycle is stalled until this can be repaired
Describe cancer as a genetic disease?
- Genetic changes (mutations) are the cause of cancer (some are inherited but the majority are sporadic)
Many mutations arise from genetic instability - Mutations in several genes (5-7) in a single cell are involved
- Examples of mutations occurring in cancer:
Point mutations, e.g. ras protein, GLY to VAL (codon 12)
Amplification (many copies of a gene): myc - leads to increased production of cell growth
Deletions
Chromosomal re-arrangements, e.g. translocations
What is another origin of cancer?
Cancer stem cells
Cancer cells that can self-renew to produce more malignant stem cells and at the same time generate non-tumorigenic cells - such as transit amplifying cells
What are epigenetic factors?
This is a change in gene expression
Expression of genes (including those involved in cancer) can be influenced by :
methylation of specific C ( cytosine/s) in promoters
Changes in chromatin structure independent of DNA – chromatin remodelling caused by e.g. post-translational modifications in histones such as acetylation/deacetylation
What are the major types of genes/proteins that are involved in cancer?
- Oncogenes/oncoprotein - pro-growth
- Tumour suppressor genes/proteins - growth suppressing
- DNA maintenance genes (involved in DNA repair) - errors go undetected, giving rise to mutations
What are the different mutation types on cancer causing disease?
Dominant mutation - gain of function
Single mutation event in proto-oncogene = oncogene
Oncogenes stimulate excessive cell survival and proliferation
Recessive mutation - loss of function
Mutation event - inactivates tumour suppressor gene (no effect in gene copy)
Second mutation event - inactivated second gene copy
This completely eliminates the tumour suppressor gene = excessive cell survival and proliferation
Describe proto-oncogenes into oncogenes?
Mutation in coding sequence - DNA, RNA, hyperactive protein made in normal amounts
Gene amplification - DNA, RNA, normal protein greatly overproduced
Chromosome rearrangement (e.g. Promotor) - two outcomes:
Nearby regulatory DNA sequence causes normal protein to be overproduced
Fusion to actively transcribe gene produces hyperactive fusion protein
Certain viruses (retroviruses) can acquire proto-oncogenes from the cellular genome and convert them into viral oncogenes
What are the functions of the proto-oncogenes?
Growth factors (e.g. platelet-derived growth factor)
Growth factor receptors (e.g. epidermal growth factor receptor)
Signal transducers (e.g. ras-GTPase)
Nuclear proto-oncogenes and transcription factors (e.g. c-myc transcription factor)
Describe tumour suppressors?
Mutation in a tumour suppressor gene causes a loss of gene function
Both copies of the tumour suppressor gene need to be inactivated by mutation to create a cancer cell - as they are recessive genes
Some DNA viruses (e.g. HPV) bind tumour suppressor gene products and inactivate or degrade them - proteolysis
Genetic and epigenetic mechanisms can inactivate them
What does the Rb gene do?
Rb - regulates between G1 and the S-phase
If mutations then this checkpoint isn’t regulated and cells proceed faster around the cycle
Any mutations acquire during the G1 phase will be passed into the S phase and will be replicated
Describe tetinoblastoma?
This is caused by mutation in a tumour suppressor gene
Hereditary retinoblastoma (contains an inherited mutant Rb gene) - occasional cell inactivates its only good Rb gene copy = both copies mutated and excessive cell proliferation leading to retinoblastoma
Therefore most people develop multiple tumours in both eyes
Non-hereditary retinoblastoma - occasional cell inactivates one of its two good Rb genes - the second copy of Rb is rarely inactivated in the same line of cells = very few excessive cell proliferation leading to retinoblastoma
Only 1 in 30,000 normal people develop a tumour in one eye
What is the p53 gene?
This is a gene normally involved in times when the cell is under stress and/or has DNA damage e.g. Oxidative stress, exposure to UV/gamma rays
It can either force a cell to undergo apoptosis or it can induce further cell division to fix an issue
If this is mutated then cells can escape apoptosis - and if the DNA is damaged this will be continually passed onto more cells
Chaotic cell proliferation can lead to activation of oncogenes and loss of tumour suppressant genes
It can also make cells resistant to anti-cancer drugs and irradiation in some tumour types
What virus can cause cancer?
HPV16 genome
This causes some cancers - head, neck and cervical
HPV16 E6 and E7 genes are virus oncogenes
E7 - targets Rb for degradation
E6 - targets p53
What bacteria can cause cancer?
Helicobacter pylori associated with gastric cancer
Elimination of H pylori by antibiotic treatment greatly reduces risk of development of gastric cancer
H pylori probably acts by chronic inflammation of gastric mucosa leading to cell proliferation
What is involved in DNA instability/mismatch repair?
In E.coli - MutS and MutL
In humans - MSH2/GTBP and MLH1/PMS1 or 2
HNPCC = Hereditary Non-polyposis Colorectal Cancer - where DNA replication is defective
Describe colorectal (bowel) cancer?
13% of all cancer in the UK
Normal epithelium - small adenoma - large adenoma - carcinoma
Adenoma (polyp in colon) - a small non-carcinogenic proliferation, that doesn’t metastasise and therefore easily excised
What are the different bowel cancers?
Inherited and sporadic colon cancer
Inherited colon cancer accounts for approx. 10-15% colon cancer
The rest are sporadic
Evidence that somatic mutations in sporadic colon cancer (diet? lifestyle?) are the same as those in inherited colon cancers
Two types
Familial adenomatous polyposis (FAP), also known as Adenomatous Polyposis Coli (APC)
Hereditary Non-Polyposis Colorectal Cancer (HNPCC)
Describe Familial adenomatous polyposis?
Approx. 0.01% colon cancer Single gene disorder 300kDa cytoplasmic protein (normal) termed APC Truncation mutations in APC protein Normal APC binds b-catenin, degrades it
What is the mechanism of action for APC?
Without Wnt signal - inactive receptor and signalling protein, active APC containing complex = degradation of B-catenin, inactive TFC complex = genes off
With Wnt signal - active receptor and signalling protein, inactive APC containing complex = stable b-catenin, active TCF complex = transcription of Wnt-responsive genes leading to proliferation of gut stem cells
Describe hereditary non-polyposis colon cancer?
Approx. 10-15% colon cancer
Increased number of adenomatous polyps, but fewer than FAP (10’s, not 1000’s)
Mutations in mis-match repair enzymes hMLH1 and hMSH2
(Note that hypermethylation of hMLH1 promoter found in sporadic colon cancers)
