Multistep tumourigenesis Flashcards
How are tumours formed and progress (in 4 basic steps)?
Origin of cells within a tumour
Multihit hypothesis
Tumour heterogeneity
Tumour microenvironment
Is cancer a genetic disease?
Yes
Cancer results from alterations in what?
DNA (mutations)
Alterations in DNA that result in cancer are caused primarily by what?
Environmental mutagens
What does the accumulation of mutations with time cause?
Carcinogenesis
The genetic changes that occur in cancer cells are responsible for inducing what?
The ‘hallmarks of cancer’
What are the two types of genes called that are involved in the development of cancer in humans?
Oncogenes and tumour suppressor genes
Are the mutations in oncogenes that cause cancer dominant or recessive?
Dominant
Are the mutations in tumour suppressor genes that cause cancer dominant or recessive?
Recessive
How many cells could a solid tumour contain when it is first detected?
> 10 to the 9
Do tumour cells descend from a single ancestral cell (monoclonal) or do they have multiple origins (polyclonal)?
Descend from a single ancestral cell, i.e. monoclonal
What are the three pieces of evidence for cancers being monoclonal?
X-inactivation mosaics
Myelomas
Chromosomal rearrangements
Every female is a mixture (mosaic) of what two types of cells?
Paternal X inactivated cells (Xp)
Maternal X inactivated cells (Xm)
When does X-inactivation occur?
In early foetal development
Is X-inactivation random?
Yes
In many patients with CML, cancer cells can be distinguished by the presence of what?
The Philadelphia (Ph1) chromosome
How does the Philadelphia (Ph1) chromosome arise?
By a translocation between chromosomes 9q and 22q
How many cell divisions are there per human in a lifetime?
~E16
What is the mutation rate in humans per gene per cell division?
E-6
How many gene mutations occur per human in a lifetime?
E10
Is a single mutation in a single cell enough to cause cancer?
No
Why is a single mutation in a single cell not enough to cause cancer?
Several independent mutations in the lineage of one cell are required for cancer
Mutations need to occur in oncogenes and tumour suppressor genes
What are the three pieces of evidence for the multihit hypothesis?
Epidemiology
Oncogene cooperation
Tumour progression
Why does the epidemiology of cancer support the multihit hypothesis?
Because the incidence of cancer increases with age
If only one mutation was required to convert a cell to a cancer cell then most cancers would be independent of age but this is not the case
Why does tumour progression fit with the multi-hit hypothesis?
Because cancer is an initial mild disorder that gradually evolves into a fully-blown disease
What are the steps of tumourigenesis?
Normal Initiated Pre-cancer (mild, moderate and severe) Carcinoma in situ Cancer
Define the breakthrough phase
A single cell develops a specific driver-gene mutation and begins to divide abnormally
Define the expansion phase
A cell develops an additional driver-gene mutation that gives rise to a benign tumour
Define the invasive phase
A cell develops an additional driver-gene mutation in at least one of the indicated pathways enabling it to invade surrounding tissues
What phases occur to get from a single abnormal cell to a metastatic cancer?
Breakthrough phase
Expansion phase
Invasive phase
What does tumour progression involve successive rounds of?
Mutation and natural selection
What do cancers arise by a process of?
Clonal selection
What does the first mutation in a cancer cell give?
A slight growth advantage
What does the second mutation in a cancer cell allow?
Its descendants to grow more uncontrollably
What does the third mutation in a cancer cell allow?
A cell to outgrow others and form a benign tumour
What types of cells are in the tumour microenvironment?
Cancer stem cell (CSC) Cancer cell (CC) Immune inflammatory cells (ICs) Invasive cancer cell Pericyte (PC) Endothelial cell (EC) Cancer-associated fibroblast (CAF)
What is tumour development dependent on? Give an example that demonstrates this
Dependent on the microenvironment
RSV implanted into chicks gives rise to a tumour; however RSV implanted into chick eggs does not give rise to a tumour
What can chronic inflammation promote?
Tumour progression
Cancers develop as a result of mutations to what types of genes?
Proto-oncogenes and tumour suppressor genes
Are cancers thought to develop from a single or multiple abnormal cells?
A single abnormal cell
Define the multihit hypothesis
Several independent mutations in the lineage of one cell are required for cancer
What is there growing evidence for as cancers evolve?
Tumour genetic heterogeneity
What is tumour development also dependent on?
The microenvironment
What is cancer?
The uncontrolled growth of cells with the ability to metastasise
What types of genes to oncogenes arise from?
Proto-oncogenes
Why is cancer deemed a genetic disease?
It is a problem with the genes, but not necessarily an inherited one
Are proto-oncogenes and tumour suppressor genes normal in the cell?
Yes, until they acquire mutations
Around what percentage of cancers of monoclonal?
99%
What is a leiomyoma?
A form of cancer
What is myc?
A classic oncogene
What are E1A and ras?
Oncogenes
What is one of the main issues in treating cancer?
Tumour heterogeneity
Essentially, what is the stroma?
All cells surrounding the tumour
What can help a tumour to grow?
The tumour microenvironment
