Lectures 1-12
Molecular basis of cancer
Cancer facts and statistics
- Major cause of mortality and morbidity in the UK
- More than 270, 000 new cases registered annually
- Breast, lung, bowel and prostate cancer account for over 50% of cases
- One in three lifetime risk of diagnosis
- One in four will die from cancer
- 200 different types of cancer
- Heterogeneity: different causes, symptoms and types of treatment
- Disease risk rises significantly with age: ~65% occurs in people over 65
Cancer is a heterogeneous group of diseases in which single cells acquire the ability to
proliferate abnormally resulting in the accumulation of progeny
Cancers are those tumours that have acquired the ability to invade through surrounding
normal tissues
The most advanced form of this invasive process is metastasis, a state in which cancer cells
escape from their original location, travel through the blood or lymphatic systems and take up
residence at distant sites
Cancer classification
Tissue of origin:
- carcinomas→ epithelial cells (i.e. cells that arise from endoderm or ectoderm)
- sarcomas→ mesoderm
- Leukaemias and lymphomas→ blood cell precursors and lymphatic
Benign (localised, non invasive) VS. malignant (capable of invasion and metastasis)
Histology (e.g. tissue architecture and cellular morphology) used to place cancers into
groups
Genetic or expression markers
Classification is important for cancer diagnosis and management to make sure the most
effective treatment is given to each patient
How cancers develop
Key concepts
- Development, invasion, metastasis, angiogenesis
- Cancer is a genetic disease
- Most cancers are derived from a single cell
- At the level of the individual, cancer is a common occurrence, whereas at the level of
the cell it is a rare event
- Cancer development is a multi-step phenomenon
- Some benign tumours can progress to malignancy this is known as progression
,Malignancy and invasion
Progression of normal tissue into an invasive cancer
As the cells start to divide more quickly they enter a
hypoplastic state (more cells present than normal)
Dysplasia means there are more cells present and cells
start to lose their shape and they lose characteristic
morphology
Gains the ability to invade surrounding tissues
Angiogenesis
Tumour growth requires formation of new blood vessels (angiogenesis, neovascularization)
Rate limiting step in growth > 1mm in size because all of the essential nutrients can no
longer enter the cells and all of the excretory products cannot move out the cells
For cancer to grow bigger than this, it needs its own blood supply
Processes apply to primary and secondary tumours
Initiated by factors produced by the cancer
Signalling molecules can promote blood vessel growth into the cancer cells
Leads to proliferation, invasion, maturation and differentiation of new capillaries within cancer
Metastasis
Cancer moving from original site to distant location
Tumour cells acquire ability to escape from primary site, and re-establish at secondary
locations
Occurs via blood vessels, lymphatic system, body cavities
Driven by specific molecular mechanisms
Present clinical problems: treatments for primary tumours often ineffective for metastasis
Primary cause of death in cancer patients
Have to think about more systemic therapies that treat the whole body
Cancer is a genetic disease
Mutational theory of cancer
Cancer can result from: germline mutations or somatic mutations
Susceptibility to some cancers inherited in families
Mutations found in sporadic cancers and subsequently found to be transforming
Chromosomal changes are common in cancers
Some cancers are associated with particular chromosomal abnormalities
Agents that damage DNA are thought to increase the susceptibility to cancer development
Some diseases are thought to arise from defects in DNA repair mechanisms that result in an
elevated cancer risk
Infection with certain viruses associated with development of specific cancer
What causes genetic changes
We have our own genetic constitution and other elements can cause predisposition to cancer
Environmental changes could be chemical changes: smoking, diet, occupation
Radiation that can come from the environment
,Exposure to carcinogens in tobacco smoke is seen to be the single greatest risk for cancer
development
Types of mutations found in cancers
Chromosome number changes
Chromosome translocations
Amplifications
Interstitial gains and losses (10’s - 1,000,000’s bps)
Small deletions, insertions and single base pair mutations
Exogenous sequences e.g. viruses in cervical cancer (HPV), Burkitt’s lymphoma (EBV),
Hepatocellular carcinomas (hepatitis virus) and kaposi's sarcoma (HIV)
Epigenetic mechanisms- promoter hypermethylation
Why is cancer such a rare event at the cellular level
Sophisticated DNA repair mechanisms can sense changes in DNA
Apoptotic mechanisms can cause cell death if there’s too much DNA damage
Mutations in many genes do not affect cell growth
Most of the DNA does not code for proteins
Rapidly dividing cell populations are numerous, it doesn’t matter if they contain mutations as
they have a fast turnover rate
Many cells do not divide all the time- they differentiate and lose their potential to divide (e.g.
muscle cells)
No single mutation can circumvent these defences (multiple mutations have to come
together to cause cancer)
Cancer is a multi-step disease
The development of cancer is a multi-step phenomenon
Multiple successive errors/cells (~6-7) are required to circumvent this protection and give rise
to abnormal growth and a malignant cancer. It takes many mutations for a single cell to
become cancerous
Chances of this are rare
However, two general mechanisms allow this progression to happen:
1. Increase cell growth, division, survival: expand target population for subsequent
mutation
2. Alter genomic stability: increase mutation rate and susceptibility to further mutations
These combined steps tell us how 6/7 mutations can come together to cause cancer
What types of genes are targets of mutations in cancer
1. Oncogenes
- Normal activity promotes proliferation, growth, invasion etc.
- Gain-of-function mutations in cancer (1 allele): excessive or inappropriate
activity (switched on permanently) as a consequence they’re driving growth all
the time
- Normal cellular versions termed proto-oncogenes, called oncogene when
mutated
2. Tumour suppressor genes
, - Normal role: inhibit events leading to cancer (e.g. regulation of cell cycle, pro-
apoptotic, genomic stability and repair)
- Loss of function mutations (affecting 2 alleles) required for inactivation and
cancer development. Both need to be switched off to allow cancer
development
Functional classification of tumour suppressor genes
- Gatekeepers: directly control proliferation
- Caretakers: control rate of mutation
Colorectal carcinoma development
1. Malignant colorectal tumours (carcinomas) arise from preexisting benign tumours
(adenomas)
2. Mutational activation of oncogenes and inactivation of tumour suppressor genes
is involved
3. The formation of a malignant tumour is a multi-step process
4. Not every tumour needs to acquire each of the mutations indicated (eg. only about
50% of colorectal tumors have K-ras mutations)
5. Other genetic events are required that are at present ill-defined (eg. metastasis
genes)
6. The order of mutations can have a significant impact on the tumorigenic process
(eg. non-dysplastic hyperproliferative epithelium with K-ras mutations that fail to
develop into cancers).
Hanahan and Weinberg’s principles
The transition of a normal cell to cancer required the acquisition of six specific capabilities
1. Independence of external growth signals
2. Insensitivity to external anti-growth signals
3. Avoidance of apoptosis
4. Indefinite replication
5. Angiogenesis
6. Invasion and metastasis
How we can tie up these types of processes with individual mutations and individual stages
of disease
Cancer genetics
Aims to understand the multi-step pathway of mutation and selection that transforms a
normal
somatic cell into a population of proliferating and invasive cancer cells
Identify and study the key events, processes and pathways in tumour development,
metastasis etc
