Overview
This lecture (session 1 of 2, addressing objectives 1 and 2: cancer genetics and molecular origins, and the hallmarks of cancer) frames tumour development as a two-step evolutionary process acting on a population of cells rather than organisms, then works through the classes of genetic damage, the concept that several mutations must accumulate in one cell, and the eight molecular hallmarks a cancer cell must acquire.
Cancer as an evolutionary process
Tumorigenesis is described as a classic evolutionary process, but compressed in time and acting on a population of cells within one organism rather than on organisms themselves. It proceeds in two steps.
Step 1: generation of genetic diversity, via DNA damage and changes to gene activity, from three sources:
- Inheritance: “old” mutations passed down through generations.
- Environment: carcinogens, radiation, viruses, inflammatory processes, microbiome.
- Bad luck (random replication errors): the human genome has 3.2 billion nucleotides; there are roughly 500 million cells/cm3 and 30 billion cells in the colon (15 million crypts); 1-3 random errors occur during each cell division, giving approximately 44 new mutations/year in a colon cell and approximately 30 new mutations/year in a stomach cell.
Step 2: natural selection, selecting for any cell that has acquired a survival or growth advantage through DNA changes; this selection process produces cancer.
In cancer, genetic changes accelerate cell proliferation and cell migration, but inhibit immune surveillance, DNA repair capability, cell sensors of stress and damage, and programmed cell death.
In normal cells, gene expression is tightly regulated in timing, anatomical location and scale, and cells are programmed for specialist functions. DNA damage removes this regulation: cancer cells no longer contribute to the organism as a whole, and are subject to continuous selection for traits that provide a survival advantage (e.g. faster growth, drug resistance). Cancer is a mutation-driven breakdown in cooperation between cells: the fitness of cancer cells increases at the expense of the fitness of the whole organism.
The integrating model: random genetic damage arises from environment, bad luck and inheritance; it is either repaired, inconsequential or lethal, or, if it strikes an oncogene or tumour suppressor gene, it proceeds through natural selection to enhanced cell division, survival and migration, producing growth of abnormal cells in the wrong place (cancer).
Types of genetic damage and the two gene classes
Genetic damage that drives abnormal proliferation, migration and survival falls into three classes: chromosomal changes (rearrangements, amplifications, deletions), simple mutations, and epigenetic changes (e.g. DNA methylation and altered histone/chromosome packaging).
Two classes of gene are affected:
- Oncogenes: promote growth/survival; cancer-associated changes are “gain of function”.
- Tumour suppressor genes: inhibit growth/survival; cancer-associated changes are “loss of function”.
Chromosomal translocation example - Burkitt lymphoma: a reciprocal translocation between chromosome 8 (carrying MYC) and chromosome 14 (carrying the immunoglobulin heavy chain locus) fuses the regulatory region of the immunoglobulin heavy chain gene with the MYC oncogene, driving MYC overexpression. Clinically this presents with a large jaw/facial mass.
Simple mutation example - KRAS: in KRAS (5,889 nucleotides), a single base change at codon 12 (DNA g to a) changes the amino acid from glycine to aspartic acid. This activates the KRAS protein and drives cell division, and is linked to over 1,000 NZ colorectal cancer cases/year.
Somatic vs germline mutations
Cancer mutations are classed by where they occur:
- Somatic mutations (arising in body/tissue cells) lead to sporadic cancer.
- Germline mutations (arising in reproductive cells) lead to inherited cancer susceptibility.
Multiple mutations and progression
One mutation is not enough: multiple mutations are required in a single cell. A tumour cell needs to acquire several new capabilities, and approximately 3-6 mutations are sufficient to cause initiation, progression and spread of a single tumour. Progression runs Normal tissue -> Benign cancer -> Invasive cancer -> Metastasis, with additional gene mutations acquired at each transition.
Colorectal cancer as a worked example (Vogelstein et al. 2013, Science 339, 1546-1558): Normal colonic epithelium -> Small adenoma (APC mutation) -> Large adenoma (RAS mutation) -> Carcinoma (PI3K / Cell Cycle-Apoptosis / TGF-beta pathway mutation), with typical patient ages of 30-50, 40-60 and 50-70 years respectively at each stage.
Inherited cancer: a germline mutation (e.g. in Gene 1) is already present in every cell from birth, a “head start” on the same Normal tissue -> Benign cancer -> Advanced cancer -> Metastasis progression.
The eight molecular hallmarks of cancer
Mutation allows cancer cells to activate capabilities normally restricted to specific times, places or cell types (e.g. rapid proliferation as in wound healing, migration as in embryonic cells, moving in and out of blood vessels as white blood cells do, recruiting blood vessels as in tissue repair, reduced reliance on oxygen as in oxygen-starved cells, hiding from the immune system as colon cells do): cancer cells have access to all the genes in the genome, not only those normally permitted for their cell type. Collateral damage: drugs that kill cancer cells will also damage normal cells.
Hanahan (2022, Cancer Discovery 12, 31-46) describes eight hallmarks:
- Sustained proliferative signaling
- Evasion of growth suppressors
- Resistance to cell death
- Limitless replication
- Invasion/metastasis
- Induction of/access to vasculature
- Evasion of the immune system
- Reprogramming cellular metabolism
1. Sustained proliferative signaling
Mutation/dysregulation of a cell-signaling pathway (growth factor -> receptor -> intracellular network -> nucleus -> altered gene activity -> cell division, migration, survival) can occur at any point along the pathway. Mechanisms: producing their own growth factors, promoting signaling from surrounding stromal cells (including inflammatory cells), increasing receptor number on the cell surface (receptor amplification, e.g. HER2 in breast cancer, giving over-activation of survival/division signaling), or proliferating in the absence of growth factor binding (specific receptor mutations cause abnormal signaling without ligand, e.g. EGFR mutation in non-small cell lung cancer).
A dense KEGG "Pathways in Cancer" reference diagram (slide 33) was assigned text-only extraction; its internal pathway labels were not recoverable, only the caption "KEGG pathways".
2. Evasion of growth suppressors
Cancer cells ignore inhibitory extracellular signals via mutation of tumour suppressor genes. DNA damage and cellular stress normally activate TP53, which stops the cell cycle and induces apoptosis; TP53 is mutated in 50% of tumours, removing this checkpoint.
3. Resistance to cell death
An average adult produces 60 billion new cells/day, and a matching 60 billion must also die by Apoptosis (cell shrinkage, condensed chromatin, nuclear and cell fragmentation). Cancer cells carry mutations in the genes controlling these apoptotic pathways.
4. Limitless replication potential
Normal cells divide only 60-70 times. Telomeres act as a counting device, consisting of hundreds of TTAGGG repeats, losing 10-20 repeats per division; the cell dies once telomeres are gone. In stem cells, telomerase maintains telomeres, and malignant cells also show enhanced telomerase activity.
5. Ability to invade/metastasise
Three steps: loss of cell-to-cell adhesion, degradation of the extracellular matrix, and movement of tumour cells into other tissue layers, the lymphatic system, the peritoneal cavity, or blood vessels.
6. Inducing/accessing vasculature
Cells need to be within 100 micrometres of a capillary. Tumours promote growth of the capillary network via increased expression of vascular endothelial growth factor; angiogenesis is enhanced by inflammation.
7. Evasion of the immune system
Two mechanisms: (i) tumour antigens are “hidden” (e.g. via disruption of the MHC antigen-presenting complex); (ii) immune cells are reprogrammed by the tumour, via the PD-1 (T cell)/PD-L1 (tumour cell) interaction, a “don’t kill me” signal that inhibits the T cell response. PD-1 inhibitor drugs (e.g. pembrolizumab/Keytruda) target this mechanism.
8. Reprogramming cellular metabolism
Increased glycolysis, i.e. a shift to anaerobic metabolism, with increased glucose uptake and consumption. This provides glycolytic intermediates for biosynthetic pathways and compensates for poor oxygen supply in large tumours. 18F-fluorodeoxyglucose (a glucose analogue) exploits this for PET imaging.
Concluding remarks
(i) Cancer is caused by natural selection of genetic variants. (ii) Its acquired characteristics are selected from the entire repertoire afforded by the genome. (iii) Eight molecular hallmarks describe a cancer cell’s survival advantage and means to autonomy.
Self-test
- Describe the two-step evolutionary model of tumorigenesis and explain why it is described as “rapid” and acting on a “population of cells”.
- List the three sources of genetic diversity in Step 1, with one example or figure for each.
- List the processes that genetic changes accelerate and those they inhibit in a cancer cell.
- Using the colon-cell figures given, explain what “bad luck” contributes to cancer risk.
- Distinguish oncogenes from tumour suppressor genes in terms of the type of function change seen in cancer.
- List the three classes of genetic damage that can drive abnormal proliferation, migration and survival.
- Describe the molecular event in the Burkitt lymphoma 8;14 translocation and its effect on MYC.
- Describe the KRAS codon 12 mutation as an example of a simple mutation, including the base and amino acid change and its functional consequence.
- Distinguish somatic from germline mutations in cancer, and their respective clinical consequences.
- Explain why “one mutation is not enough” and give the approximate number of mutations sufficient for tumour initiation, progression and spread.
- Describe the Vogelstein colorectal cancer progression model, including the stages, the pathway/gene mutated at each transition, and typical patient ages.
- Explain what gives inherited cancer a “head start” compared with sporadic cancer.
- List the eight molecular hallmarks of cancer.
- Describe the mechanisms by which a cell can achieve sustained proliferative signaling.
- Explain how TP53 normally suppresses growth, and the consequence of its mutation.
- Describe the three steps by which cancer cells invade and metastasise.
- Explain how cancer cells evade the immune system, including the role of PD-1/PD-L1 and how pembrolizumab acts on this pathway.
- Explain how cancer cells reprogram their metabolism and how this is exploited diagnostically.
Answers
Reveal answers
- Tumorigenesis is a classic evolutionary process, but on a rapid time scale and acting on a population of cells within one organism (not organisms competing against each other), proceeding through generation of genetic diversity (Step 1) followed by natural selection of the fittest cells (Step 2).
- Inheritance (old mutations passed down through generations); environment (carcinogens, radiation, viruses, inflammatory processes, microbiome); bad luck (random replication errors, e.g. ~44 new mutations/year in a colon cell, ~30/year in a stomach cell).
- Genetic changes accelerate cell proliferation and cell migration, but inhibit immune surveillance, DNA repair capability, cell sensors of stress and damage, and programmed cell death.
- With 3.2 billion nucleotides in the genome, ~500 million cells/cm3, and 30 billion cells in the colon (15 million crypts), 1-3 random replication errors per cell division accumulate to ~44 new mutations/year per colon cell purely by chance, independent of environment or inheritance.
- Oncogenes are genes that promote growth/survival and show “gain of function” changes in cancer; tumour suppressor genes inhibit growth/survival and show “loss of function” changes in cancer.
- Chromosomal changes (rearrangements, amplifications, deletions), simple mutations, and epigenetic changes.
- A reciprocal translocation fuses chromosome 8 (carrying MYC) with chromosome 14 (carrying the immunoglobulin heavy chain locus), placing the immunoglobulin heavy chain regulatory region next to MYC, which drives MYC overexpression.
- A single DNA base change (g to a) at KRAS codon 12 changes the amino acid from glycine to aspartic acid; this activates the KRAS protein and drives cell division.
- Somatic mutations occur in body/tissue cells and cause sporadic cancer; germline mutations occur in reproductive cells and cause inherited cancer susceptibility.
- A single mutation is insufficient because multiple mutations must accumulate in one cell for it to acquire the several new capabilities a tumour cell needs; approximately 3-6 mutations are sufficient for initiation, progression and spread of a single tumour.
- Normal colonic epithelium -> small adenoma (APC mutation, age 30-50) -> large adenoma (RAS mutation, age 40-60) -> carcinoma (PI3K/Cell Cycle-Apoptosis/TGF-beta pathway mutation, age 50-70).
- In inherited cancer, one germline mutation (e.g. in Gene 1) is already present in every cell from the first day of life, so fewer additional somatic mutations are needed to reach benign, advanced and metastatic cancer than in sporadic cancer.
- Sustained proliferative signaling; evasion of growth suppressors; resistance to cell death; limitless replication; invasion/metastasis; induction of/access to vasculature; evasion of the immune system; reprogramming cellular metabolism.
- Producing their own growth factors; promoting signaling from surrounding stromal/inflammatory cells; increasing receptor number on the cell surface (receptor amplification, e.g. HER2); or acquiring receptor mutations that signal even without growth factor binding (e.g. EGFR in non-small cell lung cancer).
- DNA damage and cellular stress normally activate TP53, which stops the cell cycle and induces apoptosis. TP53 is mutated in 50% of tumours, removing this checkpoint and allowing evasion of growth suppression.
- Loss of cell-to-cell adhesion; degradation of the extracellular matrix; movement of tumour cells into other tissue layers, the lymphatic system, the peritoneal cavity, or blood vessels.
- Tumour antigens can be hidden (e.g. via disruption of the MHC antigen-presenting complex), or immune cells can be reprogrammed via the PD-1 (T cell)/PD-L1 (tumour cell) interaction, a “don’t kill me” signal that inhibits the T cell response; pembrolizumab (Keytruda) is a PD-1 inhibitor that blocks this signal.
- Cancer cells increase glycolysis (shifting to anaerobic metabolism) and glucose uptake, providing glycolytic intermediates for biosynthesis and compensating for poor oxygen supply in large tumours; this increased glucose uptake is exploited diagnostically using the glucose analogue 18F-fluorodeoxyglucose for PET imaging.