nature reviews cancer

Oncogenes and tumour suppressors are mutation targets promoting the onset and maintenance of cancer. Oncogenic mutations result in gain-of-function and deregulation of the function of the oncoprotein that they encode. Tumour suppressors act to run quality checking of DNA, keep cell cycle checkpoints, and shut down mitogenic signals; mutations in genes encoding tumour suppressors can lead to absence of these checks and give activated oncoproteins the chance to run riot in a cell. Co-incidence of mutations in oncogenes and tumour suppressor genes potentially leads to cancer.


Ras is a small G protein involved in a whole host of cellular functions. Mutation of Ras at a functional site can lead to a pleiotropic phenotype. Oncogenic Ras causes inappropriate signalling through its three pathways: MAPK, PI3K, and RalGEF. Signalling through the PI3K activates antiapoptotic Akt (PKB), which acts to promote cell survival. Signalling through RalGEF causes cell motility by formation of filopodia (Cdc42) and lamellipodia (Rac), which may be associated with metastasis. Signalling through MAPK actually causes the expression of some Ras signalling inhibitors (Sproutys, SPREDs, GAPs) which shuts down the signal in normal cells.

Myc is a transcription factor with more than 8000 transcription targets. Deregulated Myc leads to cell proliferation, but does not block apoptosis. Thus, it leads to a modest amount of growth before it is eradicated by apoptosis. Inhibition of apoptosis by antiapoptotic Bcl-xL is tumourigenic in cells expressing Myc highly. Additionally, Myc is thought to contribute to the tumour microenvironment, immune evasion, and inhibition of differentiation.

Ras and Myc work together by combining their abilities. Myc promotes cell proliferation and disfavours differentiation, and Ras inhibits apoptosis. The combination of the two means that cells are allowed to proliferate without triggering apoptosis. Ras actually activates Myc in normal cells - but in normal cells, activation is transient. Ras stabilises Myc by phosphorylation on S62 through MEK signalling, but also promotes its degradation by phosphorylation on T58 through PI3K signalling. The result is transient activation of Myc by Ras. Mutations which ultimately block phosphorylation at T58 will switch activation by Ras from a transient to a constitutive response.

Tumour suppressors

p53 is the so-called guardian of the genome. High Myc and oncogenic Ras cause stabilisation and activation of p53. p53 gets two bites at the cherry to combat the inheritance of damaged genomes: at the point of DNA damage, p53 arrests the cell until the DNA is repaired. p53 decides whether the cell enters senescence or apoptosis - its own state of post-translational modifications and the genomic context of its target genes (p53 is also a TF) on the genome in that particular cell both play a role in which way the scale tips. In this way, p53’s second bite of the cherry is the selection of apoptosis in cells whose DNA is damaged beyond repair.

Rb is the keeper of the G1/S checkpoint. Loss of both copies of the Rb gene leads to retinoblastoma. Familial retinoblastoma predisposes heterozygotes with a heightened risk of retinoblastoma by loss of heterozygosity - loss of their only functional copy. This can occur by mutation, but also by mitotic recombination, gene conversion, and nondisjunction. Cells null for Rb can still enter G0 phase, as p107 and p130 share some redundant functions with Rb.

NF1 displays the phenomenon of haploinsufficiency. Nf1-/- Schwann cells can be complemented for the wild-type by Nf1+/+ mast cells, but not Nf1+/- mast cells. The former gives the wild-type; the latter causes neurofibromas.

VHL suppresses the hypoxic response in normoxia by mediating the ubiquitin-associated degradation of HIF-1α in normoxia. Loss of VHL leads to a hypoxic response no matter the oxygen level.

Further reading:

  • Hanahan, D.; Weinberg, R.A. 2011. “Hallmarks of cancer: The next generation.” Cell 144:646-674.
  • Lowe, S.W.; Cepero, E.; Evan, G. 2004. “Intrinsic tumour suppression.” Nature 432:307-315.
  • Pylayeva-Gupta, Y.; Grabocka, E.; Bar-Sagi, D. 2011. “RAS oncogenes: Weaving a tumorigenic web.” Nature Reviews Cancer 11:761-774.
  • Soucek, L.; Evan, G.I. 2010. “The ups and downs of Myc biology.” Current Opinion in Genetics and Development 20:91-95.
  • Vousden, K.H.; Prives, C.; 2009. “Blinded by the light: The growing complexity of p53.” Cell 137:413-431.
  • Burkhart, D.L.; Sage, J. 2008. “Cellular mechanisms of tumour suppression by the retinoblastoma gene.” Nature Reviews Cancer 8:671-682.

Examples of experimental models of human cancer and their use. Modelling human cancer in other organisms allows us to observe and monitor the effect of therapies against the cancer before actually administering it to patients. This is best done in animal models as their biology is most similar to humans’. Non-animal, eukaryotic models are still useful for studying oncogenic processes in pathways that are conserved between the model and humans.

Genetic strategies

Classical transgenic mice use a tissue-specific promoter to drive the expression of an gene. The aim is to express the gene only in a particular tissue, and see if it causes tumours to form. It should also identify driver and passenger mutations. The downfall of this strategy is that oncogenes usually acts to de-differentiate the cell, so that would switch off the promoter that is driving its expression, resulting in a self-inhibitory feedback loop. Classical knockout mice have one or both copies of a gene knocked out in the germline, so all cells have the knockout. This is good for studying sporadic versus familial loss of heterozygosity events, but there is no control over where and when that gene is deactivated.

Inducible systems include the tet on and tet off systems, where tetracycline/doxycyline results in the induction (tet on) or inhibition (tet off) of the transcription of a gene. In tet on, doxycyline binds a transactivator that drives transcription; in its absence, there is no transcription. In tet off, the transactivator binds the locus without doxycycline; in its presence, the transactivator dissociates from the gene.

Cre-lox systems work by recombining DNA across lox sites. Any sequences occurring in between the lox sites are said to be “floxed”, and is removed upon Cre presence.

The ER-Tam system is a switchable system that works on the protein level. Proteins fused with the estrogen recetor (ER) are not functional unless tamoxifen is present. Tamoxifen can be removed to make the protein nonfunctional again.

in vivo models

Mouse models are widely used due to their evolutionary and genetic similarity to humans. Differences do exist, such as telomere length and mutation rate. They can be the recipient of xenografts and their cancers largely resemble human cancers.

Flies and yeast do not get cancer, but instead serve as models for oncogenic pathways. They can be subject to genetic and chemical screens to identify putative driver mutations causing pathway deregulation, and to identify drugs that can combat such mutations.


Cell cultures are generally not useful for monitoring tumours, because tumours are complex organs made of many cell types, and culture conditions usually maximise prolferation. Organoid culture allows growth of organs in 3D from a patient biopsy. This can be subjected to functional assays, drug screens, and genome editing for truly personalised therapy that is specific to the patient. However, this shares a common downfall with cell culture in that there is no contribution from the tumour microenvironment in a culture.

Further reading:

  • Sharpless, N.E.; DePinho, R.A. 2006. “The mighty mouse: genetically engineered mouse models in cancer drug development.” Nature Reviews Drug Discovery 5 (9):741-754.
  • Vidal, M.; Cagan, R.L. 2006. “Drosophila models for cancer research.” Current Opinion in Genetics & Development 16:10-16.
  • Xu, H.; Tomaszewski, J.M.; McKay, M.J. 2011. “Can corruption of chromosome cohesion create a conduit to cancer?” Nature Reviews Cancer 11 (3):199-210.