This is something I wrote years and years ago, but which slipped through the great blog reorganisation a couple of years ago, back when I thought I’d be able to find the time for a whole blog about cancer biology. So I’ll dump it here for safe keeping…
This post may be a little inelegantly structured: the direction I wanted to take it in changed twice while writing it, and it wasn’t even intended for a lay audience when I started, so there are a few definitions shoved in parenthesis, and the occasional rambling sentence where I attempt to make a point that I think is interesting, but which requires quite a bit of background knowledge to understand. Cancers are a group of diseases characterised by the loss of control of the proliferation of a cell line, leading to invasion and destruction of tissues. The disease generally begins with a genetic transformation – a mutation, or chromosomal aberration – and further genetic changes accumulate as the disease progresses. Such mutations cause inappropriate proliferation by disrupting regulators of the cell cycle and programmed cell death, or the upstream signals of these. Risk factors for developing cancers can be divided into exposure to carcinogens – substances in the environment which damage DNA – and inborn genetic variation, particularly in the effectiveness of DNA damage detection and repair systems.
Those genes which lead to tumourigenesis when mutated can be roughly classified as oncogenes, which promote the cycle cycle, and tumour suppressor genes, which halt the cell cycle. Their effect on the cell cycle may be proximal, or distal. The retinoblastoma (Rb) tumour suppressor, for example, directly inhibits progression of the cell cycle into the synthesis phase by inhibiting the transcription of genes such as DNA polymerases, which are required for duplicating the DNA. Several oncogenes have a more distal effect as upstream signals. The oncogenes ER, HER2, Ras, and Raf all signal to, amongst others, Rb, and in cancers they permanently inhibit its activity.[1]
There are many different ways in which a gene can be disrupted, and different types of DNA damage can have different effects on the same gene. A gene product can be lost, for example by mutation to its promoter regions, or may be left unable to efficiently perform its role, for example by a missense mutation. The effect may be knock out an entire signalling or DNA repair pathway, the downstream effect being inappropriate promotion of the cell cycle, inappropriate gene expression, inability to trigger apoptosis, or accumulation of DNA damage. It is not just loss of a signal or inappropriate under-expression of a gene which causes problems: over-expression or activation of signalling may also be problematic. Short substitutions, deletions or missense mutations may knock out a single domain (section of the protein with a distinct function), which may be especially problematic if it is a regulatory domain: the protein will always be “switched on”. The signalling component RAS, for example, is found in about 20% of tumours to have lost the GTPase activity (if that means nothing to you, just think of it as a switch) which changes its structure, thus halting downstream signalling; it is left in a permanently “on” state, causing inappropriate transcription and cell cycle promotion.[2] Over-expression of signalling components can also be a cause of cancer: HER2, for example, is a receptor involved in the transduction of signalling from growth factors circulating in the blood, to pathways inside the cell. In around a quarter of breast cancers it is over expressed, thus inappropriate activation of downstream signals occurs (amongst them, RAS and Rb).[3] HER2 is the target of the drug Herceptin, which any British person who follows the news should recognise the name of.
In addition to small scale mutations, the majority of tumours acquire chromosomal abnormalities, and in some cases these are the initial cause of tumourigenesis. These can be in the form of deletions which knock out several genes; and insertions, inversions and translocations which create fusion genes.[4] Fusion genes may be problematic because they can combine the active regions of one gene with the promoters or regulatory sites of another, or because the resultant product looses some of its functionality. Chromosomal aberrations are commonly associated with inherited chromosomal instabilities, such as the breakpoint cluster region (Bcr). The breakpoint cluster region is on the long arm of chromosome 22 (22q), in a gene usually expressed in leukocytes (white blood cells) which produces a receptor involved in signalling. Translocation of a region around 22q11.2 frequently involves another unstable region, on chromosome 9 (9q34.1), in the abl proto-oncogene. The result of this is a fusion gene, including the bcr promoter (a section of DNA near the gene which assists in regulating when the gene should be expressed), and the domains of abl involved in signalling (the kinase domain – and some when I’ll write a post explaining what kinases do), ultimately leading to leukaemia.[5] Other chromosome aberrations occur in cancers, including aneuploidy – loss or gain or a chromosome (monosomy and triploidy respectively). Our normal compliment of chromosomes is in duplicate (actually, it’s more complicated than that with the sex chromosomes), so loss of a chromosome, does not necessarily mean complete loss of genes, but the remaining chromosome may carry defective genes which cause problems in the absence of fully functional copies. Many biological processes depend not just on the all-or-nothing expression of a gene, but on the finely balanced relative concentrations of a group of gene products, which can easily be knocked out of balance by euploidy.[6]
Tumour suppressors, the brakes of the cell cycle, and oncogenes, the accelerators of the cell cycle, are amongst the most important subjects of cancer research. The traditional methods of treating cancer involve surgery and killing cells in a crudely targeted fashion with radiation and toxic chemicals, and a good chance of failure. Advances in the pharmaceutical treatment of cancer are being made thanks to an understanding of the molecular aspects of the disease. This includes the targeting of oncogenes and tumour suppressors, as in the case of HER2 and Herceptin (and estrogen receptors and Tamoxifen) in breast cancer. Recent developments also include techniques for targeting radio- and chemotherapies which exploit the fact that, due to the many mutations that build up as a tumour develops, the more advanced tumours express many unique antigens, which can be targeted with tailor made antibodies. The field is moving forward fast at the moment, especially thanks to applications from genomics, including the genome project, and the development of high throughput methods of analysing genomes, finding mutations, and comparing expression patterns over time, between normal and diseased tissues, and in response to drug treatments. It’s a shame that the extent of the mainstream media’s coverage of biomedical issues runs to headlines like “Aspirin cuts risk of dying by 25%,” “New alert over dangers in our fruit,” and “Scientists find food that stops us getting fat,” (all in the Daily Express in the past couple of weeks[7]) entertaining though they are. Fascinating news and advances come out of the cancer molecular/cell biology field each week, but either the interesting stories pass under the radar of the newspaper editors, or by the time the story makes it to print it has been mangled beyond recognition.
References
- ^ Halaban, R. 2005. Rb/E2F: A two edged sword in the melanocytic system. Cancer and metastasis reviews 24:339-356. Full Text
- ^ Rajalingama, K., R. Schrecka, U.R. Rappa and Š. Albert. 2007. Ras oncogenes and their downstream targets. BBA Molecular Cell Research Article in Press. Full Text
- ^ Olayioye, M.A., 2001. Intracellular signaling pathways of ErbB2/HER-2 and family members. Breast Cancer Res 3:385-389 Full Text
- ^ Mitelman F., B. Johansson, and F. Mertens. 2007. The impact of translocations and gene fusions on cancer causation. Nat Rev Cancer 7(4):233-45. Full Text
- ^ Alvarez, R.H., H. Kantarjian, and J.E. Cortes. 2007. The biology of chronic myelogenous leukemia. Semin Hematol. 44(1):S4-14.
- ^ reviewed in Weavera, B.A.A. and D.W. Cleveland. 2006. Does aneuploidy cause cancer? Current Opinion in Cell Biology 18(6):658-667 doi
- ^ Daily Mail Watch, April 2007 archives