I often get asked what cancer is when people find out I do cancer research for a living and the whys and the wherefores thereof inevitably follow in conversation. The complexities of the disease often mirror the complexities of the bodies they plague and therefore I decided it might be good to get a few things written down that people could be pointed to in an effort to make things a little more lucid and also to serve as a compilation of resources people could delve into if they so desired. So here it is…
Omnis cellula e cellula
All known living organisms are made of cells, in most cases, one cell on its own is an organism, obtaining food from the environment, breathing, growing, multiplying, and carrying out a whole assortment of other life processes that are of interest to biologists, but I digress.
Cancer is fundamentally a disease of organisms that are made of communities of cells – these cells too do all of the above, but some of the more complex varieties of multicellular organisms show specialisation – brains and lungs and guts and genitals – all for the same purposes, to obtain energy, to stay alive and to reproduce; not that there is some grand predisposition to doing this with foresight, merely that those that stumble onto what is passable in the examinations posed by the brutal machinations of nature get to go on.
Starting from one cell,multicellular organisms expand to have several tissues, a whole paraphernalia of different types of cells. Some cells die out, some stay on but don’t divide unless required to make more cells, some double in number until they stumble across a battery of conditions – other cells, other molecules that tell them to stop growing, or those that induce them to multiply in a frenzy but then stop when balance has been restored.
This behaviour of cells, and the organs they form, and then the organ systems that they comprise, and the organisms themselves, emerge from interactions of the environment, both consisting of organisms and other things that appear prosaic but are nonetheless significant influences on the fates of organisms with the delightfully messy workings of the molecules within cells – from the DNA that contains all the genetic material of a cell that simply must be passed on from generation to generation to facilitate survival of the species.
Dawkins in his magnum opus; “The Selfish Gene”, popularised the notion of organisms serving as mere means for the continued survival of genes, but I shall go one step further and put it to you it isn’t just individual genes that are selfish, it is entire genomes (a collection of all the DNA in a cell/organism). Promiscuity is favoured by nature when rivals are less promiscuous and when it is possible to brutally stifle threats posed by the competition, and cancer essentially is this being taken to a horrifying extreme when genomes find ways to be malignantly selfish at the expenses of the other cells that are also integral to the survival of the organism, bringing with it much suffering and often, death…for alas! Cancer cells lack the foresight to know that their fate is tied inextricably with that of their hosts.
Of DNA, RNA and proteins…
Genomes are made of DNA, and this is the medium by which information gets passed on from generation to generation except in the case of a few viruses, but we don’t really consider viruses to be living things because they cannot reproduce on their own. But in order to help them do this, cells orchestrate a variety of biochemical functions through the medium of RNA that is transcribed from DNA, which by itself can affect other RNA or for some genes gets turned into proteins. RNA, proteins and DNA then interact with the outside environment, other DNA and proteins to give rise to the chemistry that leads to the formation of cells and organisms. This complexity is described elsewhere on the blog    and I will add links and notes at the end so you’ll be able to explore further if it interests you.
On the road towards understanding cancer…we discover cancer causing genes have cellular origins.
Towards the dusk of the first decade of the 1900s, Peyton Rous made a discovery that would shape perspectives towards cancer research for a long long time to come – he found that cancers in chicken could be transmitted akin to other known viral diseases – and the causative agent he isolated came to be known as Rous Sarcoma Virus (RSV). This immediately led people to believe that cancer was essentially a viral disease, until Michael Bishop and Harold Varmus made a revolutionary discovery – that the genes that caused cancer had a cellular origin – at some point, the virus had by sheer accident incorporated this gene while it was packaging itself up, and had no problems transmitting it because it could spread before the chickens died of cancer.
They got their hands on two strains of RSV, one with cancer causing properties, and one without, and consequently one could identify the viral gene that caused cancer as the one that was present in the former but not the latter. They made a probe of a molecule called RNA, which I shall describe later, to look for similar genes in cells, and then they found that it bound to the DNA of cells from different species, and in every species it happened to be found in the same place in the genomes of the cells (genomes are made of DNA); that gene that had been rampaging through chickens when transmitted through the virus was also found in normal cells, and when switched on in very high levels due to lots of replicating viruses, caused cells to lose control of how they grew and to take part in a frenetic orgy of cellular division, it was, in effect, an oncogene.
Then they looked elsewhere for genes with similar properties and began to identify more and more, which in cancer cells had defects in DNA that affected the function of the proteins they produced and consequently acted to launch the cells into rapidly increasing their cell numbers. On the other hand, people began to find proteins which, when altered, lost the ability to stop cells from dividing uncontrolled, these genes came to be known as tumour suppressors  and one of the breakthroughs in learning about the function of these genes came was the elucidation of Knudson’s “Two-hit” hypothesis…
Looking at genes implicated as either oncogenes or tumour suppressors people began to stumble across changes in DNA sequence compared to the sequences in normal cells that affected the proteins the genes made. These mutations, as we describe them, established the foundations of cancer genetics and genomics.
The hallmarks of cancer.
As people found more and more oncogenes and tumour suppressors they wondered what cancer was, for here was a set of diseases stemming from various tissue types that all appeared to consist of cells that grew rapidly and in many cases spread through the body, albeit at different rates. A seminal paper by Hanahan and Weinberg defined the hallmarks of cancer – traits that any disease that qualifies as a cancer *must* possess…
These include the ability to multiply abnormally without requiring external signals, and if external signals that stop normal cells from dividing are present, not pay heed to them, the failure to undergo apoptosis (a form of cell death), immortalisation, which is the ability to divide indefinitely in permissive conditions unlike normal cells, angiogenesis, where tumours induce the formation of blood vessels so they can establish a bloody supply and finally, and most critically, metastasis; the ability to spread through the body and colonise other sites in the body, which is incidentally what is thought to kill patients.
There was a recent update to the classical set of hallmarks described about and three new hallmarks entered the fray – altered cell metabolism; changes in how cancer cells generate energy, inflammation; a molecular response to wounds and injuries in normal cells that goes wrong and promotes cancer metastasis and genome instability – being prone to mutations and other structural aberrations that generate the complexities of cancer genomes, which I describe later …
More than just mutations, and how we came to find out…
People who had been studying families of proteins called transcription factors noticed that they could fundamentally alter the way the RNA of different genes in the genome was produced – they could alter when they were produced, and how much was produced. This could then affect other proteins that controlled how cells divided and interacted with the environment, in some cases, transcription factors were found to be mutated, such as p53, which is also known as the guardian of the cell because of its critical role in stopping errant cells from progressing to cancer , which explains why so many tumours modify p53 function so they can get round it,and with this came the idea that cancers would exhibit differences in gene expression relative to normal tissue and this would then contribute to the achievement of the hallmarks of cancer. See  for a description of microarrays and case studies of how looking at expression profiles helped understand cancers.
People also realised that you could get changes in expression patterns independent of transcription factors… Cancer cells are host to a wide variety of large, structural, distortions of the genome, and compared to normal cells, which have 46 chromosomes, cancer cells accumulate a variety of aberrations, ranging from small deletions and duplications of bits of chromosomes to gains and losses of whole chromosomes, or in some cases whole sets of chromosomes (The ubiquitously used cancer cell line, HeLa, has 88 chromosomes).
Changes in copy number of genes through these aberrations could also have effects on gene expression profiles. Finally, people who’d been studying epigenetic processes, which involve cells inheriting expression patterns for instance and then modifying them through modifications of DNA without changes in sequence, such as DNA methylation and Hydroxymethylation or the histones around which DNA is wound , and began to develop techniques to characterise epigenetic changes in tumours, and we therefore ended up in a situation where we had a whole panel of analyses we could do on tumours.
The Cancer Genome Atlas
While several other tumour sequencing projects were underway at the likes of the Wellcome Trust Sanger Institute, The Cancer Genome Atlas really set things going ahead with their project on the deadly brain cancer; Glioblastoma Multiforme, with sequencing for mutations, microarray analysis for Copy Number Variation and gene expression and microarray analysis for DNA methylation. They essentially found that there are four groups of glioblastomas based on patterns in gene expression and were able to correlate these with different cellular origins and different ways in which those expression profiles were achieved .
They also found a subset of tumours that had very high levels of methylation driven by mutations in a gene called IDH1, which leads to too much methylation as a direct consequence, as demonstrated in a landmark paper in the journal Nature, where they put in mutant IDH1 into astrocytes and showed it induced high methylation levels like those seen in gliomas of that type…
Since then, the TCGA has published multiple studies on breast cancer, ovarian cancer, renal clear cell carcinoma,lung adenocarcinoma and colorectal cancer to name a few  and is collecting data for more tumour types, and from 12 datasets so far a pan-cancer analysis was released recently . This has inspired the formation of the even more ambitious International Cancer Genome Sequencing Consortium which aims to widely expand the scope and the size of the type of approaches taken by the TCGA to profile the most striking molecular features of tumours and to then relate them to clinical information.
Things are not quite so simple – the problem of heterogeneity.
One would think that by understanding the make-up of tumours and figuring out what drives them, it would be easy to target altered genes, proteins and pathways with specific drugs to achieve cures, however, tumours have such unstable genomes and often contain so many cells by the time they’re detected that they are capable of a great degree of evolution, which may become reflected in resistance to the drugs used to target them. Indeed, studies starting two years ago began to show two features of tumours, firstly; they evolved through time, and therapy often had an influence on which dominant properties were seen in a patient’s disease as they relapsed. They either saw that the most dominant clone before treatment acquired new mutations and then evolved to resist therapy or a previously minor clone expanded.
At around the same time, evidence was found to strongly support the notion that cancers not only evolved in a linear manner but could evolve in parallel. Both those studies were carried out on leukaemias and the same was shown to be true of solid tumours. An analysis of a kidney tumour looking at multiple regions of the primary tumour and metastases (new outgrowths of the tumour derived from cells that had spread from the primary tumour) highlighted branched evolution and also observed that different parts of the primary tumour showed different patterns of gene expression associated with survival .
A recent study looking at multiple regions from a series of glioblastomas also found the same striking pattern; there was evidence that all four of the glioma expression subtypes discovered by the TCGA were found in that tumour . These studies have made one thing abundantly clear; that understanding and classifying tumours into subgroups may be of limited utility when the range of evolutionary invention achieved by tumours permits them to acquire different patterns of alterations for the most part in response to therapy. We will learn a lot, indubitably, from large scale analyses of the kinds already being carried out, and only recently we began to uncover what processes might contribute to the formation of mutations and how to find signatures for mutations from all that data being generated by sequencing tumour after tumour after tumour, so chances are we will have a comprehensive collection of molecular profiles to tuck into, soon, on an unprecedented scale.
Finding chinks and causes for optimism…
Another way weaknesses might be found in tumours involves approaches based on what we call synthetic lethality and collateral lethality. Synthetic lethality is when, because a gene is mutated or altered otherwise, another gene becomes essential while it was not essential if the other gene was intact. A classic example of this is PARP inhibition. PARP is an enzyme that repairs breaks in DNA, but can be dispensed with if the BRCA genes are intact. A significant proportion of Ovarian and Breast cancers, especially those that run in families, show a characteristic loss of BRCA1 or BRCA2, and this makes them especially vulnerable to the blockade of PARP.
One way of finding synthetic lethal interactions is to combine knockdown experiments, where little RNA sequences are introduced into cells to block and degrade the RNA of target genes and not permit protein to be formed from that RNA and combining that information with mutation, expression and other “-omics” data as we call them. Even without -omics data in attendance, knockdown experiments themselves can reveal certain genes that come to be required specifically in cancer, and in that way we can identify targets for chemists to then develop specific drugs against. Of course, the other approach would be to target things that appear to transcend cancers, and examples include targeting a protein called CD44 that cancer cells appear to universally express to avoid being destroyed by the immune system or to use drugs that target fundamentally common features of tumours such as DNA methylation .
Finally, knowledge of tumour evolution itself may be employed to find weaknesses, as described elsewhere on the blog, the mechanism of resistance may by itself predispose tumours to weaknesses, and this could be as simple as withdrawing the drug (letting go of the brakes suddenly when the driver’s still got the foot on the pedal to compensate for jammed brakes till that point), as discussed here .
Dealing with heterogeneity may be rendered possible by bypassing resistance mechanisms where cancers find alternate pathways to get to where they need to be to survive and expand by hitting points that are altered in cancer, but have no known alternatives for tumours to route their functioning through. Indeed, this has been shown experimentally by targeting Myc, which when activated is a potent oncogene or by targeting BIM in glioblastoma where tumour cells evolve resistance by finding other ways to prevent BIM from being turned on when the pathway they usually use to do this is blocked with drugs.
For all the complexities of cancer, there might still be ways in which we will figure out how to target and attack them successfully, and one of the keys to that I think the sense of scale and community that cancer research projects these days are marked by. I think the enduring impact of the Human Genome Project  was not just the sequencing of the human genome, but ensuring that data was openly accessible to anybody who wanted to use it for their research or look at it for general interest; the TCGA and ICGC have put in place similar policies to govern how their data is accessed, and by allowing researchers to integrate the research they do locally with data that wouldn’t have been generated without big projects like them it is possible to achieve so much more. And maybe we’ll figure out what cancer is, and then determine what they can and can’t be, someday, soon…
Links to posts on the workings of DNA, RNA and proteins.  https://exploreable.wordpress.com/2011/02/19/the-central-dogma-of-molecular-biology/ (Central Dogma of Molecular Biology)
 https://exploreable.wordpress.com/2011/01/14/right-just-as-promised-here-comes-rna-interference/ (Includes descriptions of microRNAs, RNA species that can block other RNAs from being converted to protein as per the central dogma, thereby affecting gene expression).
Oncogenes, Tumour Suppressors and the Hallmarks of Cancer
 https://exploreable.wordpress.com/2011/10/05/oncological-complications-models-surrounding-tumour-suppression/ (Contains an exposition of the two-hit theory of cancer causation and links to further material on the topic, as well as nuance about how some tumour suppressors behave differently)
 http://www.cell.com/retrieve/pii/S0092867411001279 (Updated version of the classic paper; The Hallmarks of Cancer by Hanahan and Weinberg. May be paywalled).
 https://exploreable.wordpress.com/2011/11/03/the-p53-barcode-a-brief-introduction/ (Explains how p53 functions in different contexts, basically)
Understanding Cancers and large scale analyses
 http://www.nature.com/scitable/topicpage/genetic-diagnosis-dna-microarrays-and-cancer-1017 (Nature Scitable article on gene expression and cancer).
 https://exploreable.wordpress.com/2012/01/22/an-introduction-to-epigenetics/ (An introduction to epigenetic processes).
 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2818769/ (The TCGA glioblastoma paper that documented four expression subtypes).
 https://tcga-data.nci.nih.gov/docs/publications/ (a list of papers from The Cancer Genome Atlas, most papers are openly accessible and readable should you want to, but they’re science heavy and really written for people with an in-depth understanding of cancer research. You may be able to search for materials and commentary related to them to get a more popular perspective, also look for TCGA press releases on the same site).
 http://blogs.nature.com/freeassociation/2013/09/focus-tcga-pan-cancer.html (Blogpost on the Nature blogging network containing links to further material, commentary and analysis papers from the TCGA pan-cancer project.)
Heterogeneity, synthetic lethality and the future
 https://exploreable.wordpress.com/2012/09/22/a-very-short-introduction-to-intratumour-heterogeneity/ (Blogpost on intratumour heterogeneity)
 http://www.pnas.org/content/110/10/4009.full (Paper documenting intratumour heterogeneity in glioblastoma multiforme)
 https://exploreable.wordpress.com/2013/02/24/more-is-not-always-merrier-methylation-version/ (Blogpost discussing broad spectrum effects of low doses of the DNA methylation blocker decitabine) .
 https://exploreable.wordpress.com/2013/06/21/a-window-into-acquired-resistance-to-targeted-therapies-through-the-eyes-of-a-mek-inhibitor/ (Blogpost exploring reports of how cancer cells evolved resistance to a drug and how this could be used to target the tumour).
 https://exploreable.wordpress.com/2011/05/03/the-story-of-the-human-genome-project-a-short-narration/ (Long blogpost on the Human Genome Project, written by yours truly and therefore recommended if you are a glutton for a few thousand words more having worked your way through to the end of the article).
That’s all from me now!