Following a friend’s advise (thanks Simon!), for my trip to a meeting organised at Cold Spring Harbor I brought and started reading Jerry Coyne’s book Why evolution is true.
The book is interesting and makes an enjoyable read (unless you are a creationist, that is). The first chapter summarises the modern view on evolution. According to Coyne it all boils down to the following statement: Life on Earth evolved gradually beginning with one primitive species – perhaps a self replicating molecule – that lived more than 3.5 billion years ago; it then branched out over time, throwing off many new and diverse species; and the mechanism for most (but not all) of evolutionary change is natural selection. Coyne’s six main components of evolution are : evolution, gradualism, speciation, common ancestry, natural selection and non selective mechanisms of evolutionary change. As (somatic) evolution is an important force driving cancer progression I thought it would be an interesting exercise to see how this components work in the context of cancer. Notice that this is not the first time somatic and non somatic evolution have been compared [ link ].
Evolution. That looks interesting, an ingredient of evolution is … evolution! But one feature of biological evolution is that species evolve, that is, change over time. Same for cancers, where the importance of tumour cell diversity has been recognised for a few decades (Science 1 October 1976:Vol. 194. no. 4260, pp. 23 – 28).
Gradualism. In most species, changes are gradual and new species do not appear from one generation to the next but through sequential comparatively small transformations that, eventually allow for an entire new species to emerge. In the case of cancer this is still a controversial topic as chromosomal instability is thought by many to be a common event during tumour progression, could significantly alter a cell phenotype in one single event [American Journal of Pathology, Vol. 154, No. 6, June 1999 , page 1621).
Speciation and common ancestry. Coyne mentions that these two are the two sides of the same coin although their applicability to cancer is unclear in my opinion. Speciation is commonly defined in terms of mating so one species is defined by the capability of its members of having offspring that can procreate. Since somatic cells divide asexually that measurament of species is useless in the context of cancer. An alternative one based on the differences in the genome is surely a better approach but defines species in a less clear-cut manner. An approach based on phenotypical features would not come without controversy (as there’s plenty of room for overlapping phenotypes) but since phenotypes are what selection acts on they may be the better approach.
Natural selection. That is something that works the same in the forests of Indonesia and in a tumour. Different phenotypes that can pass on their features to their offspring, put in a place in which they have to compete for limited resources (and resources are always, in the long term, limited) will undergo a proccess by which some will do better than the others and will, over time, represent an increasing part of the population…of the forest or of the tumour. What can we guess about these more successful phenotypes? they should be the ones that are more adapted and know how to better get the resources but, also, they are the ones that are better prepared to change when the environment changes and the needs are different.
Non selective mechanisms of change. This is an interesting observation by Coyne. There’s genetic drift on genes whose product does not affect the capabilities of the phenotype to adapt. When I was working evolutionary computing that was known as neutrality. A gene that has no discernible impact on the phenotype is not going to affect evolution right? Well, turns out to be not entirely true. Evolution depends on genetic history to operate. A wing does not appear out of nothing but from something already existing that can be transformed. What is not there cannot be transformed into something useful for adaptation. Neutral genes might be neutral in one context but can become very useful at some other point when circumstances change and so does natural selection. Genetic drifting allows tumours to acquire genetic diversity (even if phenotypically looks similar) that can be useful when the micorenvironment changes.
One element that is not in Coyne’s list that I think will affect out view of evolution and cancer is development. The role of cells that can differentiate and become (or produce) something else during development and wound healingis likely to have an effect on cancer progression and behaviour without changing the fact that somatic evolution is driving it.
So far this summarises my understanding on the topic but I know that some people reading this blog are likely to have a different take on this, so opinions and feedback are particularly welcome!
Hi David,
Hope that you enjoy the book, I know that the readers of your blog are not exactly the target audience however I found it very informative and I would certainly encourage everyone else to take a look. Coyne does a great job of bringing together the evidence for many different directions to establish the synthesis that is encompassed by modern evolutionary biology. His comments on evolution vs religion also spawned a wonderful series of articles on Edge, which anyone interested, who hasn’t seen them should take a look at, here
Sorry to advertise someone else on your blog!
Getting back to the cancer issue, there is a quote attributed to Darwin along the lines of “It is not the strongest of the species that survives, nor the most intelligent, but [rather] the [one] most responsive to change.” Like many of these quotes nobody actually seems to know where it comes from but it really doesn’t matter. Cancer can give rise to some very aggressive phenotypes but these can also be the most susceptible to the (woefully lacking) range of drugs currently at or disposal. Hence some of the most aggressive tumors can turn out to be definitively treatable while slower growing tumors can recur and cause problems, (I know this is a gross oversimplification).
This could relate to your comments on common ancestry. There has been a lot of work on gene (notably tumor suppressor gene) silencing (both genetic and epigenetic) and also on oncogene activation. However I’m less aware of studies looking at whether genes can be sequentially switched off and on by tumor cells based upon specific need – so if there is an unfavorable change (for example a drug hits fast growing cells) is there the ability to select a slower growing line temporarily by genetic/epigenetic regulation to revert towards a more normal phenotype? I know this result could be obtained in some of the mathematical models that the owner of your office espresso machine works on, but this would seem to be an area in which biologists should also contribute. Except in cases where chunks of chromosomes are deleted common ancestry would appear relevant, and methods to activate a more normal gene expression pattern, for example using demethylation approaches give a possibility to explore the consequences of such manipulations.
Enjoy the book.
Hi Simon,
Thanks for sharing your opinion. I am definitely enjoying the book and learning more and more facts that confirm evolution (as opposed to the mostly purely intellectual idea that I have on the topic, that is, genetic inheritance of diverse types affected by selection has to lead to evolution. Having so many samples certainly helps).
The mechanism you suggest by which tumour cells produce and stop expressing certain genes in order to be able to adapt to a changing environment is likely to be true in certain circumstances (and I say that talking as a theoretician only!). My feeling is that being able to adapt is always going to be a powerful evolutionary mechanism but I guess it is not a necessity. It would depend on the cost of being adaptable and also on how changing is the environment for this adaptability to be of any practical use. This is of course easier to study on a computer (or on a notepad!) than in a lab unfortunately.
So going back to Darwin’s quote, I’d agree that it is the most responsive to change the one that will survive…everything else being equal. Otherwise we would have to see how much of the fitness cost this adaptability represents as some very adaptable (but fitness expensive) phenotypes might not have the change to establish a beach-head from which to spread through the population when the adaptability is needed.
Evolution, Natural Selection and Cancer
The mechanism David Basanta suggested by which tumour cells are produce in human and stop expressing certain genes in order to be able to adapt to a changing environment is likely to be true in certain neoplasm that being able to adapt is always going to be a powerful evolutionary mechanism The key phenomenon of expressing theory of natural selection in Darwinian evolution are probably three. 1) Adaptation- is most important 2) conflict in population 3) environment. Human adaptation is a procedure through which a gene can promote its self replication. Differences in gene then gives rise to differences in adaptation, resulting some gene out replicating others (fitness) and thus through few successive generations a gene can accumulate more and more information when it is needed to replicate. We can see it and a gene thus uses human individual to make more replicas of gene with better adaptation.
The most surprising fact came out on completion of species specific gene sequencing which showed how similar we some species are! The mice genome does not differ much with human genome. The chimpanzee genome is almost and close copies of the human genome. The dorsephellia( Fruit fly) and human being share a great and many same genes likeHomeo box gene. Hox gene function biochemicaly to regulate the transcriptional activities of multitude of other genes that carry out differentiation of order of body segments [ and thus a human has Head neck, Thorax, Abdomen- as similar as a dorsephellia fly has], in signal transduction cascades( mutation of these genes can result disruption of cell cycle- resulting excessive growth- Neoplasia). Genes for Tyrosine kinase receptors, Ras for MAP Kinases cascade, rolled, notch genes for retinal photo receptor cell types, neuronal precursors differentiation and oocyte related genes)
What am I? What are you? I’m just collection of genes bag in my different cells. Different cells in function due to different methylation? My proteins, my fats, my carbohydrates, and so on and at sub cellular level I am just DNA sequences for my memory, for my intelligence, for my beating heart for my liver enzymes. _ all are my functioning proteins. For every species this is however true. Then what was the mechanism that shaped me a human? It is probably the Epigenetic that made me human.
the DNA methylation process that differs conservation of gene expression amongst different organ cells of a species, of an individual human and amongst different species and it is associated with conservation of DNA methyl profile.- Epigenetic thus refers to dynamic chemical modification that occur in our DNA and its subsequent association with regulatory proteins. The best recognized epigenetic modification is addition of methyl group to DNA and post transcriptional modification of Histones
Histones are organizing DNA in nuecleosomes., DNA methylation takes very important role for control of gene activities and for nuclear structure. And in human it occurs in CpG islands which are non randomly distributed in human genome. CpG islands are commonly and usually remain un methylated in normal cells and this un methylated status helps in transcriptional process through transcriptional activators. However some genes like repetitive genomes , tissue specific, germ line specific genes are heavily methylated. The maintenances of methylation state has an important role in preventing chromosomal instability and thus not stimulating oncogene.
There are two major classes of cancer genes. The first class comprises genes that directly affect cell growth either positively (oncogenes) or negatively (tumor-suppressor genes). These genes exert their effects on tumor growth through their ability to control cell division (cell birth) or cell death (apoptosis). Oncogenes are tightly regulated in normal cells. In cancer cells, oncogenes acquire mutations that relieve this control and lead to increased activity of the gene product. This mutational event typically occurs in a single allele of the oncogene and acts in a dominant fashion In contrast, the normal function of tumor-suppressor genes is to restrain cell growth, and this function is lost in cancer. Because of the diploid nature of mammalian cells, both alleles must be inactivated to completely lose the function of a tumor-suppressor gene, leading to a recessive mechanism at the cellular level. From these ideas and studies on the inherited form of retinoblastoma, Knudson and others formulated the two-hit hypothesis, which in its modern version states that both copies of a tumor-suppressor gene must be inactivated in cancer. The second class of cancer genes, the caretakers, does not directly affect cell growth but rather affects the ability of the cell to maintain the integrity of its genome. Cells with deficiency in these genes have an increased rate of mutations in all the genes, including oncogenes and tumor-suppressor genes. This “mutator” phenotype was first hypothesized by Loeb to explain how the multiple mutational events required for tumorigenesis can occur in the lifetime of an individual. A mutation phenotype has now been observed in cancer at both the nucleotide sequence and chromosomal levels.Epigenetic disruption is characteristic of many human solid cancers including bladder cancer and of Leukemias. Hypo methylation of DNA was found first epigenetic alteration found in human solid cancers and this hypo methylation is found in Repetitive DNA sequences those are evolutionary in origin. However there are many cancers like breast cancer where hyper methylation (like in BRCA1 gene) is detected. Micro RNAs with tumor suppressor factor are also silenced in Cancer cells By DNA Hypermewthylation. In leukemia translocations involve histone acetyl transferases and Methyle Transferase genes1 Gene encoding MRNAs with 3` containing multiple set of Let-7 complementary sites are also found. Let-7 hasalso important role in development of human cancer. Over expressionof Let-7 repress and inhibition of native let7 enhances expression ofRas protein.Let-7 complementary sites in human N Ras, Kras 3`UTRspecifically mediate let-7 dependent repression. Down regulation ofexpression of let-7 may be hence marker of Lung cancer, squamouscell cancer and indicate poor prognosis.
Global DNA hypomethylation contributes to origin of cancers by generation of chromosomal instability, translocation, reactivation of transposoble elements & loss of genetic material. Patterns of DNA methylation in cancer cells deviate from those in healthy cells. In particular, selected CpG-islands (CpG-rich regions typically located around gene transcription start sites) become hypermethylated. Paradoxically, at the same time, the amount of 5-methylcytosine across the genome is often diminished, a phenomenon termed global hypomethylation. These changes are to some extent specific for tumour type and stage. For example, in bladder cancer, global hypomethylation is widespread from early stages, whereas the frequency and density of CpG-island hypermethylation increase with tumour stage and grade. Progress in past years suggests that hypermethylation might be caused by an aberrant reactivation of protein complexes, which normally mediate the silencing of genes by DNA methylation and chromatin remodelling during development. The causes of hypomethylation remain unknown. Factors discussed include defective coordination between cell cycling pathways and DNA methyltransferase action or DNA demethylase activity Furthermore, maintenance of DNA-methylation patterns during cell proliferation needs adequate concentrations of the methyl group donor S-adenosylmethionine (SAM). In tumour cells, hyperproliferation and the associated increased requirement for methionine and nucleotide precursors, might restrict the amount of intracellular SAM. Therefore, global hypomethylation could result from insufficient amounts of methyl-group donors. Indeed, decreased 5-methylcytosine concentrations are also seen in leucocytes of healthy people with inadequate supplies of essential nutrients, such as folate, vitamin B12, and methionine that are needed for effective methylation. Importantly, nutritional deficiencies are exacerbated by several genetic polymorphisms that change the activities of enzymes involved in SAM synthesis and recycling. The combination of a poor diet and an unfavourable genotype might therefore predispose to cancer2
A cancer cell also needs massive adaptive changes for its survival, and metastasis. As for example it needs creation of new vascular supply, needs nerve innervations, for its metastasis needs secretion of E cathedrin molecules which are all probably some sort of adaptive changes for its hostile environment in the host’s new places . The cell adherence E- Cathedrin gene becomes methylated and are silenced inducing the metastasis. The cancer cell in new location are to be survived and have to establish on interaction with their new surroundings. Subsequent loss of methylation will thus help them to survive in the host. Out of essential differences between cancer cell genetics and epigenetic is the DNA methylation and histone modification changes are reversible under right circumstances1 and thus epigenetic alteration are one of the weakest point in the differences of cancer cells, because hypermethylated tumor suppressor genes can be reactivated with right drugs regimes and can exert their growth inhibitory functions as such two families of drugs like DNA de-methylating agents and inhibitory of histone de acetylase are most promising agents and four pharmaceuticals compounds are today approved fro treatment of leukemias, lymphomas and epithelial solid cancer by FDA. Drugs that induce DNA demethylation, such as 5-aza-2´-deoxycytidine, can lead to re expression of silenced genes in cancer cells with restoration of function. However, 5-aza-2´-deoxycytidine has limited aqueous solubility and is myelo suppressive. Other inhibitors of DNA methyltransferases are in development. In ongoing clinical trials, inhibitors of DNA methylation are being combined with HDA inhibitors3. Aberrant signal transduction pathways activate a number of transcription factors that promote tumor cell proliferation and survival. These include signal transducer and activator of transcription (STAT)-3 and STAT5, NF?, ß-catenin (a component ofthe APC tumor-suppressor pathway), the hetero dimer of c-Jun and Fos known as AP1, and c-Myc. The ability to target these transcription factors therapeutically does not currently exist. However, structural and molecular approaches may make it possible to identify small molecules that would inhibit protein-protein interactions needed for transcription factor dimerization or interaction with co activator proteins. A small-molecule inhibitor has been developed that blocks the association of Myc with its partner Max, thereby inhibiting Myc-induced transformation. Many transcription factors are activated by phosphorylation, which can be prevented by tyrosine- orserine/threonine kinase inhibitors. The transcription factor NF is a heterodimer composed of p65 and p50 subunits that associate with an inhibitor, I, in the cell cytoplasm. In response to growth factor or cytokine signaling, a multi-subunit kinase called IKK (I?B-kinase) phosphorylates I?B and directs its degradation by the ubiquitin/proteasome system. NF?B, free of its inhibitor, translocates to the nucleus and activates target genes, many of which promote the survival of tumor cells. Novel drugs called proteasome inhibitors block the proteolysis of I?B, thereby preventing NF?B activation. For unexplained reasons, this is selectively toxic to tumor cells. Further studies have indicated that the anti tumor effects of proteasome inhibitors are more complicated and involve the inhibition of the degradation of multiple cellular proteins. Proteasome inhibitors [bortezomib (Velcade)] have shown very significant activity in patients with multiple myeloma, including partial and complete remissions. Inhibitors of IKK are also in development, with the hope of more selectively blocking the degradation of I?B, thus “locking” NF?B in an inhibitory complex and rendering the cancer cell more susceptible to apoptosis-inducing agents.3 More over cancer cell also needs to acquire adaptive changes for chemotherapy, radiotherapy or hormonal therapy that makes it resistant to these agents. This is needed for it survival.
References.
1) Manel Esteller “ Epigenetic in evolution and diseases” in book “Darwin Gifts” The Lancet special issue, December b2008, Edited by ane Godsland, Ros Osmond & Piz pine; page 590-96.
2]. Wolfgang A Schulz Do DNA-methylation changes also occur in blood Lancet Oncology 2008; 9:312-313DOI:10.1016/S1470-2045(08)70083-4
3] Dan L Longo APPROACH TO THE PATIENT WITH CANCER – ONCOLOGY AND HEMATOLOGY. Section 1 – Neoplastic DisordersPART FIVE – Harrison’s Text Book of Medicine 16 th Edition
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