cells, regulated by cancer stem cells. all cancers arise as a result of somatic evolution, but only some of them fit the cancer stem cell hypothesis. the evolutionary processes do not cease when a population of cancer stem cells arises in a tumor. cancer treatment drugs pose a strong selective force on all types of cells in tumors, including cancer stem cells, which would be forced to evolve resistance to the treatment. cancer stem cells do not always have to have the highest resistance among the cells in the tumor to survive chemotherapy and re-emerge afterwards. the surviving cells might be in a special microenvironment, which protects them from adverse effects of treatment. it is currently unclear as to whether cancer stem cells arise from adult stem cell transformation, a maturation arrest of progenitor cells, or as a result of dedifferentiation of mature cells. somatic evolution in therapeutic resistance therapeutic resistance has been observed in virtually every form of therapy, from the beginning of cancer therapy. in most cases, therapies appear to select for mutations in the genes or pathways targeted by the drug. resistance to methotrexate some of the first evidence for a genetic basis of acquired therapeutic resistance came from studies of methotrexate. methotrexate inhibits the dihydrofolate reductase (dhfr) gene. however, methotrexate therapy appears to select for cells with extra copies (amplification) of dhfr, which are resistant to methotrexate. this was seen in both cell culture and samples from tumors in patients that had been treated with methotrexate. resistance to 5-fluorouracil a common cytotoxic chemotherapy used in a variety of cancers, 5-fluorouracil (5-fu), targets the tyms pathway and resistance can evolve through the evolution of extra copies of tyms, thereby diluting the drug's effect. resistance to bcr-abl targeting drugs in the case of gleevec (imatinib), which targets the bcr-abl fusion gene in chronic myeloid leukemia, resistance often develops through a mutation that changes the shape of the binding site of the drug. sequential application of drugs can lead to the sequential evolution of resistance mutations to each drug in turn. gleevec is not as selective as was originally thought. it turns out that it targets other tyrosine kinase genes and can be used to control gastrointestinal stromal tumors (gists) that are driven by mutations in c-kit. however, patients with gist sometimes relapse with additional mutations in c-kit that make the cancer cells resistant to gleevec. resistance to egfr targeting drugs gefitinib(iressa) and erlotinib (tarceva) are epidermal growth factor receptor (egfr) tyrosine kinase inhibitors used for non-small cell lung cancer patients whose tumors have somatic mutations in egfr. however, most patients' tumors eventually become resistant to these drugs. two major mechanisms of acquired resistance have been discovered in patients who have developed clinical resistance to gefitinib or erlotinib: point mutations in the egfr gene targeted by the drugs, and amplification of met, another receptor tyrosine kinase, which can bypass egfr to activate downstream signaling in the cell. in an initial study, 22% of tumors with acquired resistance to gefitinib or erlotinib had met amplification. to address these issues, clinical trials are currently assessing irreversible egfr inhibitors (which inhibit growth even in cell lines with mutations in egfr), the combination of egfr and met kinase inhibitors, and hsp90 inhibitors (egfr and met both require hsp90 proteins to fold properly). in addition, taking repeated tumor biopsies from patients as they develop resistance to these drugs would help to understand the tumor dynamics. resistance to selective estrogen receptor modulator drugs selective estrogen receptor modulators (serms) are a commonly used adjuvant therapy in estrogen-receptor positive (erα+) breast cancer and a preventive treatment for women at high risk of the disease. there are several possible mechanisms of serm resistance, though the relative clinical importance of each is debated. these include: loss of estrogen receptor alpha (erα) although this may be a mechanism of resistance in a minority of women, most erα+ tumors that become resistant to serms remain erα+ increased relative expression of erβ compared to erα interference/cross-talk with growth factor signaling pathways such as egfr/her2 mutations in estrogen receptors alterations in co-regulatory proteins interactions between the serm, er, and co-regulatory proteins may influence whether the serm acts as an estrogen antagonist or as an estrogen agonist. reduced metabolic activation of tamoxifen polymorphisms in cyp2d6 show variable rates of conversion of tamoxifen to its activated, anti-estrogenic form. resistance to anti-androgen therapy most prostate cancers derive from cells that are stimulated to proliferate by androgens. most prostate cancer therapies are therefore based on removing or blocking androgens. mutations in the androgen receptor (ar) have been observed in anti-androgen resistant prostate cancer that makes the ar hypersensitive to the low levels of androgens that remain after therapy. likewise, extra copies of the ar gene (amplification) have been observed in anti-androgen resistant prostate cancer. these additional copies of the gene are thought to make the cell hypersensitive to low levels of androgens and so allow them to proliferate under anti-androgen therapy. resistance to radiotherapy resistance to radiotherapy is also commonly observed. however, to date, comparisons of malignant tissue before and after radiotherapy have not been done to identify genetic and epigenetic changes selected by exposure to radiation. in gliomas, a form of brain cancer, radiation therapy appears to select for stem cells, though it is unclear if the tumor returns to the pre-therapy proportion of cancer stem cells after therapy or if radiotherapy selects for an alteration that keeps the glioma cells in the stem cell state. harnessing evolution in therapeutics cancer drugs and therapies commonly used today are evolutionary inert and represent a strong selection force, which leads to drug resistance. a possible way to avoid that is to use a treatment agent that would co-evolve alongside cancer cells. anoxic bacteria anoxic bacteria could be used as competitors or predators in hypoxic environments within tumors. scientists have been interested in the idea of using anoxic bacteria for over 150 years, but until recently there has been little progress in that field. according to jain and forbes, several requirements have to be met by the cells to qualify as efficient anticancer bacterium: the bacterium cannot be toxic to the host. its population should be restricted to the tumor mass. it should be able to disperse evenly throughout the neoplasm. at the end of the treatment bacterium should be easily eliminated from the host. it should not be causing severe immune response. it should be able to cause tumor cells death through competition for nutrients. in the process of the treatment, cancer cells are most likely to evolve some form of resistance to the bacterial treatment. however, being a living organism, bacteria would coevolve with tumor cells, potentially eliminating the possibility of resistance. possible limitations since bacteria prefer an anoxic environment, they are not efficient at eliminating cells on the periphery of the tumor, where oxygen supply is efficient. a combination of bacterial treatment with chemical drugs will increase chances of destroying the tumor. oncolytic viruses oncolytic viruses are engineered to infect cancerous cells. limitations of that method include immune response to the virus and the possibility of the virus evolving into a pathogen. natural selection by manipulating the tumor environment, it is possible to create favorable conditions for the cells with least resistance to chemotherapy drugs to become more fit and outcompete the rest of the population. the chemotherapy, administered directly after, should wipe out the predominant tumor cells. glossary mapping between common terms from cancer biology and evolutionary biology: driver mutation — a mutation that gives a selective advantage to a clone in its microenvironment, through either increasing its survival or reproduction. driver mutations tend to cause clonal expansions. passenger mutation — a mutation that has no effect on the fitness of a clone but may be associated with a clonal expansion because it occurs in the same genome with a driver mutation. this is known as a hitchhiker in evolutionary biology. clone — a set of cells that all descend from a common ancestor cell. a clone is usually distinguished through inheritance of a distinctive genetic lesion (mutation) that occurred in the ancestor cell. neoplastic progression — the somatic evolutionary process by which normal tissue changes into malignant (cancerous) tissue.