Abstract
All malignant cancers, whether inherited or sporadic, are fundamentally governed by Darwinian dynamics. The process of carcinogenesis requires genetic instability and highly selective local microenvironments, the combination of which promotes somatic evolution. These microenvironmental forces, specifically hypoxia, acidosis and reactive oxygen species, are not only highly selective, but are also able to induce genetic instability. As a result, malignant cancers are dynamically evolving clades of cells living in distinct microhabitats that almost certainly ensure the emergence of therapy-resistant populations. Cytotoxic cancer therapies also impose intense evolutionary selection pressures on the surviving cells and thus increase the evolutionary rate. Importantly, the principles of Darwinian dynamics also embody fundamental principles that can illuminate strategies for the successful management of cancer.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Nowell, P. C. The clonal evolution of tumor cell populations. Science 194, 23–28 (1976).
Jones, S. et al. Comparative lesion sequencing provides insights into tumor evolution. Proc. Natl Acad. Sci. USA 105, 4283–4288 (2008).
Gerlinger, M. et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N. Engl. J. Med. 366, 883–892 (2012).
Gerlinger, M. & Swanton, C. How Darwinian models inform therapeutic failure initiated by clonal heterogeneity in cancer medicine. Br. J. Cancer 103, 1139–1143 (2010).
Greaves, M. & Maley, C. C. Clonal evolution in cancer. Nature 481, 306–313 (2012).
Gatenby, R. A., Gillies, R. J. & Brown, J. S. Of cancer and cave fish. Nature Rev. Cancer 11, 237–238 (2011).
Gillies, R. J., Robey, I. & Gatenby, R. A. Causes and consequences of increased glucose metabolism of cancers. J. Nucl Med 49 Suppl 2, 24S–42S (2008).
Allred, D. C. et al. Ductal carcinoma in situ and the emergence of diversity during breast cancer evolution. Clin. Cancer Res. 14, 370–378 (2008).
Gatenby, R. A. & Gillies, R. J. A microenvironmental model of carcinogenesis. Nature Rev. Cancer 8, 56–61 (2008).
Gatenby, R. A. & Gillies, R. J. Why do cancers have high aerobic glycolysis? Nature Rev. Cancer 4, 891–899 (2004).
Loeb, L. A. Mutator phenotype may be required for multistage carcinogenesis. Cancer Res. 51, 3075–3079 (1991).
Cahill, D. P., Kinzler, K. W., Vogelstein, B. & Lengauer, C. Genetic instability and darwinian selection in tumours. Trends Cell Biol. 9, M57–M60 (1999).
Garber, J. E. & Offit, K. Hereditary cancer predisposition syndromes. J. Clin. Oncol. 23, 276–292 (2005).
Chung, C. C. & Chanock, S. J. Current status of genome-wide association studies in cancer. Hum. Genet. 130, 59–78 (2011).
Negrini, S., Gorgoulis, V. G. & Halazonetis, T. D. Genomic instability--an evolving hallmark of cancer. Nature Rev. Mol. Cell Biol. 11, 220–228 (2010).
Podsypanina, K. et al. Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems. Proc. Natl Acad. Sci. USA 96, 1563–1568 (1999).
Michiels, F. M. et al. Development of medullary thyroid carcinoma in transgenic mice expressing the RET protooncogene altered by a multiple endocrine neoplasia type 2A mutation. Proc. Natl Acad. Sci. USA 94, 3330–3335 (1997).
Ferrara, N. et al. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 380, 439–442 (1996).
Zhang, Q. et al. Acceleration of emergence of bacterial antibiotic resistance in connected microenvironments. Science 333, 1764–1767 (2011).
Davies, P. C. & Lineweaver, C. H. Cancer tumors as Metazoa 1.0: tapping genes of ancient ancestors. Phys. Biol. 8, 015001 (2011).
Goncharova, E. I., Nadas, A. & Rossman, T. G. Serum deprivation, but not inhibition of growth per se, induces a hypermutable state in Chinese hamster G12 cells. Cancer Res. 56, 752–756 (1996).
Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).
Grivennikov, S. I., Greten, F. R. & Karin, M. Immunity, inflammation, and cancer. Cell 140, 883–899 (2010).
Aggarwal, B. B., Vijayalekshmi, R. V. & Sung, B. Targeting inflammatory pathways for prevention and therapy of cancer: short-term friend, long-term foe. Clin. Cancer Res. 15, 425–430 (2009).
Papp-Szabo, E., Josephy, P. D. & Coomber, B. L. Microenvironmental influences on mutagenesis in mammary epithelial cells. Int. J. Cancer 116, 679–685 (2005).
Reynolds, T. Y., Rockwell, S. & Glazer, P. M. Genetic instability induced by the tumor microenvironment. Cancer Res. 56, 5754–5757 (1996).
Wilkinson, D., Sandhu, J. K., Breneman, J. W., Tucker, J. D. & Birnboim, H. C. Hprt mutants in a transplantable murine tumour arise more frequently in vivo than in vitro. Br. J. Cancer 72, 1234–1240 (1995).
Scheffner, M., Werness, B. A., Huibregtse, J. M., Levine, A. J. & Howley, P. M. The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell 63, 1129–1136 (1990).
Brechot, C., Pourcel, C., Louise, A., Rain, B. & Tiollais, P. Presence of integrated hepatitis B virus DNA sequences in cellular DNA of human hepatocellular carcinoma. Nature 286, 533–535 (1980).
Anand, P. et al. Cancer is a preventable disease that requires major lifestyle changes. Pharm. Res. 25, 2097–2116 (2008).
Minamoto, T., Mai, M. & Ronai, Z. Environmental factors as regulators and effectors of multistep carcinogenesis. Carcinogenesis 20, 519–527 (1999).
DeMarini, D. M. Genotoxicity of tobacco smoke and tobacco smoke condensate: a review. Mutat. Res. 567, 447–474 (2004).
Ikehata, H. & Ono, T. The mechanisms of UV mutagenesis. J. Radiat. Res. 52, 115–125 (2011).
Chitneni, S. K., Palmer, G. M., Zalutsky, M. R. & Dewhirst, M. W. Molecular imaging of hypoxia. J. Nucl. Med. 52, 165–168 (2011).
Wykoff, C. C. et al. Expression of the hypoxia-inducible and tumor-associated carbonic anhydrases in ductal carcinoma in situ of the breast. Am. J. Pathol. 158, 1011–1019 (2001).
Gillies, R. J. & Gatenby, R. A. Adaptive landscapes and emergent phenotypes: why do cancers have high glycolysis? J. Bioenerg. Biomembr. 39, 251–257 (2007).
Bristow, R. G. & Hill, R. P. Hypoxia and metabolism. Hypoxia, DNA repair and genetic instability. Nature Rev. Cancer 8, 180–192 (2008).
Klein, T. J. & Glazer, P. M. The tumor microenvironment and DNA repair. Semin. Radiat. Oncol. 20, 282–287 (2010).
Lu, Y., Chu, A., Turker, M. S. & Glazer, P. M. Hypoxia-induced epigenetic regulation and silencing of the BRCA1 promoter. Mol. Cell. Biol. 31, 3339–3350 (2011).
Mihaylova, V. T. et al. Decreased expression of the DNA mismatch repair gene Mlh1 under hypoxic stress in mammalian cells. Mol. Cell. Biol. 23, 3265–3273 (2003).
Hammond, E. M., Dorie, M. J. & Giaccia, A. J. ATR/ATM targets are phosphorylated by ATR in response to hypoxia and ATM in response to reoxygenation. J. Biol. Chem. 278, 12207–12213 (2003).
Graeber, T. G. et al. Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature 379, 88–91 (1996).
Shi, Q. et al. Constitutive and inducible interleukin 8 expression by hypoxia and acidosis renders human pancreatic cancer cells more tumorigenic and metastatic. Clin. Cancer Res. 5, 3711–3721 (1999).
Bindra, R. S. & Glazer, P. M. Genetic instability and the tumor microenvironment: towards the concept of microenvironment-induced mutagenesis. Mutat. Res. 569, 75–85 (2005).
Young, S. D., Marshall, R. S. & Hill, R. P. Hypoxia induces DNA overreplication and enhances metastatic potential of murine tumor cells. Proc. Natl Acad. Sci. USA 85, 9533–9537 (1988).
Rice, G. C., Hoy, C. & Schimke, R. T. Transient hypoxia enhances the frequency of dihydrofolate reductase gene amplification in Chinese hamster ovary cells. Proc. Natl Acad. Sci. USA 83, 5978–5982 (1986).
Otsuka, J. The large-scale evolution by generating new genes from gene duplication; similarity and difference between monoploid and diploid organisms. J. Theor. Biol. 278, 120–126 (2011).
van Sluis, R. et al. In vivo imaging of extracellular pH using 1H MRSI. Magn. Reson. Med. 41, 743–750 (1999).
Gillies, R. J., Liu, Z. & Bhujwalla, Z. 31P-MRS measurements of extracellular pH of tumors using 3-aminopropylphosphonate. Am. J. Physiol. 267, C195–203 (1994).
Morita, T., Nagaki, T., Fukuda, I. & Okumura, K. Clastogenicity of low pH to various cultured mammalian cells. Mutat. Res. 268, 297–305 (1992).
Zhang, H. Y., Hormi-Carver, K., Zhang, X., Spechler, S. J. & Souza, R. F. In benign Barrett's epithelial cells, acid exposure generates reactive oxygen species that cause DNA double-strand breaks. Cancer Res. 69, 9083–9089 (2009).
Xiao, H., Li, T. K., Yang, J. M. & Liu, L. F. Acidic pH induces topoisomerase II-mediated DNA damage. Proc. Natl Acad. Sci. USA 100, 5205–5210 (2003).
Hashim, A. I., Zhang, X., Wojtkowiak, J. W., Martinez, G. V. & Gillies, R. J. Imaging pH and metastasis. NMR Biomed. 24, 582–591 (2011).
Webb, B. A., Chimenti, M., Jacobson, M. P. & Barber, D. L. Dysregulated pH: a perfect storm for cancer progression. Nature Rev. Cancer 11, 671–677 (2011).
Radu, C. G., Nijagal, A., McLaughlin, J., Wang, L. & Witte, O. N. Differential proton sensitivity of related G protein-coupled receptors T cell death-associated gene 8 and G2A expressed in immune cells. Proc. Natl Acad. Sci. USA 102, 1632–1637 (2005).
Leffler, A., Monter, B. & Koltzenburg, M. The role of the capsaicin receptor TRPV1 and acid-sensing ion channels (ASICS) in proton sensitivity of subpopulations of primary nociceptive neurons in rats and mice. Neuroscience 139, 699–709 (2006).
Dong, X. et al. Expression of acid-sensing ion channels in intestinal epithelial cells and their role in the regulation of duodenal mucosal bicarbonate secretion. Acta Physiol. (Oxf.) 201, 97–107 (2011).
Yun, J. et al. Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells. Science 325, 1555–1559 (2009).
Rose, C. J. et al. Quantifying spatial heterogeneity in dynamic contrast-enhanced MRI parameter maps. Magn. Reson. Med. 62, 488–499 (2009).
Kawata, Y. et al. Quantitative classification based on CT histogram analysis of non-small cell lung cancer: Correlation with histopathological characteristics and recurrence-free survival. Med. Phys. 39, 988 (2012).
Drew, P. J. et al. Dynamic contrast enhanced magnetic resonance imaging of the breast is superior to triple assessment for the pre-operative detection of multifocal breast cancer. Ann. Surg. Oncol. 6, 599–603 (1999).
Knopp, M. V., Giesel, F. L., Marcos, H., von Tengg-Kobligk, H. & Choyke, P. Dynamic contrast-enhanced magnetic resonance imaging in oncology. Top. Magn. Reson. Imag. 12, 301–308 (2001).
Lamer, S. et al. Radiologic assessment of intranodal vascularity in head and neck squamous cell carcinoma. Correlation with histologic vascular density. Invest. Radiol 31, 673–679 (1996).
Venkatasubramanian, R., Arenas, R. B., Henson, M. A. & Forbes, N. S. Mechanistic modelling of dynamic MRI data predicts that tumour heterogeneity decreases therapeutic response. Br. J. Cancer 103, 486–497 (2010).
Helmlinger, G., Yuan, F., Dellian, M. & Jain, R. K. Interstitial pH and pO2 gradients in solid tumors in vivo: high-resolution measurements reveal a lack of correlation. Nature Med. 3, 177–182 (1997).
Kimura, H. et al. Fluctuations in red cell flux in tumor microvessels can lead to transient hypoxia and reoxygenation in tumor parenchyma. Cancer Res. 56, 5522–5528 (1996).
Costouros, N. G. et al. Microarray gene expression analysis of murine tumor heterogeneity defined by dynamic contrast-enhanced MRI. Mol. Imag. 1, 301–308 (2002).
Guccione, S. et al. Functional genomics guided with MR imaging: mouse tumor model study. Radiology 228, 560–568 (2003).
Hobbs, S. K. et al. Magnetic resonance image-guided proteomics of human glioblastoma multiforme. J. Magn. Reson. Imag. 18, 530–536 (2003).
Winge, O. Zytologische untersuchungen uber die natur maligner tumoren. II. Teerkarzinome bei mausen. Z. Zellforsch. Mikrosk. Anat. 10, 683–735 (1930).
Sandberg, A. A. & Hossfeld, D. K. Chromosomal abnormalities in human neoplasia. Annu. Rev. Med. 21, 379–408 (1970).
Bakhoum, S. F., Danilova, O. V., Kaur, P., Levy, N. B. & Compton, D. A. Chromosomal instability substantiates poor prognosis in patients with diffuse large B-cell lymphoma. Clin. Cancer Res. 17, 7704–7711 (2011).
Loeb, L. A. Human cancers express mutator phenotypes: origin, consequences and targeting. Nature Rev. Cancer 11, 450–457 (2011).
Yachida, S. et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 467, 1114–1117 (2010).
Araujo, R. P., Liotta, L. A. & Petricoin, E. F. Proteins, drug targets and the mechanisms they control: the simple truth about complex networks. Nature Rev. Drug Discov. 6, 871–880 (2007).
Lage, H. An overview of cancer multidrug resistance: a still unsolved problem. Cell. Mol. Life Sci. 65, 3145–3167 (2008).
Marty, M. et al. Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group. J. Clin. Oncol. 23, 4265–4274 (2005).
Mahtani, R. L. & Vogel, C. L. Pleomorphic lobular carcinoma of the breast: four long-term responders to trastuzumab--coincidence or hint? J. Clin. Oncol. 26, 5823–5824 (2008).
Untch, M. et al. Pathologic complete response after neoadjuvant chemotherapy plus trastuzumab predicts favorable survival in human epidermal growth factor receptor 2-overexpressing breast cancer: results from the TECHNO trial of the AGO and GBG study groups. J. Clin. Oncol. 29, 3351–3357 (2011).
Druker, B. J. et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N. Engl. J. Med. 355, 2408–2417 (2006).
Engelman, J. A. & Settleman, J. Acquired resistance to tyrosine kinase inhibitors during cancer therapy. Curr. Opin. Genet. Dev. 18, 73–79 (2008).
Aktipis, C. A., Kwan, V. S., Johnson, K. A., Neuberg, S. L. & Maley, C. C. Overlooking evolution: a systematic analysis of cancer relapse and therapeutic resistance research. PLoS ONE 6, e26100 (2011).
O'Hare, T., Corbin, A. S. & Druker, B. J. Targeted CML therapy: controlling drug resistance, seeking cure. Curr. Opin. Genet. Dev. 16, 92–99 (2006).
Blackwell, K. L. et al. Randomized study of Lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. J. Clin. Oncol. 28, 1124–1130 (2010).
Massarweh, S. & Schiff, R. Resistance to endocrine therapy in breast cancer: exploiting estrogen receptor/growth factor signaling crosstalk. Endocr. Relat. Cancer 13 Suppl. 1, 15–24 (2006).
Baselga, J. et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N. Engl. J. Med. 366, 520–529 (2012).
Komarova, N. L. & Wodarz, D. Drug resistance in cancer: principles of emergence and prevention. Proc. Natl Acad. Sci. USA 102, 9714–9719 (2005).
Chmielecki, J. et al. Optimization of dosing for EGFR-mutant non-small cell lung cancer with evolutionary cancer modeling. Sci Transl Med 3, 90ra59 (2011).
Gatenby, R. A., Brown, J. & Vincent, T. Lessons from applied ecology: cancer control using an evolutionary double bind. Cancer Res. 69, 7499–7502 (2009).
Gatenby, R. A., Silva, A. S., Gillies, R. J. & Frieden, B. R. Adaptive therapy. Cancer Res. 69, 4894–4903 (2009).
Mirski, S. E., Gerlach, J. H. & Cole, S. P. Multidrug resistance in a human small cell lung cancer cell line selected in adriamycin. Cancer Res. 47, 2594–2598 (1987).
Abrahamsson, P. A. Potential benefits of intermittent androgen suppression therapy in the treatment of prostate cancer: a systematic review of the literature. Eur. Urol. 57, 49–59 (2010).
Beex, L. et al. Continuous versus intermittent tamoxifen versus intermittent/alternated tamoxifen and medroxyprogesterone acetate as first line endocrine treatment in advanced breast cancer: an EORTC phase III study (10863). Eur. J. Cancer 42, 3178–3185 (2006).
Farber, S. & Diamond, L. K. Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid. N. Engl. J. Med. 238, 787–793 (1948).
De Bock, K., Mazzone, M. & Carmeliet, P. Antiangiogenic therapy, hypoxia, and metastasis: risky liaisons, or not? Nature Rev. Clin. Oncol. 8, 393–404 (2011).
Iwamoto, F. M. et al. Patterns of relapse and prognosis after bevacizumab failure in recurrent glioblastoma. Neurology 73, 1200–1206 (2009).
Jain, R. K. Lessons from multidisciplinary translational trials on anti-angiogenic therapy of cancer. Nature Rev. Cancer 8, 309–316 (2008).
Goel, S. et al. Normalization of the vasculature for treatment of cancer and other diseases. Physiol. Rev. 91, 1071–1121 (2011).
Chan, D. A. et al. Targeting GLUT1 and the Warburg effect in renal cell carcinoma by chemical synthetic lethality. Sci Transl Med 3, 94ra70 (2011).
Ganapathy-Kanniappan, S. et al. 3-bromopyruvate: a new targeted antiglycolytic agent and a promise for cancer therapy. Curr. Pharm. Biotechnol. 11, 510–517 (2010).
Michelakis, E. D., Webster, L. & Mackey, J. R. Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer. Br. J. Cancer 99, 989–994 (2008).
Le, A. et al. Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression. Proc. Natl Acad. Sci. USA 107, 2037–2042 (2010).
Gatenby, R. A., Gawlinski, E. T., Gmitro, A. F., Kaylor, B. & Gillies, R. J. Acid-mediated tumor invasion: a multidisciplinary study. Cancer Res. 66, 5216–5223 (2006).
Ibrahim Hashim, A. et al. Reduction of metastasis using a non-volatile buffer. Clin. Exp. Metastasis 28, 841–849 (2011).
Hashim, A. I. et al. Sytemic buffers inhibit carcinogenesis in TRAMP mice. J. Urology (2012). (in press Jan, </pub>2012).
Ibrahim Hashim, A. et al. Reduction of metastasis using a non-volatile buffer. Clin Exp Metastasis (2011).
Wojtkowiak, J. W., Verduzco, D., Schramm, K. J. & Gillies, R. J. Drug resistance and cellular adaptation to tumor acidic pH microenvironment. Mol. Pharm. 8, 2032–2038 (2011).
Ghobrial, I. M., Witzig, T. E. & Adjei, A. A. Targeting apoptosis pathways in cancer therapy. CA Cancer J. Clin. 55, 178–194 (2005).
Ludwig, H., Khayat, D., Giaccone, G. & Facon, T. Proteasome inhibition and its clinical prospects in the treatment of hematologic and solid malignancies. Cancer 104, 1794–1807 (2005).
Madhok, B. M., Yeluri, S., Perry, S. L., Hughes, T. A. & Jayne, D. G. Dichloroacetate induces apoptosis and cell-cycle arrest in colorectal cancer cells. Br. J. Cancer 102, 1746–1752 (2010).
Holoch, P. A. & Griffith, T. S. TNF-related apoptosis-inducing ligand (TRAIL): a new path to anti-cancer therapies. Eur. J. Pharmacol. 625, 63–72 (2009).
Smolewski, P. Recent developments in targeting the mammalian target of rapamycin (mTOR) kinase pathway. Anticancer Drugs 17, 487–494 (2006).
Agulnik, M. New developments in mammalian target of rapamycin inhibitors for the treatment of sarcoma. Cancer 118, 1486–1497 (2012).
Houghton, P. J. Everolimus. Clin. Cancer Res. 16, 1368–1372 (2010).
Pouget, J. P. et al. Clinical radioimmunotherapy--the role of radiobiology. Nature Rev. Clin. Oncol. 8, 720–734 (2011).
Richman, C. M. et al. High-dose radioimmunotherapy combined with fixed, low-dose paclitaxel in metastatic prostate and breast cancer by using a MUC-1 monoclonal antibody, m170, linked to indium-111/yttrium-90 via a cathepsin cleavable linker with cyclosporine to prevent human anti-mouse antibody. Clin. Cancer Res. 11, 5920–5927 (2005).
Behr, T. M. et al. High-linear energy transfer (LET) alpha versus low-LET beta emitters in radioimmunotherapy of solid tumors: therapeutic efficacy and dose-limiting toxicity of 213Bi- versus 90Y-labeled CO17-1A Fab' fragments in a human colonic cancer model. Cancer Res. 59, 2635–2643 (1999).
Chatal, J. F., Davodeau, F., Cherel, M. & Barbet, J. Different ways to improve the clinical effectiveness of radioimmunotherapy in solid tumors. J. Cancer Res. Ther. 5 Suppl. 1, S36–40 (2009).
Wilson, W. R. & Hay, M. P. Targeting hypoxia in cancer therapy. Nature Rev. Cancer 11, 393–410 (2011).
Duan, J. X. et al. Potent and highly selective hypoxia-activated achiral phosphoramidate mustards as anticancer drugs. J. Med. Chem. 51, 2412–2420 (2008).
Meng, F. et al. Molecular and cellular pharmacology of the hypoxia-activated prodrug TH-302. Mol. Cancer Ther. 6, 6 (2011).
Sun, J. D. et al. Selective tumor hypoxia targeting by hypoxia-activated prodrug TH-302 inhibits tumor growth in preclinical models of cancer. Clin. Cancer Res. 18, 758–770 (2011).
Tian, L. & Bae, Y. H. Cancer nanomedicines targeting tumor extracellular pH. Colloids Surf B Biointerfaces DOI colsurfb.2011.10.039 (2011).
Kaminskas, L. M. et al. Doxorubicin-conjugated PEGylated dendrimers show similar tumoricidal activity but lower systemic toxicity when compared to PEGylated liposome and solution formulations in mouse and rat tumor models. Mol. Pharm. 9, 422–432 (2012).
Gatenby, R. A. & Vincent, T. L. Application of quantitative models from population biology and evolutionary game theory to tumor therapeutic strategies. Mol. Cancer Ther. 2, 919–927 (2003).
Casanueva, M. O., Burga, A. & Lehner, B. Fitness trade-offs and environmentally induced mutation buffering in isogenic C. elegans. Science 335, 82–85 (2012).
Jacob, F. Evolution and Tinkering. Science 196, 1161–1166 (1977).
Acknowledgements
The authors would like to thank Z. Bhujwalla, K. Brindle, J. Brown, J. Evelhoch, A. Giuliano, P. Glazer, C. Hart, L. Loeb, T. Sellers, B. Vogelstein and J. Zhang for their insightful and helpful comments. Supported by a grant from the McDonnell Foundation and US NIH grants U54 CA143970 (“Physical Sciences in Oncology”) and R01 CA077575 (“Causes and Consequences of Acid pH in Tumors”) to R.A.G. and R.J.G.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
Speaking honorarium $500, Threshold Pharmaceuticals (RJG) Consultancy $1000, Intenzyne Corporation (RJG)
Related links
FURTHER INFORMATION
Glossary
- Atavistic
-
Reverting to or suggesting the characteristics of a remote ancestor or primitive type. In the current context, atavism is the expression of behaviours in cancer cells that are not normally observed in normal metazoan cells, but that are observed in prokaryotes and/or protozoa.
- Clades
-
A taxonomic group of organisms classified together on the basis of homologous features traced to a common ancestor. In the current context, groups of cancer cells evolve in physically distinct niches, and exhibit local genetic homogeneity.
- Nuclear grade
-
Breast cancers are assessed for the appearance of nuclei within the tumour cells and assigned a grade from 1 (small uniform cells) to 3 (marked nuclear variation).
- Supervene
-
Describes a mathematical and philosophical formalism that characterizes the relationship between two sets — in this case phenotype (or more broadly adaptive strategies) and genotypes. In the subvenient set (genetics) each point will map to a point in the phenotype set, and in the supervenient set (phenotypes) each adaptive strategy can map too many different points in the genotype set.
- Teleological
-
Describes a doctrine that final causes exist, and thus that purpose is a part of nature. In the current context, teleology dictates that cancers exist for a (self-serving) purpose. Thus, we ask why, and not how, cancers behave the way they do.
- Theory
-
A coherent group of general propositions that can be used as principles of explanation and prediction for a class of phenomena. A proposed explanation the status of which is still conjectural and subject to experimentation.
Rights and permissions
About this article
Cite this article
Gillies, R., Verduzco, D. & Gatenby, R. Evolutionary dynamics of carcinogenesis and why targeted therapy does not work. Nat Rev Cancer 12, 487–493 (2012). https://doi.org/10.1038/nrc3298
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrc3298
This article is cited by
-
Dietary acid load in health and disease
Pflügers Archiv - European Journal of Physiology (2024)
-
Computational approaches to modelling and optimizing cancer treatment
Nature Reviews Bioengineering (2023)
-
Contributions of viral oncogenes of HPV-18 and hypoxia to oxidative stress and genetic damage in human keratinocytes
Scientific Reports (2023)
-
How protons pave the way to aggressive cancers
Nature Reviews Cancer (2023)
-
Quantifying dietary acid load in U.S. cancer survivors: an exploratory study using NHANES data
BMC Nutrition (2022)