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Classifying the evolutionary and ecological features of neoplasms

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      Neoplasms change over time through a process of cell-level evolution, driven by genetic and epigenetic alterations. However, the ecology of the microenvironment of a neoplastic cell determines which changes provide adaptive benefits. There is widespread recognition of the importance of these evolutionary and ecological processes in cancer, but to date, no system has been proposed for drawing clinically relevant distinctions between how different tumours are evolving. On the basis of a consensus conference of experts in the fields of cancer evolution and cancer ecology, we propose a framework for classifying tumours that is based on four relevant components. These are the diversity of neoplastic cells (intratumoural heterogeneity) and changes over time in that diversity, which make up an evolutionary index (Evo-index), as well as the hazards to neoplastic cell survival and the resources available to neoplastic cells, which make up an ecological index (Eco-index). We review evidence demonstrating the importance of each of these factors and describe multiple methods that can be used to measure them. Development of this classification system holds promise for enabling clinicians to personalize optimal interventions based on the evolvability of the patient’s tumour. The Evo- and Eco-indices provide a common lexicon for communicating about how neoplasms change in response to interventions, with potential implications for clinical trials, personalized medicine and basic cancer research.

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      Hallmarks of Cancer: The Next Generation

      The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors. The hallmarks constitute an organizing principle for rationalizing the complexities of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. Conceptual progress in the last decade has added two emerging hallmarks of potential generality to this list-reprogramming of energy metabolism and evading immune destruction. In addition to cancer cells, tumors exhibit another dimension of complexity: they contain a repertoire of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the "tumor microenvironment." Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer. Copyright © 2011 Elsevier Inc. All rights reserved.
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        Understanding the Warburg effect: the metabolic requirements of cell proliferation.

        In contrast to normal differentiated cells, which rely primarily on mitochondrial oxidative phosphorylation to generate the energy needed for cellular processes, most cancer cells instead rely on aerobic glycolysis, a phenomenon termed "the Warburg effect." Aerobic glycolysis is an inefficient way to generate adenosine 5'-triphosphate (ATP), however, and the advantage it confers to cancer cells has been unclear. Here we propose that the metabolism of cancer cells, and indeed all proliferating cells, is adapted to facilitate the uptake and incorporation of nutrients into the biomass (e.g., nucleotides, amino acids, and lipids) needed to produce a new cell. Supporting this idea are recent studies showing that (i) several signaling pathways implicated in cell proliferation also regulate metabolic pathways that incorporate nutrients into biomass; and that (ii) certain cancer-associated mutations enable cancer cells to acquire and metabolize nutrients in a manner conducive to proliferation rather than efficient ATP production. A better understanding of the mechanistic links between cellular metabolism and growth control may ultimately lead to better treatments for human cancer.
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          Cancer genome landscapes.

          Over the past decade, comprehensive sequencing efforts have revealed the genomic landscapes of common forms of human cancer. For most cancer types, this landscape consists of a small number of "mountains" (genes altered in a high percentage of tumors) and a much larger number of "hills" (genes altered infrequently). To date, these studies have revealed ~140 genes that, when altered by intragenic mutations, can promote or "drive" tumorigenesis. A typical tumor contains two to eight of these "driver gene" mutations; the remaining mutations are passengers that confer no selective growth advantage. Driver genes can be classified into 12 signaling pathways that regulate three core cellular processes: cell fate, cell survival, and genome maintenance. A better understanding of these pathways is one of the most pressing needs in basic cancer research. Even now, however, our knowledge of cancer genomes is sufficient to guide the development of more effective approaches for reducing cancer morbidity and mortality.

            Author and article information

            [1 ]Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, 1001 S. McAllister Ave, Tempe, Arizona 85287, USA
            [2 ]Department of Psychology, Center for Evolution and Medicine, Arizona State University, 651 E. University Drive, Tempe, Arizona 85287, USA
            [3 ]Evolution and Cancer Laboratory, Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK
            [4 ]Centre for Evolution and Cancer, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London SM2 5NG, UK
            [5 ]Department of Anthropology, University of California Santa Barbara, Santa Barbara, California 93106, USA
            [6 ]Department of Medical Oncology, Dana–Farber Cancer Institute, 450 Brookline Avenue D740C, Boston, Massachusetts 02215, USA
            [7 ]Department of Cancer Imaging and Metabolism, Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, Florida 33612, USA
            [8 ]Centre for Evolution and Cancer, Division of Molecular Pathology, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK
            [9 ]Brady Urological Institute, The Johns Hopkins School of Medicine, 600 N. Wolfe Street, Baltimore, Maryland 21287, USA
            [10 ]Cancer Biology and Evolution Program, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, Florida 33612, USA
            [11 ]Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, Paul O’Gorman Building, 72 Huntley Street, London WC1E 6BT, UK
            [12 ]Department of Biochemistry, Genetics and Immunology and Biomedical Research Center (CINBIO), University of Vigo, Spain; Galicia Sur Health Research Institute, Vigo, 36310, Spain
            [13 ]Department of Ecology and Evolution, University of Chicago, Chicago, Illinois 60637, USA
            [14 ]Departments of Pediatrics and Oncological Sciences, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, Utah 84108, USA
            [15 ]Department of Surgery, Duke University and Duke Cancer Institute, 465 Seeley Mudd Building, Durham, North Carolina 27710, USA
            [16 ]Integrated Mathematical Oncology Department, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, Florida 33612, USA
            [17 ]Department of Pathology, Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Avenue, NOR2424, Los Angeles, California 90033, USA
            Author notes
            Correspondence to C.C.M. Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, 1001 S. McAllister Avenue, Tempe, Arizona 85287, USA. maley@
            Nat Rev Cancer
            Nat. Rev. Cancer
            Nature reviews. Cancer
            2 February 2018
            15 September 2017
            October 2017
            13 February 2018
            : 17
            : 10
            : 605-619
            28912577 5811185 10.1038/nrc.2017.69 NIHMS939413

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