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Current Opinion in Oncology:
doi: 10.1097/CCO.0000000000000028
CANCER BIOLOGY: Edited by Pierre Hainaut and Amelie Plymoth

The genetic–metabolic duality of cancer

Hainaut, Pierrea; Plymoth, Amelieb

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aInternational Prevention Research Institute, Ecully, France

bDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

Correspondence to Pierre Hainaut, International Prevention Research Institute, 15 Chemin du Saquin, 69130 Ecully, France. Tel: +33 4 72 11 17 86, Mobile: +33 7 87 51 76 89; e-mail: pierre.hainaut@i-pri.org

Cancer biology has long been a fragmented area. Until recently, there was little conceptual continuity between the multiple different biological mechanisms that underlie cancer at gene, cell, tissue, organ, person or population level. One of the major achievements of the past decade is the development of a comprehensive framework that describes the multiple dimensions of cancer as an integrated system. The concept of ‘Hallmarks of Cancer’ developed by Hanahan and Weinberg in 2000 and augmented in 2011 [1,2], signals the turning point between the gradualist conception of cancer as a stepwise process resulting from the sequential alteration of additive mechanisms and the vision of a seamless process of interplay between cells and their environment, engulfing cancer and chronic metabolic, immune and inflammatory diseases in a continuum. In this respect, there is an interesting parallelism between the conceptual developments of physics in the early 20th century and those of cancer biology at the turn of the 21st century. In physics, the wave–matter duality concept formulated by de Broglie in 1924 represented a major paradigm shift for quantum mechanics, encapsulating several decades of research on the nature of matter. Likewise, the nature of cancer cannot be adequately described without taking into account its dual genetic and metabolic character.

This Cancer Biology issue brings to the fore a series of reviews that shed new lights on the genetic–metabolic duality of cancer and further demonstrates how these aspects constitute the two sides of the same coin. The review on chromothripsis proposed by Klosterman, Koster and Molenaar demonstrates the departure from the gradualist view of cancer by emphasizing the role of massive complex genomic rearrangement in shaping the landscape of somatic mutations in cancer cells. Moreover, the role and significance of adaptive responses driven by epigenetic mechanisms is illustrated by Wang, Rousseau and Kochbin, who describe how ‘out-of-context’ activation of genes that are normally restricted to very specific cells and tissues can provide a powerful mechanism to sustain cell growth – as well as a range of new biomarkers and pharmacological targets for cancer detection and treatment. Wang and Gu summarize breakthrough research that demonstrates how the p53 tumor suppressor protein operates as a fundamental link between genome stability, cell proliferation, cell senescence and control of bioenergetics metabolism. They show that, by regulating the expression of a large panel of genes involved in metabolic regulation, p53 suppresses the metabolic context that supports rapid cell growth but may also contribute to protect cancer cells against excess radical damage. Further, Kfoury, Virard, Renno and Coste introduce the reader to the Janus-faced activities of Myd88. This dual-function protein operates as an adapter in inflammation signaling in response to cytokines or to nonspecific pathogens, as well as a building block for the assembly of the RAS/RAF/ERK signaling cascade that mediates cell proliferation signals, providing a unique example of how the same molecule may exert autonomous roles in cell transformation and inflammation.

Next, two reviews highlight how metabolic deregulation may profoundly modify the interplay between precancer or cancer cells and their local or distant environment. Huang and Mellor address how local inflammation and innate immune sensing promote amino acid catabolism that is pivotal in initiating and sustaining immune resistance and in attenuating antitumor immunity. Lade, Noon and Friedman summarize the accumulating evidence on the molecular and cellular mechanisms linking nonalcoholic fatty liver diseases (NAFLD) with the development of hepatocellular carcinoma (HCC), emphasizing the role of gut microflora, bile acid receptors and Vitamin D in regulating the progression from NAFLD to HCC.

Finally, three reviews address possible mechanisms for controlling factors at the interface between cell proliferation, inflammation, metabolism and immune response. Schulz and Moll review the sweeping roles of macrophage inhibitory factor (MIF) as promoter of tumor-specific inflammation and inhibitor of antitumor immune responses. As MIF is a ‘client’ of the heat-shock protein 90 chaperone (Hsp90), they propose that targeting Hsp90 may provide an effective mechanism for MIF attenuation in cancer and they review current progress on phase I/II clinical trials of synthetic inhibitors of Hsp90. Addressing the specific context of melanoma, Jochemsem explains how new drugs aimed at reactivating the p53 suppressor protein may alleviate resistance to therapy and lead to better and more durable treatment of melanoma patients. Finally, taking the high-vantage grounds of epidemiology, Elfström, Herweijer, Sundström and Arnheim-Dahlström provide an extensive survey of the effectiveness of current prevention strategies for reducing mortality by cervical cancer, including screening methods and prophylactic human papilloma virus vaccine.

In selecting this collection of topics, our aim has been to give the floor to scientists and clinicians who have made groundbreaking contributions within the past 2 years. It is expected that these reviews will entice readers to dig deeper in the rich annotated bibliographies and to share the excitement of research moving forward at an unprecedented pace.

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Acknowledgements

None.

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Conflicts of interest

The authors have no conflicts of interest to declare.

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REFERENCES

1. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100:57–70.

2. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011; 144:646–674.

© 2014 Lippincott Williams & Wilkins, Inc.

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