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Current Opinion in Oncology:
doi: 10.1097/CCO.0b013e32835b651e
CANCER BIOLOGY: Edited by Pierre Hainaut and Amelie Plymoth

Targeting the hallmarks of cancer: towards a rational approach to next-generation cancer therapy

Hainaut, Pierrea; Plymoth, Amelieb

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aInternational Prevention Research Institute, Lyon, France

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

Correspondence to Pierre Hainaut, PhD, International Prevention Research Institute, 95 cours Lafayette, 69006 Lyon, France. Tel: +33 4 72 17 11 99; fax: +33 4 72 17 11 90; e-mail: pierre.hainaut@i-pri.org

In 2000, Hanahan and Weinberg [1] proposed that the remarkable diversity of neoplastic diseases and of their underlying molecular mechanisms could be rationalized into six biological processes that, together, constitute the molecular and cellular infrastructure of cancer, thus identifying the ‘Hallmarks of Cancer’. To the six initial Hallmarks’ processes (sustaining proliferative signalling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis and activating invasion and metastasis), advances in the past decade have added four biological processes, including genome instability, tumour-promoting inflammation, reprogramming of cell bioenergetics and evading immune destruction [2].

The concept of ‘Hallmarks of cancer’ is a powerful guide for translational research aimed at improving and developing early detection, screening, treatment and quality of life of cancer patients. The main lessons can be captured in a few basic messages. First, in order to develop and evolve towards a malignant, invasive status, cancer cells must acquire modifications in almost each of the 10 processes. This underlines the complex molecular nature of cancer, which results from coordinated and complementary functional changes in multiple pathways. Second, only cells with a high developmental plasticity, such as stem and progenitor cells, may sustain the complex scenarios supporting coordinated perturbation of multiple hallmarks. The same reasoning holds for cancer lesions: only a fraction of seed cells within a lesion can sustain progression towards invasion and metastasis. The third lesson is that cancer development requires feedback interactions between cancer cells and their microenvironment, within a systemic context involving inflammation, immune responses and metabolism. This vision emphasizes that cancer cells exchange local and long-range signals with cells of the stroma, vasculature, inflammation and immunity to reprogram their environment in a way conducive for invasion. Conversely, the environment may impose its programming capacity onto cancer cells, constraining their development and preventing metastasis despite important genetic changes in tumour cells.

This ‘Cancer Biology’ section offers a selection of reviews that illustrates some of these lessons. The section opens with two reviews revisiting essential aspects of mechanisms governing cell proliferation and fate. The review by Warfel and El-Diery (pp. 52–58) on the p21WAF1 gene and its role in tumourigenesis marks the 20th anniversary of its discovery by El-Deiry and collaborators of p21WAF1 as the first target gene regulated by p53. Over 20 years, its analysis has delivered unexpected lessons on the molecular networks that link cell growth control, cell-cycle arrest, DNA repair, senescence and differentiation. Next, Telerman and Amson (pp. 59–65) provide an overview of the molecular mechanisms of tumour reversion and develop a vision, very much based on their seminal work, of how the reversion phenomenon can be exploited in cancer therapy. Following these reviews, the section takes a look at how tumour cells interact with their microenvironment, in particular in the process of metastasis. Martins et al. (pp. 66–75) summarize how tumour-derived microvesicles and exosomes operate as signalling platforms for short-range and long-range exchanges of molecular information between different types of cells, leading to the reprogramming of cell microenvironment and to the priming of metastatic niches in lymph nodes and in distant organ sites. On a related theme, the review by Katsuno et al. (pp. 76–84) provides a synthetic coverage of the essential roles of tumour growth factor beta signalling in the regulation of epithelium to mesenchyme transition, the most critical step in the process of metastasis of epithelial cancers. The two final chapters take us one step further in addressing how tumour cells interfere with the organism's biological responses. Menendez and Resnick (pp. 85–92) develop an overview of how p53 regulates a network of innate immune responses through Toll-like receptors, underlying links between growth suppression, immunity and inflammation that are critical for cancer control through immune responses. The review by Pereira and Godinho Fereira (pp. 93–98) is an eye-opener on the complex and somewhat paradoxical associations between cell senescence, organismal ageing and cancer, defining a general model to understand how telomere shortening can operate both as a protective mechanism against early cancer and as a risk factor for cancer occurring later in life.

Two common themes run across these reviews. The first is that the functional entities defined by the Hallmarks of cancer are not separate biological pathways. The second is that many of the factors involved in these processes have ‘Dr Jekyll and Mr Hyde’ properties, with the capacity to favour or counteract carcinogenesis depending upon genetic and metabolic context, age, state of immunity and inflammatory responses. The future of cancer therapy may lie in simple drugs targeting the communication routes interconnecting the Hallmarks of Cancer processes and, specifically, modulating critical factors in a way that enables them to express their protective potential.

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Acknowledgements

None.

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Conflicts of interest

There are no conflicts of interest.

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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.

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