Hallmarks of cancer: of all cancer cells, all the time? Se ´ bastien L. Floor 1 , Jacques E. Dumont 1 , Carine Maenhaut 1, 2 and Eric Raspe 1, 2 1 Institute for Interdisciplinary Research in Human Molecular Biology (IRIBHM), Universite ´ Libre de Bruxelles, B-1070 Brussels, Belgium 2 Walloon Excellence in Life Sciences and Biotechnology (WELBIO), Universite ´ Libre de Bruxelles, B-1070 Brussels, Belgium In two landmark articles, Hanahan and Weinberg synthe- sized into one conceptual framework ‘the hallmarks of cancer’, a massive amount of information describing the characteristics of a cancer cell. Although this is neither the intention nor the belief of the authors, hallmarks are often interpreted as applying to a canonic cancer cell, or equally to all cells within a cancer. In this article, we clarify the separate concepts of causes, oncogenic events, signal transduction programs, and hallmarks to show that there is no unimodal relation between these con- cepts but a complex network of interrelations that vary in different cells, between cells, and at different times in any given cell. We consider cancer as an evolving, dynam- ic, and heterogeneous system, explaining, at least in part, the difficulty of treating cancer and supporting the use of simultaneous, multitarget therapies. The ‘cancer cell’ or cancer as a dynamic heterogeneous system Scientific concepts are fashioned by the experimental mod- els used and, we, molecular biologists, working on cancer cell lines or transformed cells tend to consider these cells as homogeneous populations. Pathologists confronted with real tumors have a different view and recognize the het- erogeneity of cancers. Cancers are diseases that are caused by deviant cells unable to form stable functional structures, which multiply anarchically and invade the organism. Populations of can- cer cells, or their models the cancer cell lines, display many biochemical and biological features; some are common to most cancers, and some are particular to distinct tumor types. In a landmark, thought-provoking synthesis, Hana- han and Weinberg [1] regrouped these common character- istics into a few general cell biology properties necessary to achieve the cancer phenotype. Recently, they updated their synthesis to incorporate newly developed concepts and attempted to integrate these in the framework, including the role of the tumor microenvironment [2]. Their work synthesizes and organizes the deluge of information on cancer biology in a general conceptual framework: the ‘cancer cell’. In this article we analyze these concepts and try to further develop this framework, emphasizing the multimodality of signaling and the dynamic and spatial heterogeneity of tumors. We wish to better connect cancer molecular biology and clinical oncology, to show that sim- ple concepts of molecular oncology can account for the complexity of cancer disease, but these concepts must be carefully formulated and combined. The concept of a hallmark (see Glossary) Cancers are a family of diseases that can affect any organ of the body and which share many features, such as their origins from normal cells, their proliferation that escapes normal tissue constrains, loss of differentiation, and inva- sion of surrounding tissues in situ that leads to extravasa- tion and metastases to other sites in the body. In their classic 2000 review [1], Hanahan and Weinberg clearly stated their aim: to delineate ‘a small number of underly- ing principles’ of cancer that were described as ‘acquired capabilities shared by most and perhaps all types of human cancers’. These characteristics would have to be acquired ‘in order for a cell to become cancerous’. The concepts they described clearly apply to the canonical ‘cancer cell’ and molecular biologists working on transformed cells, cancer cell lines, and transgenic models would indeed consider cancer cells or their models as homogeneous populations of cells that have acquired the characteristic hallmarks. In- cluded in the review was a figure on ‘the emergent circuit of the cell’ that describes the postulated signaling pathways operating in the cancer cell to generate the aforementioned hallmarks. Thus, although not considered as such by the authors, the concept of hallmarks is often considered in the Opinion Glossary Cause: the origin of an oncogenic event. In general, this is the cause of a mutation, such as X-rays, viral infection, carcinogens, somatic mutations, teratogens, or UV light. CSC–TPC (cancer stem cells–tumor propagating cells): a general term that refers to cells expressing so-called CSC markers, cells capable of generating tumors in xenotransplants, cells resistant to chemotherapy, or the most aggressive cancer cells. EMT (epithelial–mesenchymal transition): cells of epithelial origin developing a mesenchymal phenotype. This transition is necessary for epithelial cells to migrate individually. In cancer cells it is considered as the first step in the sequence: migration, extravasation, and metastasis. Hallmarks: cell characteristics acquired by cells to generate a cancer. Also called essential characteristics or alterations, acquired capabilities, traits, or programs. Oncogenic events: are the primary event, initiating the oncogenic cascade, the direct mechanism by which tumorigenic capacity is acquired (e.g., the mutation of one proto-oncogene into an oncogene). These can be genetic (e.g., mutations or rearrangements affecting proto-oncogenes or tumor suppressor genes), epigenetic, or regulatory (e.g., lysogenic type mechanism). Programs: signal transduction pathways leading to the induction or suppres- sion of characteristics in response to oncogenic events, other signaling pathways, or hallmarks themselves. Corresponding author: Dumont, J.E. (jedumont@ulb.ac.be) Keywords: oncogenic events; signaling; hallmarks; dynamic heterogeneity of cancer tissue.cells and of time. 1471-4914/$ – see front matter ß 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.molmed.2012.06.005 Trends in Molecular Medicine, September 2012, Vol. 18, No. 9 509