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A close look at cancerAlison Farrell
Advances in cancer research are enabling fast-paced discovery and translation of results into potential clinical tools. Here we consider some of the most influential findings of the past two years, selected by experts in the cancer field.
in 2010, we asked more than 400 experts to help us identify papers published within the previous two years that have made a significant impact on the field of cancer. By doing so we hoped to highlight those papers influencing current thinking and funding trends, pinpoint key questions stimulating the cancer field and help identify gaps in the knowledge and focus of cancer research. One hundred and fifty respondents recom-mended 319 papers (compiled in the tables on p 280), and the most frequently selected papers are discussed in greater depth in News & Views and Research Highlights in the ensu-ing pages.
A quick glance at the most highly cited papers in our survey and our tally of selected papers by topic reveals several areas that are clearly inspiring strong interest within the field. These include, but are not limited to, cancer genomics, cancer stem cells and new cancer-driving mutations as well as tumor cell signaling and metastasis, mechanisms of drug resistance, and recent preclinical and clinical advances in cancer immunology and therapy.
Two areas in particular stand out from this exercise in terms of capturing peoples atten-tion: cancer stem cells and cancer genom-ics. The first is dominated by a single paper describing the frequency of tumor-forming cells in metastatic melanoma1, and the sec-ond is a discovery approach represented by a collection of at least eight papers detailing the genomic landscape of a variety of tumors29. Underlining the interest in cancer genomics as a powerful tool to rapidly identify new onco-genic drivers are three more of the most highly cited papers, which followed upwithin the space of two yearsan original finding from a genomic study2 that identified isocitrate dehydrogenase-1 (IDH1) as a candidate onco-
protein in glioblastoma multiforme1012 and shed fresh mechanistic insights on the role of metabolic changes in cancer (see News & Views, p 291).
The list of papers is by no means complete. There are instances in which highly related papers published simultaneously or before 2008 did not receive the same numbers of votes, or in some instances were not selected by our respondents. The oversights are unin-tentional, and are no doubt due to our request that respondents cite off the top of their heads their choice of the most interesting and note-worthy papers of the preceding two years. The omissions do not negate the contribution of related or preceding papers; instead, the exis-tence of related papers probably served to strengthen the interest in and recognition of the concepts collectively presented.
A second point worth mentioning is that the papers selected by experts were frequently outside the main focus of their own research. This finding emphasizes the broad appeal of papers that shed new light on tumor biology and that can be generalized across cancer dis-ciplines, and the importance of communicat-ing new results to the widest possible audience so as to inform research and encourage col-laboration in disparate cancer fields.
Here we discuss some of the key areas of interest cited in this survey, and we consider their impact on basic and applied cancer research and how they are paving the way to future discoveries (Fig. 1).
The search for cancer stem cellsThe cancer stem cell hypothesis proposed that a subset of cancer cells is able to maintain and propagate a tumor. Although these were origi-nally thought to comprise a very small frac-tion (less than 0.1%) of the cells in a tumor13, a study in 2007 suggested that this assumption might be based on the constraints imposed by xenotransplantation of human tumor cells
into mice14. By transplanting mouse leukemia and lymphoma cells into histocompatible mice, the authors showed that at least 10% of the cancer cells could regenerate tumors in vivo.
What remained untested was whether these findings were restricted to tumors of hematopoietic origin or whether solidand more heterogeneoustumors also had a higher frequency of tumor-initiating cells than previously predicted when the immune background was made more permissive to their growth. As clearly indicated by our respondents, and described in a Research Highlight (p 294), Elsa Quintana and col-leagues provided a singularly important con-tribution to this discussion by showing that as many as 25% of cells in advanced human melanoma are capable of initiating tumors in immunodeficient mice1.
In order to develop effective therapies, it is essential to put the cancer stem cell hypothesis to the test, as it contends that targeting the tumor-initiating cells, regardless of their fre-quency, will be required to eradicate tumors. And consistent with their distinct biology that enables cancer stem cells to sustain tumor growth, their susceptibility to antitumor agents may also be distinct from that of the bulk of tumor cells. But whether cancer stem cells are a component of every tumor type is now a matter of debate, and the stem cell hypothesis continues to evolve to consider the possibility that these cells comprise dif-ferent fractions of a tumor in different indi-viduals, that tumor cells in general may be sufficiently plastic to interconvert between tumor stem and non-stem cells, and that the tumor microenvironment and an epithelial-to-mesenchymal transition15 may have key roles in influencing this plasticity16.
Although candidate markers of tumor stem cells exist, it is an open question whether there are identifiable molecular markers of tumor Alison Farrell is a senior editor of Nature Medicine.
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Cell of originRole of EMT
Identification ofgenomic and
epigenetic alterationsand validation of
Metabolic changesCancer cell
Colonizationor dormancyRole of the
Cancer stem cell Tumor cellActivated fibroblast
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stem cells that are relevant to their function and that can distinguish them from their more differentiated descendants, and whether such markers are common to tumor stem cells of different tissues of origin. More data are needed from human tumors to provide some answers to these questions and to determine the dependence of clinical outcome in can-cer patients on tumor stem cells. Whether the growth of metastases is dependent on the stem cell phenotype, whether plasticity or a fixed phenotype determines a tumor cells ability to colonize a distant site or go dormant, and whether adjuvant chemotherapy killing of disseminated tumor stem cells accounts for tumor remission in patients are all ques-tions with important implications for future clinical decisions. These issues and others are discussed in the Review by Hans Clevers (p 313).
Funding agencies and universities have invested enormously in the study of cancer stem cells since the initial identification of a population of tumor-initiating cells in solid (breast) tumors mirrored earlier findings in acute myelogenous leukemia13,17. And outgrowths of this concentrated effort have yielded important new insights, including into the cells of origin of different tumors, such as colon18, as noted by our respondents, and more recently of the prostate18,19. The impor-tance of studies showing that tumor-initiating ability is not restricted to a very small subset of cells, and of the possibility of interconver-sion of tumor stem and non-stem cells, lies not in discounting the stem cell hypothesis or its ramifications. Rather, such reports underline the need to test the limitations of experimen-tal assays, to incorporate into stem cell studies findings and technologies from the full spec-trum of cancer research, and alsoin the face of the as-yet-incomplete understanding of the biological diversity of cancerto recognize a hypothesis for what it is.
Cashing in on cancer genomicsThe response we received in support of can-cer genomics as an area of great impact was overwhelming. Eight separate studies ana-lyzing the genomic and transcriptomic pro-files of tumors arising in the brain, pancreas, breast, colon and hematopoietic system were identified by our experts as key advances of the last two years29. In their delineation of nucleotide sequence, epigenetic modifications and transcriptional profiles of solid tumors and leukemias, these studies have catalogued the candidate oncogenic drivers as well as the predicted nontumorigenic passenger muta-tions accumulated by established tumors.
The premisemuch debatedof these
sequencing studies was to generate a com-prehensive characterization of the profile of genetic alterations in tumors, with the hope that this approach would elucidate the under-pinnings of cancer through more rapid iden-tification of the key genetic events driving tumorigenesis and of candidate therapeutic targets than existing, hypothesis-driven strat-egies. Thus far, these studies have generated new insights into cancer causation, including, but not limited to, the identification of IDH1 and IDH2 as oncogenic drivers in glioblas-toma and in acute myeloid leukemia, and of germline mutations in the gene encoding anaplastic lymphoma kinase (ALK) in familial neuroblastoma (see News & Views on p 290). They have identified mutations associated with environmental factors (tobacco smoke), crucial pathways that are altered in pancre-atic cancer, and evidence of high intertumor variation in mutated pathway components, emphasizing the need to target tumor nodes rather than individual gene products.
These studies provide a wealth of data to explore for new players and pathways driving mutagenesis, but separating oncogenic driv-ers from passenger mutations is no easy task. These designations are initially assigned on the basis of statistical analysis and recurrence in multiple tumors, but such assumptions must be borne out by functional valida-tion, a requirement that limits the speed of translation of genomic information into new therapeutic targets or mechanisms. Similarly, distinguishing genetic alterations that are
tumor-initiating events from those that are tumor promoting or that impinge more spe-cifically on metastasis, as well as the interde-pendence of the three classes in giving rise to a tumor with metastatic potential, will require a substantial investment of time, effort and funds.
Yet the Cancer Genome Atlas Project, overseen by the US National Cancer Institute and the National Human Genome Research Institute, intends to spend an estimated $1 billion to sequence thousands more tumor samples over the next five years. Although technological advances will further reduce the cost of these efforts, and high-through-put functional validation of candidate genes of interest can be envisaged, doubts remain as to whether large-scale sequencing efforts are time and cost effective as well as how much more new information will be generated by new sequencing studies beyond that con-tained in the enormous amount of data col-lected to date (http://news.Sciencemag.org/scienceinsider/2010/04/a-skeptic-questions-cancer-genom.html).
The counterargument is that the utility of these studies lies not solely in their identifi-cation of oncogenes and tumor suppressors but also in their potential to provide new biomarkers for early detection, insights into pathway interactions and epigenetic modula-tion of tumor phenotypes, an understanding of the maternal versus paternal contribution to cancer, and mechanisms of drug resistance that will complement existing studies in
Figure 1 Notable advances in cancer research. In a survey of cancer researchers, recent reports on cancer stem cells, cancer genomes and cancer therapies garnered the most attention from respondents. Cancer stem cell (CSC) studies have yielded new insights into the cells of origin of some tumors, the role of the epithelial-to-mesenchymal transition (EMT) in conferring stem celllike properties and the contribution of CSCs to drug resistance, and they have also triggered questions about the CSC hypothesis itself. Cancer genome sequencing studies continue to yield data on cancer-initiating and -promoting mutations as well as insights into epigenetic and metabolic changes in tumors that offer the potential for the discovery of new therapeutic targets and mechanisms of tumorigenesis. Reports of clinical advances in immunotherapy and targeted molecular therapy, as well as mechanisms of treatment resistance, also provoked significant interest, as did studies of the role of the immune system and new molecular players in tumor growth, signaling and metastasis. The image depicts a metastasizing tumor and highlights the areas of cancer research most frequently selected by the survey respondents.