i n t ro d u c t i o n

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 people’s 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 tumors2–9. 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 up—within the space of two years—an original finding from a genomic study2 that identified isocitrate dehydrogenase-1 (IDH1) as a candidate onco-

protein in glioblastoma multiforme10–12 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 solid—and more heterogeneous—tumors 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.

262 volume 17 | number 3 | mArch 2011 nature medicine

© 2

011

Nat

ure

Am

eric

a, In

c. A

ll ri

gh

ts r

eser

ved

.

Cell of originRole of EMT

Drug resistance

Identification ofgenomic and

epigenetic alterationsand validation of

candidate oncogenicdrivers

Metabolic changesCancer cell

signalingTumor immunology

Angiogenesis

Colonizationor dormancyRole of the

microenvironment

Targeted therapiesImmunotherapy

Primary tumor

Secondarytumor

Immature DCMacrophage

Cancer stem cell Tumor cellActivated fibroblast

T cells

nature medicine volume 17 | number 3 | mArch 2011 263

i n t r o d u c t i o n

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 cell’s 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 also—in the face of the as-yet-incomplete understanding of the biological diversity of cancer—to 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 years2–9. 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 premise—much debated—of 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 cell–like 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.

Kat

ie V

icar

i

© 2

011

Nat

ure

Am

eric

a, In

c. A

ll ri

gh

ts r

eser

ved

.

i n t r o d u c t i o n

different systems and in a shorter timeframe (see the Perspectives by Lynda Chin and René Bernards and their respective colleagues on pp 297 and 304). Genomic studies are gener-ally static, however, analyzing tumor samples at a single point in time, and they are restricted to those tumors for which there is sufficient high-quality material available for study. Extending these studies to draw a dynamic map of sequence alterations acquired from preneoplasia to metastasis—in human tumors, tumor cell lines or mouse models—would provide new information of the sequence of events required for tumorigenesis and might either allay critics or support their concerns if the patterns of mutation acquisition among tumors are similar.

Insights into treatment failureAlthough most recent cancer sequencing efforts still have a long way to go toward generating tangible therapeutic advances, where they may succeed in providing action-able clinical information is in determining the mutation spectrum induced or selected by cancer therapy and influenced by pre-existing genetic background that may one day guide personalized cancer treatment. In the meantime, informative, directed studies on the mechanisms of resistance to BRAF inhibitors, PARP inhibitors, adverse effects of antiangiogenic therapy and an in vitro model of drug resistance invoking epigenetic rather than genetic alterations were at the top of our respondents’ list of advances from the last two years.

Three papers identified in our survey describe the unanticipated effect of BRAF inhibitors on tumor cells and highlight the importance of continued analysis of cancer therapies at the bench while clinical studies are ongoing20–22. The three reports show that BRAF inhibitors activate, rather than inhibit, downstream MEK signaling, thereby promot-ing tumor cell proliferation, and offer different mechanistic explanations by which this may occur. The findings explain the unanticipated skin cell hyperproliferation seen in some mel-anoma trials of BRAF inhibitors and, based on the mechanisms elucidated, suggest that the use of BRAF inhibitors should be restricted to tumors with activating BRAF mutations (see Julian Downward’s News & Views on p 286).

Similarly, a study investigating mechanisms of resistance to poly(ADP-ribose) polymerase (PARP) inhibitors reported that intragenic deletion of BRCA2 led to restoration of homologous recombination in BRCA2 mutant cells, ablating the sensitivity of these cells to PARP inhibitors23. In a separate report, muta-tions in BRCA2 were also found to account

for cisplatin resistance24. PARP inhibitors are now in clinical trials for the treatment of BRCA mutant tumors, and the interest in their use is reflected in our respondents’ pick of the phase 1 trial of the PARP inhibitor ola-parib, which showed antitumor activity and fewer side effects than conventional chemo-therapy25 (for additional detail, see the News & Views on p 283). However, it is important to now verify in the olaparib-treated patients whether treatment resistance is associated with restoration of BRCA2 function, as was seen in cisplatin-treated patients, and to tailor therapy decisions accordingly.

An alternative approach to identifying mechanisms of resistance to chemotherapy is to analyze cells that survive long-term cul-ture with cytotoxic agents. Using this method, Sharma et al. reported that a drug-tolerant state was acquired by cells cultured with an EGFR inhibitor through global modification of DNA methylation (see News & Views by Stephen Baylin on p 288 and the Review of cancer epi-genetics by Manuel Rodríguez-Paredes and Manel Esteller on p 330). Reduced chromatin methylation was caused by the upregulation of a histone demethylase, KDM5A, which in turn was triggered by IGF-1 receptor signal-ing26. Interestingly, this drug-tolerant state was reversible, the upregulation of KDM5A correlated with expression of markers associ-ated with cancer stem cells, and drug tolerant cells could be killed using HDAC inhibitors or an IGF-1R inhibitor. The findings suggest both an underappreciated role of epigenetics in mediating drug sensitivity and a need to consider epigenetic modifications in addi-tion to genetic alterations when searching for mechanisms of drug resistance. And although the in vivo relevance of these mechanisms still needs to be demonstrated, the findings sug-gest that therapeutic approaches that corner a tumor cell into adopting a less fit state or one that has greater susceptibility than the paren-tal tumor cell to a second drug regimen may help staunch treatment failure.

Immune mechanisms in cancerThe past two years have seen the field of cancer immunotherapy finally come to the fore. Although monoclonal antibodies are a mainstay of cancer therapy, the mechanisms underlying their efficacy are now recog-nized to include immune-mediated effects. More directed immunotherapy approaches have been approved recently (the Provenge dendritic cell vaccine for the treatment of advanced prostate cancer) or are showing promising results in clinical trials (ipilimumab in patients with metastatic melanoma27), showcasing the potential of harnessing the

immune system as a means to treat cancer patients. Drew Pardoll briefly reviews the advances in cancer immunotherapy since 1999 in the Timeline on p 293.

The interest in tumor immunology does not lie solely in the results of immunotherapy tri-als but extends to prognostic information that can be derived from the presence of immune cells in tumors as well as to ongoing insights from the bench, with a focus on the role of myeloid cells, their modulation of the tissue microenvironment and their pro- and antitu-morigenic potential. Two preclinical studies in particular, on the intersection of myeloid cells with adaptive immunity, resonated with our survey respondents because they suggest that T and B cells may have an adverse role in tumorigenesis (see News & Views by Alberto Mantovani on p 285)28,29. If a similar role for T and B cells is shown in human tumors, such findings may need to be taken into account in immunotherapy regimens and applied to a broader understanding of the factors that drive and maintain tumorigenesis than may be derived from the sequence analysis of tumor cells alone. Mina Bissell and Curt Hines expand on this idea that tumors don’t arise in a vacuum, and on the importance of the microenvironment in both restraining and promoting tumor development, in their Review on p 320.

Summing upIt is striking to consider, in this survey of the most influential findings of the past two years, that only a handful of the selected stud-ies are clinical trials of potential new cancer therapies. Instead, the majority of the papers cited report basic biological insights that must now be translated into clinical advances. And although not all of the findings described in experimental systems will prove to have clear relevance to human cancer, the high ratio of basic to applied studies underlines the wealth of information that exists with the potential for clinical insights, as well as the bottleneck limiting its therapeutic application. But new technologies, increased collaboration on an individual as well as organizational level, and the speed of response of the research com-munity—as seen in the validation of findings and evolution of ideas in the past two years alone—will breach this bottleneck.

Advances in science can often seem incre-mental when viewed up close and in a topic-focused manner. But when we take a step back to look at the accomplishments of the cancer field as a whole, those achieved in the last two years and informed by those of the past decade, it is clear that enormous strides have been made at the bench and in the clinic that

264 volume 17 | number 3 | mArch 2011 nature medicine

© 2

011

Nat

ure

Am

eric

a, In

c. A

ll ri

gh

ts r

eser

ved

.

i n t r o d u c t i o n

nature medicine volume 17 | number 3 | mArch 2011 265

17. Al-Hajj, M. et al. Proc. Natl. Acad. Sci. USA 100, 3983–3988 (2003).

18. Barker, N. et al. Nature 457, 608–611 (2009).19. Goldstein, A.S. et al. Science 329, 568–571 (2010).20. Poulikakos, P.I. et al. Nature 464, 427–430 (2010).21. Hatzivassiliou, G. et al. Nature 464, 431–435

(2010).22. Heidorn, S.J. et al. Cell 140, 209–221 (2010).23. Edwards, S.L et al. Nature 451, 1111–1115 (2008).24. Sakai, W. et al. Nature 451, 1116–1120 (2008).25. Fong, P.C. et al. N. Engl. J. Med. 361, 123–134

(2009).26. Sharma, S.V. et al. Cell 141, 69–80 (2010).27. Weber, J.S. et al. J. Clin. Oncol. 26, 5950–5956

(2008).28. DeNardo, D.G. et al. Cancer Cell 16, 91–102

(2009).29. Andreu, P. et al. Cancer Cell 17, 121–134 (2010).

1061–1068 (2008).4. Jones, S. et al. Science 321, 1801–1806 (2008).5. Mardis, E.R. et al. N. Engl. J. Med. 361, 1058–1066

(2009).6. Mossé, Y.P. et al. Nature 455, 930–935 (2008).7. Wood, L.D. et al. Science 318, 1108–1113 (2007).8. Pleasance, E.D. et al. Nature 463, 184–190

(2010).9. Mullighan, C.G. et al. Science 322, 1377–1380

(2008).10. Yan, H. et al. N. Engl. J. Med. 360, 765–773 (2009).11. Dang, L. et al. Nature 462, 739–744 (2009).12. Ward, P.S. et al. Cancer Cell 17, 225–234 (2010).13. Lapidot, T. et al. Nature 367, 645–648 (1994).14. Kelly, P.N. et al. Science 317, 337 (2007).15. Mani, S.A. et al. Cell 133, 704–715 (2008).16. Rosen, J.M. & Jordan, C.T. Science 324, 1670–1673

(2009).

benefit all arms of biomedical research and that lay a firm foundation for true gains for cancer patients in the future.

ACKNOWLEDGMENTSWe thank all of our survey respondents for their seminal insights into the recent advances in cancer research and the authors of the Book Reviews, News & Views, Timeline, Perspectives and Reviews for their crucial contributions to this Focus on Cancer.

1. Quintana, E. et al. Nature 456, 593–598 (2008).2. Parsons, D.W. et al. Science 321, 1807–1812

(2008).3. Cancer Genome Atlas Research Network. Nature 455,

© 2

011

Nat

ure

Am

eric

a, In

c. A

ll ri

gh

ts r

eser

ved

.