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introduction

A close look at cancer


Alison 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.

I n 2010, we asked more than 400 experts to


help us identify papers published within
the previous two years that have made a
protein in glioblastoma multiforme10–12 and
shed fresh mechanistic insights on the role
of metabolic changes in cancer (see News &
into mice14. By transplanting mouse leukemia
and lymphoma cells into histocompatible
mice, the authors showed that at least 10%
© 2011 Nature America, Inc. All rights reserved.

significant impact on the field of cancer. By Views, p 291). of the cancer cells could regenerate tumors
doing so we hoped to highlight those papers The list of papers is by no means complete. in vivo.
influencing current thinking and funding There are instances in which highly related What remained untested was whether
trends, pinpoint key questions stimulating papers published simultaneously or before these findings were restricted to tumors of
the cancer field and help identify gaps in 2008 did not receive the same numbers of hematopoietic origin or whether solid—
the knowledge and focus of cancer research. votes, or in some instances were not selected and more heterogeneous—tumors also had
One hundred and fifty respondents recom- by our respondents. The oversights are unin- a higher frequency of tumor-initiating cells
mended 319 papers (compiled in the tables tentional, and are no doubt due to our request than previously predicted when the immune
on p 280), and the most frequently selected that respondents cite off the top of their heads background was made more permissive to
papers are discussed in greater depth in News their choice of the most interesting and note- their growth. As clearly indicated by our
& Views and Research Highlights in the ensu- worthy papers of the preceding two years. The respondents, and described in a Research
ing pages. omissions do not negate the contribution of Highlight (p 294), Elsa Quintana and col-
A quick glance at the most highly cited related or preceding papers; instead, the exis- leagues provided a singularly important con-
papers in our survey and our tally of selected tence of related papers probably served to tribution to this discussion by showing that
papers by topic reveals several areas that are strengthen the interest in and recognition of as many as 25% of cells in advanced human
clearly inspiring strong interest within the the concepts collectively presented. melanoma are capable of initiating tumors in
field. These include, but are not limited to, A second point worth mentioning is that immunodeficient mice1.
cancer genomics, cancer stem cells and new the papers selected by experts were frequently In order to develop effective therapies, it is
cancer-driving mutations as well as tumor outside the main focus of their own research. essential to put the cancer stem cell hypothesis
cell signaling and metastasis, mechanisms This finding emphasizes the broad appeal of to the test, as it contends that targeting the
of drug resistance, and recent preclinical and papers that shed new light on tumor biology tumor-initiating cells, regardless of their fre-
clinical advances in cancer immunology and and that can be generalized across cancer dis- quency, will be required to eradicate tumors.
therapy. ciplines, and the importance of communicat- And consistent with their distinct biology that
Two areas in particular stand out from this ing new results to the widest possible audience enables cancer stem cells to sustain tumor
exercise in terms of capturing people’s atten- so as to inform research and encourage col- growth, their susceptibility to antitumor
tion: cancer stem cells and cancer genom- laboration in disparate cancer fields. agents may also be distinct from that of the
ics. The first is dominated by a single paper Here we discuss some of the key areas of bulk of tumor cells. But whether cancer stem
describing the frequency of tumor-forming interest cited in this survey, and we consider cells are a component of every tumor type
cells in metastatic melanoma1, and the sec- their impact on basic and applied cancer is now a matter of debate, and the stem cell
ond is a discovery approach represented by a research and how they are paving the way to hypothesis continues to evolve to consider
collection of at least eight papers detailing the future discoveries (Fig. 1). the possibility that these cells comprise dif-
genomic landscape of a variety of tumors2–9. ferent fractions of a tumor in different indi-
Underlining the interest in cancer genomics as The search for cancer stem cells viduals, that tumor cells in general may be
a powerful tool to rapidly identify new onco- The cancer stem cell hypothesis proposed that sufficiently plastic to interconvert between
genic drivers are three more of the most highly a subset of cancer cells is able to maintain and tumor stem and non-stem cells, and that the
cited papers, which followed up—within the propagate a tumor. Although these were origi- tumor microenvironment and an epithelial-
space of two years—an original finding from nally thought to comprise a very small frac- to-mesenchymal transition15 may have key
a genomic study2 that identified isocitrate tion (less than 0.1%) of the cells in a tumor13, roles in influencing this plasticity16.
dehydrogenase-1 (IDH1) as a candidate onco- a study in 2007 suggested that this assumption Although candidate markers of tumor stem
might be based on the constraints imposed cells exist, it is an open question whether there
Alison Farrell is a senior editor of Nature Medicine. by xenotransplantation of human tumor cells are identifiable molecular markers of tumor

262 volume 17 | number 3 | march 2011 nature medicine


introduction

stem cells that are relevant to their function


and that can distinguish them from their more Targeted therapies
differentiated descendants, and whether such Immunotherapy
markers are common to tumor stem cells
Colonization
of different tissues of origin. More data are Identification of
or dormancy
genomic and Primary tumor
needed from human tumors to provide some epigenetic alterations Cell of origin
Role of the
Role of EMT
answers to these questions and to determine and validation of microenvironment
candidate oncogenic Drug resistance
the dependence of clinical outcome in can- drivers
cer patients on tumor stem cells. Whether Metabolic changes
the growth of metastases is dependent on the Cancer cell Secondary
stem cell phenotype, whether plasticity or a signaling tumor

Katie Vicari
Tumor immunology
fixed phenotype determines a tumor cell’s
Angiogenesis Macrophage Immature DC T cells
ability to colonize a distant site or go dormant,
Activated fibroblast Cancer stem cell Tumor cell
and whether adjuvant chemotherapy killing
of disseminated tumor stem cells accounts
Figure 1 Notable advances in cancer research. In a survey of cancer researchers, recent reports on
for tumor remission in patients are all ques- cancer stem cells, cancer genomes and cancer therapies garnered the most attention from respondents.
tions with important implications for future Cancer stem cell (CSC) studies have yielded new insights into the cells of origin of some tumors, the
clinical decisions. These issues and others role of the epithelial-to-mesenchymal transition (EMT) in conferring stem cell–like properties and the
are discussed in the Review by Hans Clevers contribution of CSCs to drug resistance, and they have also triggered questions about the CSC hypothesis
(p 313). itself. Cancer genome sequencing studies continue to yield data on cancer-initiating and -promoting
© 2011 Nature America, Inc. All rights reserved.

Funding agencies and universities have 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
invested enormously in the study of cancer in immunotherapy and targeted molecular therapy, as well as mechanisms of treatment resistance, also
stem cells since the initial identification of a provoked significant interest, as did studies of the role of the immune system and new molecular players
population of tumor-initiating cells in solid in tumor growth, signaling and metastasis. The image depicts a metastasizing tumor and highlights the
(breast) tumors mirrored earlier findings areas of cancer research most frequently selected by the survey respondents.
in acute myelogenous leukemia13,17. And
outgrowths of this concentrated effort have sequencing studies was to generate a com- tumor-initiating events from those that are
yielded important new insights, including into prehensive characterization of the profile of tumor promoting or that impinge more spe-
the cells of origin of different tumors, such genetic alterations in tumors, with the hope cifically on metastasis, as well as the interde-
as colon18, as noted by our respondents, and that this approach would elucidate the under- pendence of the three classes in giving rise to
more recently of the prostate18,19. The impor- pinnings of cancer through more rapid iden- a tumor with metastatic potential, will require
tance of studies showing that tumor-initiating tification of the key genetic events driving a substantial investment of time, effort and
ability is not restricted to a very small subset tumorigenesis and of candidate therapeutic funds.
of cells, and of the possibility of interconver- targets than existing, hypothesis-driven strat- Yet the Cancer Genome Atlas Project,
sion of tumor stem and non-stem cells, lies not egies. Thus far, these studies have generated overseen by the US National Cancer Institute
in discounting the stem cell hypothesis or its new insights into cancer causation, including, and the National Human Genome Research
ramifications. Rather, such reports underline but not limited to, the identification of IDH1 Institute, intends to spend an estimated
the need to test the limitations of experimen- and IDH2 as oncogenic drivers in glioblas- $1 billion to sequence thousands more tumor
tal assays, to incorporate into stem cell studies toma and in acute myeloid leukemia, and samples over the next five years. Although
findings and technologies from the full spec- of germline mutations in the gene encoding technological advances will further reduce
trum of cancer research, and also—in the face anaplastic lymphoma kinase (ALK) in familial the cost of these efforts, and high-through-
of the as-yet-incomplete understanding of the neuroblastoma (see News & Views on p 290). put functional validation of candidate genes
biological diversity of cancer—to recognize a They have identified mutations associated of interest can be envisaged, doubts remain as
hypothesis for what it is. with environmental factors (tobacco smoke), to whether large-scale sequencing efforts are
crucial pathways that are altered in pancre- time and cost effective as well as how much
Cashing in on cancer genomics atic cancer, and evidence of high intertumor more new information will be generated by
The response we received in support of can- variation in mutated pathway components, new sequencing studies beyond that con-
cer genomics as an area of great impact was emphasizing the need to target tumor nodes tained in the enormous amount of data col-
overwhelming. Eight separate studies ana- rather than individual gene products. lected to date (http://news.Sciencemag.org/
lyzing the genomic and transcriptomic pro- These studies provide a wealth of data to scienceinsider/2010/04/a-skeptic-questions-
files of tumors arising in the brain, pancreas, explore for new players and pathways driving cancer-genom.html).
breast, colon and hematopoietic system were mutagenesis, but separating oncogenic driv- The counterargument is that the utility of
identified by our experts as key advances of ers from passenger mutations is no easy task. these studies lies not solely in their identifi-
the last two years2–9. In their delineation of These designations are initially assigned on cation of oncogenes and tumor suppressors
nucleotide sequence, epigenetic modifications the basis of statistical analysis and recurrence but also in their potential to provide new
and transcriptional profiles of solid tumors in multiple tumors, but such assumptions biomarkers for early detection, insights into
and leukemias, these studies have catalogued must be borne out by functional valida- pathway interactions and epigenetic modula-
the candidate oncogenic drivers as well as the tion, a requirement that limits the speed of tion of tumor phenotypes, an understanding
predicted nontumorigenic passenger muta- translation of genomic information into new of the maternal versus paternal contribution
tions accumulated by established tumors. therapeutic targets or mechanisms. Similarly, to cancer, and mechanisms of drug resistance
The premise—much debated—of these distinguishing genetic alterations that are that will complement existing studies in

nature medicine volume 17 | number 3 | march 2011 263


introduction

different systems and in a shorter timeframe for cisplatin resistance24. PARP inhibitors immune system as a means to treat cancer
(see the Perspectives by Lynda Chin and René are now in clinical trials for the treatment patients. Drew Pardoll briefly reviews the
Bernards and their respective colleagues on of BRCA mutant tumors, and the interest in advances in cancer immunotherapy since
pp 297 and 304). Genomic studies are gener- their use is reflected in our respondents’ pick 1999 in the Timeline on p 293.
ally static, however, analyzing tumor samples of the phase 1 trial of the PARP inhibitor ola- The interest in tumor immunology does not
at a single point in time, and they are restricted parib, which showed antitumor activity and lie solely in the results of immunotherapy tri-
to those tumors for which there is sufficient fewer side effects than conventional chemo- als but extends to prognostic information that
high-quality material available for study. therapy25 (for additional detail, see the News can be derived from the presence of immune
Extending these studies to draw a dynamic & Views on p 283). However, it is important cells in tumors as well as to ongoing insights
map of sequence alterations acquired from to now verify in the olaparib-treated patients from the bench, with a focus on the role of
preneoplasia to metastasis—in human tumors, whether treatment resistance is associated myeloid cells, their modulation of the tissue
tumor cell lines or mouse models—would with restoration of BRCA2 function, as was microenvironment and their pro- and antitu-
provide new information of the sequence of seen in cisplatin-treated patients, and to tailor morigenic potential. Two preclinical studies
events required for tumorigenesis and might therapy decisions accordingly. in particular, on the intersection of myeloid
either allay critics or support their concerns An alternative approach to identifying cells with adaptive immunity, resonated with
if the patterns of mutation acquisition among mechanisms of resistance to chemotherapy our survey respondents because they suggest
tumors are similar. is to analyze cells that survive long-term cul- that T and B cells may have an adverse role in
ture with cytotoxic agents. Using this method, tumorigenesis (see News & Views by Alberto
Insights into treatment failure Sharma et al. reported that a drug-tolerant state Mantovani on p 285)28,29. If a similar role for
Although most recent cancer sequencing was acquired by cells cultured with an EGFR T and B cells is shown in human tumors, such
© 2011 Nature America, Inc. All rights reserved.

efforts still have a long way to go toward inhibitor through global modification of DNA findings may need to be taken into account
generating tangible therapeutic advances, methylation (see News & Views by Stephen in immunotherapy regimens and applied
where they may succeed in providing action- Baylin on p 288 and the Review of cancer epi- to a broader understanding of the factors
able clinical information is in determining genetics by Manuel Rodríguez-Paredes and that drive and maintain tumorigenesis than
the mutation spectrum induced or selected Manel Esteller on p 330). Reduced chromatin may be derived from the sequence analysis
by cancer therapy and influenced by pre- methylation was caused by the upregulation of tumor cells alone. Mina Bissell and Curt
existing genetic background that may one of a histone demethylase, KDM5A, which in Hines expand on this idea that tumors don’t
day guide personalized cancer treatment. In turn was triggered by IGF-1 receptor signal- arise in a vacuum, and on the importance of
the meantime, informative, directed studies ing26. Interestingly, this drug-tolerant state the microenvironment in both restraining
on the mechanisms of resistance to BRAF was reversible, the upregulation of KDM5A and promoting tumor development, in their
inhibitors, PARP inhibitors, adverse effects correlated with expression of markers associ- Review on p 320.
of antiangiogenic therapy and an in vitro ated with cancer stem cells, and drug tolerant
model of drug resistance invoking epigenetic cells could be killed using HDAC inhibitors Summing up
rather than genetic alterations were at the top or an IGF-1R inhibitor. The findings suggest It is striking to consider, in this survey of
of our respondents’ list of advances from the both an underappreciated role of epigenetics the most influential findings of the past two
last two years. in mediating drug sensitivity and a need to years, that only a handful of the selected stud-
Three papers identified in our survey consider epigenetic modifications in addi- ies are clinical trials of potential new cancer
describe the unanticipated effect of BRAF tion to genetic alterations when searching for therapies. Instead, the majority of the papers
inhibitors on tumor cells and highlight the mechanisms of drug resistance. And although cited report basic biological insights that must
importance of continued analysis of cancer the in vivo relevance of these mechanisms still now be translated into clinical advances. And
therapies at the bench while clinical studies needs to be demonstrated, the findings sug- although not all of the findings described in
are ongoing20–22. The three reports show that gest that therapeutic approaches that corner a experimental systems will prove to have clear
BRAF inhibitors activate, rather than inhibit, tumor cell into adopting a less fit state or one relevance to human cancer, the high ratio of
downstream MEK signaling, thereby promot- that has greater susceptibility than the paren- basic to applied studies underlines the wealth
ing tumor cell proliferation, and offer different tal tumor cell to a second drug regimen may of information that exists with the potential
mechanistic explanations by which this may help staunch treatment failure. for clinical insights, as well as the bottleneck
occur. The findings explain the unanticipated limiting its therapeutic application. But new
skin cell hyperproliferation seen in some mel- Immune mechanisms in cancer technologies, increased collaboration on an
anoma trials of BRAF inhibitors and, based on The past two years have seen the field of individual as well as organizational level, and
the mechanisms elucidated, suggest that the cancer immunotherapy finally come to the the speed of response of the research com-
use of BRAF inhibitors should be restricted to fore. Although monoclonal antibodies are a munity—as seen in the validation of findings
tumors with activating BRAF mutations (see mainstay of cancer therapy, the mechanisms and evolution of ideas in the past two years
Julian Downward’s News & Views on p 286). underlying their efficacy are now recog- alone—will breach this bottleneck.
Similarly, a study investigating mechanisms nized to include immune-mediated effects. Advances in science can often seem incre-
of resistance to poly(ADP-ribose) polymerase More directed immunotherapy approaches mental when viewed up close and in a topic-
(PARP) inhibitors reported that intragenic have been approved recently (the Provenge focused manner. But when we take a step back
deletion of BRCA2 led to restoration of dendritic cell vaccine for the treatment of to look at the accomplishments of the cancer
homologous recombination in BRCA2 mutant advanced prostate cancer) or are showing field as a whole, those achieved in the last
cells, ablating the sensitivity of these cells to promising results in clinical trials (ipilimumab two years and informed by those of the past
PARP inhibitors23. In a separate report, muta- in patients with metastatic melanoma27), decade, it is clear that enormous strides have
tions in BRCA2 were also found to account showcasing the potential of harnessing the been made at the bench and in the clinic that

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seminal insights into the recent advances in cancer 9. Mullighan, C.G. et al. Science 322, 1377–1380 23. Edwards, S.L et al. Nature 451, 1111–1115 (2008).
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