Manuscript title: Cancer: endgame or shifting goalposts
Running title: Cancer: endgame or shifting goalposts
Author: Mostafa Fatehi, BSc., MSc. Student, Department of Molecular Genetics, University of Toronto
Room 540 Center for Cellular and Biomolecular Research,
160 College Street,
Toronto, Ontario,
Canada, M5S3E1
m.fatehi@utoronto.ca
Introduction
In 1971, the National Cancer Institute (NCI) supported cancer research projects
to the tune of $80 million; almost 40 years later, that amount has increased to over $4
billion (1). The massive increase in funding has yielded great benefits. These funds
have enabled thousands of bright minds to start their research careers in cancer
research labs under the tutelage of the pioneering scientists of the 70s and 80s. The
combined financial and human resources devoted to cancer have transformed cancer
from a likely death sentence to a disease where the relative 5-year survival is almost
70% in the US (2).
In the process, we have learnt that cancer is, in fact, a collection of hundreds of
diseases that will require a multiplicity of treatment strategies. Moreover, there are wide
discrepancies in the five-year survival rates associated with different cancer types
ranging from 5% in the case of pancreatic cancer to over 99% in non-melonoma skin
cancer (2). In addition, improvements in prognosis have also been varied across cancer
types. Improvements to lung cancer prognoses have not mirrored the amazing
improvements in testicular cancer or retinoblastoma.
Despite the inherent differences between various cancer types, there are some
common management strategies. Perhaps, the most far-reaching information to emerge
from cancer studies points to prevention as the most efficient way of battling cancer (3)
and prevention is now at the forefront of cancer management. Cancer prevention
encompasses a wide range of highly developed science and clinical impact which are
crucially linked. Enhanced understanding of the cellular and biochemical mechanisms of
carcinogenesis have led to new legislations like smoking bans and laws against
asbestos use. The promise of integrative research is to improve the ability of clinical
prevention to reduce the burden of cancer.
Since the 1950s a major concern of cancer research has been to model and
understand tumor initiation and progression. Early findings that age-dependent
incidence data met the requirement of several probabilistic events for cancer evolution
led to the multistep theory of carcinogenesis (4-7). Later, Knudson’s statistical analysis
of Retinoblastoma gave rise to the concept of a tumor-suppressor gene (8). The finding
that only a subset of cancer cells has in vivo tumor-initiation ability, and the recent
isolation of these cells in various cancers, has led to the cancer stem cell hypothesis.
There is some controversy regarding the origin of cancer stem cells (CSCs) but their
role in tumor growth, metastasis and the evolution of drug-resistance has made CSCs
the focus of much research activity. Because CSCs are more resistant to conventional
therapeutics than their non-CSC counterparts, and because CSCs are able to
regenerate differentiated progeny, there is a need for more CSC-specific therapies (9).
Novel treatment strategies provided by the progress in understanding genetic
mutations, cellular pathways, cancer stem cells and drug delivery promise major
advances in cancer treatment. This is not to claim that cancer has been cured or to
trivialize the real anxiety that is still associated with the diagnosis of cancer. Rather, a
better understanding of our accomplishments in battling cancer can invigorate further
research, highlight shortcomings and help guide new research. As mentioned, some
cancer types still have miserably low survival rates while others require expensive lifelong treatments. Furthermore, the lag in knowledge transfer to developing nations
threatens to make cancer a crippling epidemic in these countries. Hence, while there is
much to be proud of in our battle against cancer, there are still important objectives to
be reached before we can declare victory over cancer.
In this article, I will present incidence rates for some cancers and underscore
some significant improvements in prognosis before discussing some cancer types that
are still largely incurable. Most of the data presented here will be from the United States
but the trends should match those in Canada and other developed nations quite closely.
Great attention has been focused on cancer prevention; and, I will highlight some of the
more recent prevention targets. Finally, I will introduce the concept of cancer stem cells;
this model of cancer initiation, progression and regeneration has major implications for
cancer prevention and the development of novel therapies.
Cancer is not a single disease
From a clinical point of view, cancer is a large group of diseases that vary in their
age of onset, rate of growth, state of cellular differentiation, diagnostic detectability,
invasiveness, metastatic potential, response to treatment, and prognosis. Technical
advances have allowed larger numbers of individuals with a given disease to be
studied. As previously unappreciated “subclasses” of disease are detected, the
accuracy of prognosis has improved. Most recently, there are attempts to further
classify cancers in terms of global gene/protein expression patterns by employing postgenome era technologies such as oligonucleotide arrays and proteomics (10).
Today, there are over 200 different types of cancers and many have subtypes.
The most common cancer worldwide is non-melonoma skin cancer (NMSC) which
represents nearly half of all cancers diagnosed in the United States (more than 1million
new cases estimated in 2009). Another common cancer worldwide and in the US is lung
cancer with over 200000 new cases in the US in 2009. However, the mortalities
associated with these two cancer type are very different (<1000 for NMSC and more
than 150000 for lung cancer) (2). As shown in Figure 1, age-adjusted incidence rates for
most invasive cancer types have fluctuated over the past 35 years but the recent trend
for major cancers is downward which reflects better preventative behaviour in the
United States (a significant exception is lung cancer in females which mirrors the rise
and subsequent stabilization of tobacco use in this section of the population). However,
most developing nations lag behind in implementing preventative measures and, as
these populations age, the rate of new cancers are expected to rise dramatically. The
World Health Organization predicts a 50% increase in new cancer cases worldwide
from 10 million in 2000 to 15 million in 2020 (11).
A)
B)
C)
Figure1. A) Age-adjusted incidence rates for four of the major cancers in the United States have had a
downward trend in the past decade. Colorectal and stomach cancer have been grouped together with
other digestive tract cancers. B) Three less common cancer types that have had relatively stable
incidence rates. C) The overall incidence rate, influenced by decreases in the major cancer types, has
dropped slightly in the past decade.
Cancer sites include invasive cases only. Data source: SEER 9 areas (San Francisco, Connecticut, Detroit,
Hawaii, Iowa, New Mexico, Seattle, Utah, and Atlanta).
While age-adjusted incidence rates have only started to drop in the past decade,
the overall five-year relative survival rates have been increasing steadily over the past
40 years. Significant improvements have been seen in prostate and breast cancer, but
as illustrated in Figure 2, the progress in lung and pancreatic cancer has been modest.
Part of this discrepancy may be explained by disparities in research effort and funding;
U.S. breast cancer funding was more than double that of lung cancer funding and 10
times that of pancreatic cancer in the past 10 years (National Cancer Institute). In some
cases, there have been dramatic improvements due to revolutionary new treatments
(Gleevec for Chronic Myeloid Leukemia and Cisplatin for testicular cancer). Better
molecular-level understanding of breast cancer has allowed for more type-specific
treatments while earlier detection of the disease (through regular screening of woman
over 50) has allowed treatment of less progressed cancers.
On the other hand, cancers which suffer from low survival rates like lung and
pancreatic cancer have few reliable screening modalities and are largely symptom-free
in early stages; thus, patients are usually first diagnosed when the cancer is in an
advanced stage. Furthermore, all cancers are not equally amenable to treatments such
as surgical resection or aggressive chemotherapy. Finally, there are differences in the
microenvironment for each cancer type. For example, in the case of pancreatic cancer,
the unique tumor microenvironment confers relative chemoresistance to agents that are
effective in treating breast and prostate cancer (12).
Figure2. A) Improving 5-Year relative survival rates for some of the major cancer types. Leukemia
treatment has benefited from the use of Gleevec starting in 2001.B) Three cancer types that still have
poor 5-year survival rates.
Cancer sites include invasive cases only. Data source: SEER 9 areas (San Francisco, Connecticut,
Detroit, Hawaii, Iowa, New Mexico, Seattle, Utah, and Atlanta).
Perhaps the most telling statistic in the fight against cancer may be the mortality
rate. Like all other cancer statistics, the mortality rate varies considerably for different
ages, cancer types and ethnicity but as illustrated in Figure 3, the age-adjusted1
mortality rate for all races and sexes has consistently dropped in the past 40 years (2).
Using linear curves to fit this trend may allow us to extrapolate future mortality rates with
the caveat that this fit will account for advances in technology and novel treatments that
may accelerate the decreasing trend. Conversely, as mortality rates drop, fewer major
discoveries remain to be made and thus, the future trend will be a competition between
improved technology and the difficulty of completing the cure of all types of cancer.
Regardless, using data from 1980-2006, it may be postulated that mortality rates will
drop 50% from their current levels by 2050 in the United States.
Hence, a major goal of cancer research should be to better understand the
molecular characteristics of cancer types that have poorer prognoses and use this
knowledge to develop better curative strategies for these diseases. Applying knowledge
of cancer stem cells in pancreatic and lung cancers may highlight novel therapeutic
targets. In addition, there is a need to expand upon and improve existing screening and
diagnostic modalities so that cancers are detected in their earlier, more manageable,
stages.
1
The NCI defines the age-adjusted rate as “a weighted average of the age-specific (crude) rates, where the weights
are the proportions of persons in the corresponding age groups of a standard population”. This rate is used in
comparisons to reduce the confounding effect of an aging population. All data presented here used the 2000 U.S.
population.
U.S. Mortality (Total U.S.) - AA Rates for White/Black/Other, 1969-2006
With linear curve fit to estimate future mortality rates
1400
1200
Rates per 100000
1000
800
600
400
200
0
1960
1980
2000
2020
2040
Year of Death
Actual Mortality rates
Linear fit to data
Linear Fit to 1980-2006 Data
Figure 3. Age-adjusted mortality rates for all races and sexes from 1969-2006 in the U.S. I have
included two linear fits one with for the 1969-2006 data and the other for the 1980-2006 data to
account for the sharp decrease in mortality from 1969-1980. I have used the linear fits to extrapolate
mortality rates for 2050.
Cancer Prevention
Cancer prevention is an expansive field where scientific advances in
understanding carcinogenic initiation and progression are used to modify guidelines and
public health policy. In its most general sense, cancer prevention can be divided into
three parts.
In primary prevention the goal is to identify and avoid exposure to carcinogens
and carcinogenic behaviour. This area of prevention is perhaps the most difficult to fully
implement because of its dependence on public participation and behavioural
modifications like dietary changes and increased physical activity. Battling tobacco use
is an example of the potential of primary prevention and the challenges associated with
its implementation. Since the late 50s, scientists have presented increasingly robust
evidence that tobacco use increases ones chance of developing lung cancer and
tobacco use has fallen quite dramatically in Canada (35% of the population in 1985 to
18% in 2008) and the United States (42% of population in 1966 to less than 20% in
2006)(13,14). In developing countries, however, tobacco use rose considerably in the
past five decades (already 82% of smokers live in developing countries) and is
projected to rise further unless more action is taken. Tobacco causes 80-90% of lung
cancers in developing countries (11) and thus, decreasing tobacco consumption will be
of paramount importance in controlling the incidence rate of this disease (Figure 4).
The goal of secondary cancer prevention is to detect cancer at an early stage
and prevent the progression to invasive disease. Attempts are focused at eliminating or
reducing existing risk in a generally more-specified risk population. Ideally, molecular
screening helps to identify those at higher risk prior to the development of premalignant
lesions. For example, germline BRCA mutation carriers can choose prophylactic
mastectomy or patients with colorectal adenomas can be monitored and treated with
nonsteroidal anti-inflammatory drugs (NSAIDs) (3).
Figure 4. Tobacco consumption trends. Obtained with permission from the Food and Agriculture
Organization of the United Nations (15).
Finally, in tertiary prevention the aim is to prevent recurrence of disease in
successfully treated patients. For example, in patients who have had breast conserving
surgery, post-operative radiotherapy (50Gy for whole breast) decreases local
recurrence from 35% to 10% and there are further improvements with additional doses
(16). In more advanced cases, the objective is to minimize disease symptoms (such as
managing pain with morphine and nausea with compazine) and the morbidity
associated with the treatment (3).
New molecular insights point to improvements in all three levels of prevention.
For example in primary prevention, information about the role of human
papillomavirus(HPV) in cervical cancer and hepatitis B virus(HBV) in hepatocellular
cancer led to successful clinical trials for vaccines against these viruses. In secondary
prevention, there is mounting evidence that premalignant lesions are more common
than previously thought and this highlights the need for more accurate risk stratification
and improved screening modalities. Furthermore, there is much interest in
understanding the mechanism by which premalignant lesions develop into cancer. For
example, it is well known that the stromal environment is altered in a premalignant
lesion and that these changes may facilitate tumor progression through angiogenesis
and heightened growth factor levels. Because of the powerful effect of stromal
components, influencing disease progression and modulating the signals in
premalignant lesions is an emerging area of cancer prevention. Finally, in tertiary
prevention it was recently shown that administration of agonist CD137 monoclonal
antibodies stimulate expansion of tumor antigen–specific memory T cells (Tms) in
mouse models with surgical resection of primary tumors. These cells are essential for
the surveillance of residual and metastatic tumors and thus their activation is an exciting
target of tertiary prevention (17).
Hence, it is clear that prevention will be a major prerequisite if we are to
successfully control cancer. The world health organization predicts that at least one
third of cancer cases can be prevented and this makes prevention the most costeffective long term strategy for cancer control. Moreover, there has been great progress
in identifying targets for prevention and accelerated translation of this knowledge into
clinical impact promises major improvements in cancer management.
Cancer Stem Cells
Understanding early neoplastic changes, tumor initiation, metastasis and tumor
progression is important for cancer prevention and effective targeting of cancer cells in
treatment. Our evolving knowledge of these processes has led to several different
models in the past, the multistep model for carcinogenesis, the tumor suppressor gene
and most recently the cancer stem cell (CSC) model (4-8).
As illustrated in Figure 5, the essential concepts of the CSC hypothesis are that
(a) tumors originate in either tissue stem cells or their immediate progeny through
dysregulation of the normally tightly regulated process of self-renewal. As a result of
this, (b) tumors contain a cellular subcomponent that retains key stem cell properties.
These properties include self-renewal, which drives tumorigenesis, and differentiation
albeit aberrant that contributes to cellular heterogeneity (18). There has also been some
controversy regarding the similarities between cancer stem cells and normal stem cells
(19); however, there is little doubt that there is a distinct subset of cancer cells with the
ability to self-renew and differentiate.
Figure5. Stem-differentiation hierarchy. Increased plasticity may be present within cancer populations,
enabling some bidirectional interconvertability between CSCs and non-CSCs. This may be a result of
contextual cues such as hypoxia-induced factors. (Image modified with permission from Dr. Robert
Weinberg)
The earliest evidence for the CSC hypothesis came from studies that reported
cells from both solid tumors and leukemia varied in their ability to form colonies in vitro
and in vivo (20, 21). The first patient-derived cancer stem cells were isolated in the Dick
laboratory and these leukemia cells were capable of initiating de novo leukemia in SCID
mice (22,23). Since then, numerous papers have reported stem-like cells in breast,
lung, brain, liver, melanoma, colon, prostate, ovarian and pancreatic cancers (24-35).
Cancer stem cells contribute to tumour growth, maintenance, and recurrence
after therapy through multiple mechanisms and networks. One important characteristic
of these cells is their ability to restrict DNA damage sustained during radiation or
chemotherapy by reduction of reactive oxygen species (ROS) and enhanced activity of
DNA checkpoint kinases (36,37). These cells are further protected against
chemotherapy by their cell membrane transporters that lower intracellular drug
concentrations and by their own microenvironment that supports self-renewal.
Experimental evidence has also demonstrated that cancer stem cells regulate tumour
angiogenesis by vascular endothelial growth factor (VEGF) signalling (9). In addition,
cancer stem cells are implicated in developing drug resistance in some cancers such as
chronic myeloid leukemia (CML) (4).
Due to their significance in maintaining tumors, CSCs are increasingly studied as
targets for treatment and there are indications that some previously difficult cancers to
treat such as lung and pancreatic cancer will benefit immensely from these novel
therapies. In fact, CSCs are thought to be partially responsible for the failure of current
chemotherapy of lung cancer (23). Moreover, experimental evidence indicates that stem
cell factor (SCF) and its receptor c-kit (CD117) play an important role in survival and
proliferation of lung CSCs (38). Thus, molecularly targeting highly tumorigenic and
metastatic CSCs must be considered for improving the efficacy of current anti-cancer
strategy. Recent studies in pancreatic cancer, found the CD44+CD22+ESA(epithelialspecific antigen)+ subpopulation of cancer cells is highly tumorigenic and exhibits
characteristics of stem cells such as self renewal, the ability to produce differentiated
progeny and increased sonic hedgehog expression(12).
It is clear that any truly curative treatment of cancer will have to target CSCs;
however, overlap of phenotype and cell signalling pathways between somatic and
cancer stem cells indicate that a main prerequisite for successful therapy is the ability to
avoid targeting normal stem cells. There is not enough literature in this field yet but an
effective way to contrast somatic and cancer stem cells may be in evaluating protein
expression levels and looking for mutant proteins specific to cancerous cells. For
example, low levels of telomerase are expressed in adult stem cells (39) and also in
more than 80% of tumor cells (40) but there may be targetable differences in expression
levels in CSCs. Alternatively, targeting a gene that is synthetic lethal2 to a cancerrelevant mutation should only kill the cancer stem cells (41). This concept is currently
being widely investigated; for breast cancer alone there are several studies in varying
phases of clinical trials targeting deficiencies in DSB repair (42). Finally, the epigenetic
landscape of some normal cancer cells has been found to be considerably different
from normal cells and hence using interfering RNA to epigenetically modify cancer cells
2
Two genes are synthetic lethal if mutation of either alone is compatible with viability but mutation of
both leads to death.
has become an area of much interest. Therapies based on synthetic lethality or using
RNAi when applied to CSCs should drastically improve our cancer treating capabilities.
The concept of CSCs has radically changed the view of cancer therapy and
prevention. A majority of current treatment modalities target the differentiated cancer
cells and avoid the drug resistant cancer-initiating stem cells and this impacts their
efficacy. It is now clear that any true cure for cancers will need to target the
subpopulation of cancerous cells that have the ability to self renew and differentiate
while distinguishing between these cells and somatic stem cells. Insights into the
genotype and phenotype of CSCs, their unique microenvironment and signalling
pathways will guide the development of selective treatments and will be a major
breakthrough in the battle against cancer.
Conclusions
Since the signing of the National Cancer Act of 1971, great resources have been
devoted to the battle against cancer. It was not the goal of this paper to present new
data, there are already over 100 thousand papers about cancer. Neither was it my intent
to just review the existing literature as great reviews are published every month. Rather,
I wanted to stand back, take a general’s perspective of the battlefield and try to discern
areas of progress and areas where further progress is required.
To this end, I have contrasted the current state of affairs of different cancer
types. There are large discrepancies in the improvements in 5-year survival rates
between different cancers. Further, I have evaluated preventative measures and the
science that is helping to guide these measures. Cancer prevention will obviously be
important in managing cancer in developed countries but will be of tremendous
importance in controlling cancer in developing countries. Finally, I have also highlighted
the most recent model for cancer initiation and progression, the cancer stem cell model.
The resistance of CSCs against conventional chemotherapy and their ability to
regenerate tumors after therapy has led to a paradigm shift in designing novel therapies
that target CSCs(43).
Furthermore, the rapid generation of high-quality genetic data and the increasing
ability to analyze this data will lead to accelerated development of personalized
treatments through pharmacogenomics. Novel treatment strategies like using interfering
RNA to epigenetically modify cancer cells or using synthetic lethality for treatment as
described above will allow exquisite targeting of cancer cells while minimizing damage
to somatic cells. However, in addition to targeting the bulk of the tumor cells, these
novel treatments should aim to specifically target CSCs.
Considering our scientific advances, the prospects for controlling cancer through
prevention and treatment look bright; at least in the developed countries. The situation
in the developing world will be quite different. Due to increasing life expectancies and
lack of effective preventative measures, developing countries will bear the brunt of the
emerging cancer epidemic in the next 50 years and there is an urgent need for the
implementation of cancer prevention in these countries. There will also be a need to
make newer treatments available to these countries at lower costs. Hence, as the
developed countries approach the endgame in battling cancer in the next 50 years, the
goal posts are shifting in developing countries.
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