Cancer Biology
The most remarkable progress in the last 25 years has been in
our knowledge of cancer biology. We are finally beginning to understand
what is required to turn a normal cell into a cancer cell. Cancer
arises when a single cell changes so that it divides continuously, released
from the controls that constrain the replication of normal cells. This
transformation is due to changes in the function and activity of genes,
which are segments of DNA containing the information that directs a cell
to make a particular protein product. Of the 100,000 genes found in the
human genome, only the altered activities of a small number of genes are
responsible for transforming a normal, well-behaved cell--be it in the
breast, brain, blood, colon, prostate, or other organ--into a cancer cell.
Identifying these "cancer genes" defines the central scientific
hunt in cancer biology. Their identification provides an unprecedented
window into the nature of cancer. These genes normally function to instruct
cells to produce accelerators that drive cells to proliferate, brakes that
control proliferation, or mechanisms that underlie the repair of DNA damage
or the elimination of damaged cells. Some individuals inherit an altered
form of a cancer gene. These individuals carry a very high lifetime risk
of developing cancer because fewer subsequent changes in DNA are required
to take place in one of the trillions of cells in our bodies to transform
that cell into a cancer cell.
We now know that DNA changes are the fundamental cause of all cancers.
These changes can occur due to chemicals, viruses, radiation, and mistakes
made each day in the course of duplicating the three billion units in our
DNA when a cell divides. DNA, the molecule of life, is very vulnerable
to damage, but each cell has the remarkable ability to recognize damage
and correct it. The changes in DNA required to produce cancer result from
the imbalance between damage and the cell's ability to repair the damage.
When a normal cell recognizes damage to its DNA, it stops the process of
growth and division called the cell cycle. A normal cell either repairs
the damage or, if it fails, undergoes programmed cell death (apoptosis).
In the development of cancer, checkpoint controls are lost and the cell
continues to divide, transmitting its damaged DNA to its descendants. It
is for this reason that cancer is beginning to be seen as a problem of
genetic instability.
No one genetic alteration, however, is enough to make a normal, healthy
cell a cancer cell. Rather, an accumulation of changes during the lifetime
of a cell in a relatively small number of genes is required. This understanding
allows us to begin to define the development and evolution of cancer from
predisposition to pre-cancer to cancer. Each cancer is ultimately defined
by its particular pattern of altered and normal gene activity. This pattern
determines the cancer's rate of growth, tendency to spread, responsiveness
to hormones and therapies, and defines the ability of a person's immune
system to recognize and respond to a cancer. These patterns will define
what each cancer is and how many different cancers there are.
By defining these molecular patterns, we are beginning to be able to describe
what distinguishes each cancer from its normal counterpart. Advances in
our ability to detect, diagnose, and treat each cancer will most likely
be found in these differences.
Cancer Risk
Research on cancer risk quantifies the risk of developing cancer
in various populations and strives to identify the factors responsible
for these risks. Research in this area is critical to linking our knowledge
of biological processes to the detection, management, and ultimately, prevention
of cancer. Studying people who are at high risk of cancer is particularly
important, since it may be possible to identify more readily the factors
influencing risk and to assess means for prevention and risk reduction.
Behavioral scientists also contribute to understanding risk by studying
how people perceive cancer-related risks and by learning how to motivate
health professionals and high-risk persons to practice cancer risk reduction
strategies.
Epidemiology is the principal discipline used to study cancer patterns
in the population and the determinants of cancer risk. Epidemiologists
have uncovered distinct cancer patterns among various population groups.
For example, African American men have the highest prostate cancer risk
of any group in the world, while men in Asian countries have a relatively
low risk. Similarly, women in most Asian countries have the lowest rates
of breast cancer, while those in the West have the highest. Interestingly,
when Asian women migrate to the United States, their breast cancer risk
rises over several generations until it matches that found in U.S. white
women. These striking variations among populations have proven particularly
useful in targeting further epidemiologic research into the causes of cancer.
These studies underlie the commitment of the NCI to address the burden
of cancer in all population groups in the United States to assure that
all benefit from our research.
The epidemiologic approach has been successful in identifying many factors
that increase cancer risk, some of which are environmental and lifestyle-related,
while others are part of a person's genetic makeup. With the exception
of a few genetic conditions, however, it is still not possible to predict
with any degree of certainty that a person having one or more of these
factors will develop cancer. This uncertainty is related to the need for
a number of alterations to accumulate in the genetic material (DNA) of
a single cell for that cell to be transformed into a malignant state.
The single most important exposure that increases cancer risk is the use
of tobacco products, particularly cigarette smoking. Smoking is believed
to contribute to more than 30 percent of all cancer deaths. In addition,
certain aspects of the diet, particularly diets lacking in fruits and vegetables
or high in fats, appear to be important contributors to cancer risk. An
excess risk of cancer also has been linked to alcohol consumption, radiation
(e.g., ultraviolet and x-rays), certain occupational exposures (e.g., asbestos),
environmental pollution (e.g., arsenic), some pharmaceutical agents (e.g.,
estrogenic drugs), certain viral infections (e.g., human immunodeficiency
virus [HIV], and human papilloma virus [HPV]), and hormonal factors. In
addition, epidemiology plays a key role in revealing inherited cancer predisposition
syndromes, as are seen in women who inherit alterations in the BRCA1 gene.
A Breast and Ovarian Cancer Gene
With recent major advances in molecular biology, a strategy called molecular
epidemiology has emerged, combining the strengths of epidemiology with
sensitive laboratory probes and providing new insights into genetic susceptibility
and gene-environment interactions. This kind of interdisciplinary approach
promises to elucidate the risk profiles and biologic mechanisms involved
in cancer etiology, making it possible to predict cancer risk with greater
certainty.
Cancer Interventions
Ultimately, the purpose of understanding tumor biology and identifying
cancer risk is to uncover effective ways to intervene in the cancer process.
Important advances in both areas are leading to new strategies to prevent,
detect, diagnose, and treat cancer.
Our ability to prevent cancer depends on identifying and removing (or at
least reversing the effects of) specific risk factors. Clearly, the most
important of these is tobacco use. The NCI has strongly supported recent
initiatives to avert the initiation of tobacco use among children and teenagers
and continues to develop a variety of approaches to cessation among those
already addicted. The effect of dietary modification and administration
of preventive agents to forestall the occurrence of cancer in high-risk
populations is under study. The testing of tamoxifen as a breast cancer
preventive in women at high risk for breast cancer is one approach. It
should be quite clear, however, that major improvements in chemoprevention
will depend on a better understanding of the fundamental mechanisms of
carcinogenesis--the process by which normal cells are induced to become
malignant.
Anti Spit-Tobacco Trading Cards For Kids-The NCI has strongly supported
recent initiatives to decrease tobacco use among children and teenagers
and continues to examine approaches to behavior modification and prevention
in high-risk populations.
We have learned to see inside the body of a living human being with a precision
that could not have been anticipated by a previous generation of physicians.
Computed tomography, magnetic resonance imaging, and ultrasonography simply
did not exist as useful clinical tools 25 years ago. Their development
depended on first learning how the body interacts with x-rays, magnetic
fields, and sound waves, and then figuring out how to create images from
these interactions. These technologies permit us to locate internal tumors
with unprecedented accuracy and to biopsy internal organs without the need
for major surgical procedures. There is every reason to believe that further
improvement in their powers of resolution will enhance our ability to detect
small tumors even earlier than is possible with currently available methods,
such as x-ray mammography. Invasive procedures, such as colonoscopy and
bronchoscopy, are on the verge of giving way to "virtual" procedures
involving the imaging of these internal structures without any actual invasion
of the body by tubes or scopes.
The diagnosis of cancer depends on the microscopic appearance of tissue
samples taken from growths or other suspicious lesions in the body. Advances
in biological knowledge have improved our ability to subclassify cancers
into accurate categories. For example, a better understanding of normal
immune system development and biology has led directly to molecular techniques
for classifying, for the first time, immune system tumors (lymphomas).
More precise classification of cancers is important because it will lead
to more precise prediction of clinical outcome for patients and to the
discovery of more effective therapies. The experience with lymphoma serves
as a model for what will very likely occur in a variety of malignancies.
We expect that tumor diagnosis and classification will be revolutionized
in the coming years by application of emerging knowledge in molecular genetics.
The past quarter century has seen major progress in our ability to treat
certain cancers. In addition to well-publicized improvements in the cure
rates for many uncommon tumors, such as Hodgkin's disease, certain lymphomas,
testicular cancer, and a variety of childhood cancers, adding chemotherapy
to surgery and/or radiation has increased the cure rates for patients with
breast and colorectal cancer. High-dose chemotherapy with stem-cell rescue
is effective in the leukemias and is undergoing definitive testing in breast
cancer. The application of molecular biology to the drug discovery process
has ushered in the era of biological therapy by permitting the large-scale
production of so-called "recombinant" proteins. Following directly
from this approach, the availability of interferon-alpha has markedly improved
the outlook for patients with a rare form of leukemia. Both interferon
and interleukin-2 provide improved tumor shrinkage for some patients with
kidney cancer. The availability of bone-marrow stimulatory factors has
enhanced the quality of supportive care by mitigating the toxicity of chemotherapy
to the blood elements. Over the past 15 years, the formidable problem of
treatment-related nausea and vomiting has been markedly lessened by the
development of truly effective drugs that reduce this side effect.
NCI is committed to research to improve the quality of life for
those who develop cancer. As treatment becomes increasingly effective
in the coming years, we shall continue to see the emergence of certain
problems associated with surviving cancer. These are of two general types.
The first are the challenges to an optimal quality of life posed by the
effects of cancer treatment itself. Although most acute side effects of
treatment are rapidly reversible, some, such as the loss of a body part,
have a lasting impact. The widespread use of techniques such as breast
reconstruction, conservative surgery, and customized limb prostheses have
greatly improved the emotional and functional outlook for survivors of
breast and bone cancer. The knowledge, gained in a landmark clinical trial,
that chemotherapy followed by radiation treatment is as effective as total
removal of the voicebox for cancer of the larynx has made preservation
of natural speech possible for many patients with this condition. The recent
Food and Drug Administration (FDA) approval of effective drugs for protecting
against the cardiac toxicity of the anthracycline antibiotics and the kidney
toxicity of cisplatin can be expected to reduce the overall incidence of
two particularly troublesome chronic effects of chemotherapy.
The second general problem is the propensity of many cancer survivors to
develop second cancers at the same or other body sites. In some cases,
this is a treatment effect; many current therapies that effectively treat
the patient's primary cancer unfortunately also promote the development
of second cancers in a small fraction of people who receive them. So, for
example, women who have received radiation therapy to the chest for the
treatment of Hodgkin's disease are at increased risk for developing breast
cancer; and certain chemotherapy regimens are associated with the late
appearance of acute leukemia in some patients who survive for years after
the treatment. Sometimes, however, the development of a second cancer stems
from influences having nothing to do with the therapy. Patients who survive
a first cancer of the lung or oral cavity, for example, have a high incidence
of subsequent tumors at those sites, probably because of the long-lasting
carcinogenic influences of tobacco. Inherited risk may also play a role.
Some breast, ovarian, and colorectal cancer patients have a genetic predisposition
to those cancers and are likely to develop other primary cancers. The solution
to these persistent problems clearly is to discover more targeted and less
toxic treatments and to develop better surveillance and prevention strategies
for people whose risk is elevated for reasons unrelated to treatment.
Psychosocial and behavioral research has fundamental contributions to make
to all aspects of cancer survivorship, both in improving the quality of
life for cancer patients as well as those at increased risk of developing
cancer. Psychosocial research investigates how cancer affects quality of
life and finds ways to address survivors' needs so they can meet the everyday
demands of life and return to a productive lifestyle. NCI is committed
to such research to complement its cancer prevention, detection, and treatment
research programs. We expect that this research will assume even greater
importance as genetic advances pose difficult prevention and treatment
choices.
Research has shown that diets rich in fruits and vegetables are associated
with lower cancer and heart disease risk. NCI's Five-a-Day program works
through partnerships with the Produce for Better Health Foundation and
supermarkets across the country to educate the public on the benefits of
a healthy diet.
Cancer Control
Cancer control research bridges the gap between laboratory, clinical,
and population-based research, and health care by focusing on how to bring
our discoveries to the practice of cancer prevention, detection, treatment,
and rehabilitation. Effective application is a challenge well-illustrated
by the fact that significant smoking rate reductions have taken over 30
years to achieve since the first Surgeon General's Report that showed conclusively
the causal link between smoking and cancer.
The science of cancer control is necessarily multidisciplinary and involves
behavioral research, epidemiology, health services research, and communication.
A cross-cutting theme is to identify the environmental, genetic, physiological,
and psychosocial determinants of health, in order to achieve the adoption
of new behaviors that can reduce the risk of cancer or improve the prognosis
for persons with cancer.
Behavioral research is central to cancer control. A large proportion
of cancer is caused or linked to behaviors such as smoking or diet. Through
behavioral research, we can modify the behavior of individuals and health
care professionals toward the adoption or promotion of healthy practices,
such as smoking cessation, adoption of a low-fat, high-fiber, balanced
diet, and practicing cancer screening regimens. We urgently need the development
and rigorous evaluation of smoking cessation interventions to assist the
45 million Americans who currently smoke, particularly those who smoke
heavily. Research is underway to integrate effective pharmacotherapies
with self-help approaches that address both the addictive and behavioral
aspects of smoking. Of equal concern is developing strategies to prevent
smoking among adolescents. To this end, behavioral scientists are trying
to understand why African American adolescents are avoiding tobacco while
white youths have been more resistant to messages about the harms of tobacco.
An important aspect of cancer control research is finding those factors
that facilitate adoption of recommended regimens. This requires understanding
the population in need. Regimens must be sensitive to the economic, cultural,
ethnic and social forces acting upon populations. For example, to increase
the adoption of Pap smears, which can prevent needless deaths from cervical
cancer, we must understand the practices and customs of individuals, their
communities, and health care professionals and tailor interventions appropriately.
Cancer control research often begins by studying the patterns of cancer
in populations through epidemiological studies or through the NCI surveillance
system that monitors cancer incidence, mortality, and survival. Evaluating
cancer patterns provides insight into who is developing cancer and what
factors may have contributed to their disease. Researchers examine not
only the changing burden of cancer, but also the public's and health profession's
knowledge, attitudes, and practices related to cancer prevention, early
detection, treatment, and rehabilitation. All of this information is essential
for designing and evaluating interventions that may reduce the cancer burden.
For example, surveillance data have shown clearly that there are survival
differences between African American and white populations. Research is
underway to identify the factors underlying these differences.
Effective and widespread communication plays a critical part in applying
the knowledge gained in biology, epidemiology, and intervention research.
The NCI supports research on cancer communication as well as innovative
programs to provide information on cancer to the public and to the Nation's
health professionals. Our scientific journal, the Journal of the National
Cancer Institute (JNCI), is one of the premier cancer journals in the
world. Although designed primarily to facilitate communication between
scientists and clinicians, the JNCI is often cited in the popular
press and therefore is an important channel for public information. The
NCI also supports communications between scientists, physicians, and the
public through its nationwide Cancer Information Service (1-800-4-CANCER)
and the PDQ computer-based cancer and clinical trials information system.
These communication systems pro-vide Americans--patients, the public, and
physicians--with the most current information possible on cancer treatments
and on effective prevention, early detection, and supportive care technologies.
New challenges for cancer control research abound. Our evolving health
care system poses the challenge of how to introduce cancer discoveries
in these settings, and especially important, to find ways that cancer research
can be directly integrated into health care through clinical studies. Developing
cost-effective cancer interventions is essential and is an important part
of cancer-related health services research.
Discoveries in genetics and clinical science pose special challenges for
cancer control. For example, with the advent of more precise and individual-specific
ways of assessing the risk of developing cancer, we are faced with an array
of new challenges in living with and understanding risk, and with tailoring
prevention, detection, and treatment to individual needs.
Indeed, each research advance brings its own challenges which must be met
to realize the promise of research. And that is the challenge for cancer
control.