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Explain and discuss the meaning of the term "cancer"
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Describe the basics of Oncology
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Identify and describe the role of clinical trials in cancer
treatment
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List and discuss the most common types of cancer
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Describe the basics of radiation therapy
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Explain what is meant by “chemotherapy” and
discuss its key elements
The
topic "Cancer" is profound and multifaceted. In
reality, despite considerable advances in research and technology,
it remains somewhat of an unsolved mystery to medical science.
Even today, the media is full of confirmation of the “mystery”
status of cancer. For example, the following article was published
in the New York Times in August of 2006:
Scientists
Begin to Grasp the Stealthy Spread of Cancer
August 15, 2006-New York Times-By Laurie Tarkan
The moment when a cancer begins to spread throughout the body
- metastasis - has always been the most dreaded turning point
of the disease.
Without metastasis, cancer would barely be a blip on the collective
consciousness. Fewer than 10 percent of cancer deaths are
caused by the primary tumor; the rest stem from metastasis
to vital sites like the lungs, the liver, the bones and the
brain.
Though
chemotherapy
and other treatments have lengthened the lives of people with
metastasized cancer, no drugs have been specifically formulated
to halt the process. That is because metastasis has remained
something of a mystery until the last five years or so.
"In the last 30 years, we've learned all about identifying
genes whose mutations initiate tumors," said Dr. Joan
Massagué, chairman of the Cancer Biology and Genetics
Program at Memorial
Sloan-Kettering Cancer Center in New York. But these advances,
he added, did not explain the metastatic process.
Now,
knowledge of metastasis is beginning to accumulate to the
point that new therapies are entering the pipeline. "In
terms of milestones or breakthroughs, most of them are about
to be made," said Dr. Massagué.
Dr. Patricia S. Steeg, chief of the women's cancers section
of the Laboratory of Molecular Pharmacology at the National
Cancer Institute, said she was optimistic for the first
time. "The trickle is close, the first agents are in
early clinical testing or will be soon," she said. "I'm
very enthusiastic, much more than I was five years ago."
The complexity of metastasis may well have discouraged research.
To metastasize, cancer cells have to acquire several dozen
genetic alterations - in contrast with the handful typically
necessary to initiate a primary tumor, Dr. Massagué
said. Further complicating matters, each case of metastasis
- breast cancer that spreads to a lung, for instance, or prostate
cancer that spreads to bone - is genetically and molecularly
different from the rest.
Studying
metastasis is expensive and time-consuming, and it requires
animal studies to track cancer cells that spread.
Dr.
Danny Welch, professor of pathology at the University of Alabama
at Birmingham, said scientists had avoided this area of inquiry.
"There are under 100 people in the world whose labs focus
on understanding more about how metastasis works," he
said.
Scientists
have long had a rudimentary understanding of the process.
Some have estimated that a million cancer cells a day break
away from a tumor roughly two-fifths of an inch in diameter
and that maybe one in hundreds of millions will thrive. If
it weren't so seldom, cancer would be far more deadly. More
than 80 percent of cancers arise in the inside lining of organs.
To metastasize, a cancer cell must break cellular bonds to
dislodge itself, break down the mortar of the connective tissue,
change shape and sprout "legs" that can pull it
through the densely packed tissue.
After
accomplishing this Houdini-like escape, the metastatic cell
passes through a capillary into the blood stream, where it
is tossed and tumbled and can be ripped apart by the sheer
force of circulation, or attacked by white blood cells. If
the malignant cell survives, it clings to a tiny capillary
at another site, until it can eventually make its way out
of that capillary into the tissue of a new organ.
In
foreign tissue, the cancer cell, now called a micrometastasis,
faces a hostile environment. The liver, for instance, is foreign
territory to a breast cell. Some die immediately, others divide
a few times, then die. Others stay dormant. The surviving
cancer cells regenerate and colonize, becoming a macrometastasis
that can be seen on diagnostic tests. As the metastasis grows,
it becomes lethal by crowding out normal cells and compromising
the function of the organ.
In
recent years, scientists have begun to investigate each of
these steps to identify the genes and their molecular products
that drive the changes. Several emerging fields of study have
generated excitement among cancer researchers. One focuses
on the notion that the environment of the invaded organ, the
microenvironment, plays a critical role in the metastatic
process.
This
is not an entirely novel idea. In 1889, the British pathologist
Stephen Paget proposed the "seed and soil hypothesis,"
which suggested that the cancer cell depended on the secondary
organ to thrive.
Today,
it is well understood that an organ has to become somewhat
receptive to the tumor. The more welcoming it is and the fewer
hurdles it puts up, the easier it is for a cancer to survive.
This theory partly explains why certain primary cancers prefer
to spread to certain other organs. For example, breast cancers
metastasize to the brain, liver, bones and lungs; prostate
cancers prefer the bones, and colon carcinomas often metastasize
to the liver.
"We've
been focused on the seed for a long time, and we're now starting
to understand more about the soil and the interaction between
the seed and the soil," said Dr. Lynn M. Matrisian, chairman
of cancer biology studies at Vanderbilt University. "In
my mind, the real opportunity comes from understanding what
makes a certain organ receptive to a metastatic cell growing
there versus not receptive," Dr. Matrisian said.
Researchers are looking at a number of events that occur in
the microenvironment that give a cancer cell a leg up as soon
as it arrives. These changes involve both normal cells that
reside in that tissue and the body’s roaming immune
cells. "The tumor cells co-opt these cells to act in
a way that's conducive for the growth of the metastasis,"
Dr. Massagué said.
There is evidence, for example, that a type of white blood
cell, the macrophage, may help initiate colonization. It was
once thought that high numbers of macrophages found in metastatic
cancer colonies were there to do battle with the cancer. Now
it is believed that they somehow promote factors that help
tumors progress. Other normal cells are believed to make enzymes
that loosen the cellular structure of the new host organ,
making room for tumor cells to proliferate.
Another
example comes from the understanding of bone metastasis. Breast
cancer cells are known to activate normal cells called osteoclasts
that break down bone. Bone is a dynamic tissue constantly
being broken down and rebuilt. But when bone is degraded,
it releases growth factors that incidentally fuel cancer.
Many
people with bone metastasis are now being treated with a class
of osteoporosis drugs known as bisphosphonates that inhibit
osteoclasts. The idea is to prevent the breakdown of bone,
and to interrupt the vicious cycle.
Taking
the microenvironment theory a step further, some researchers
are looking into differences in genetic makeup that can make
one person more - or less - tumor-friendly than another. This
could lead to a simple blood test to predict who is at risk
for metastasis. The goal would be more customized treatment,
and those at high risk would be treated more aggressively.
Those unlikely to progress would avoid unnecessary and toxic
treatments.
Dr. Kent Hunter, an investigator at the Laboratory of Population
Genetics at the National Cancer Institute, recently performed
a breakthrough study in mice, which provided evidence that
the DNA of an organism plays an important role in determining
the risk of cancer spreading. Dr. Hunter bred a strain of
mice susceptible to metastasis with about 30 other strains
of mice, and found that the offspring had varying rates of
metastasis.
"Since
these animals are all getting the same oncogene by breeding,
the most likely explanation is that the changes are due to
the differences in the genotype or genetic background of the
mouse," Dr. Hunter said.
In
an epidemiological study of 300 women with breast cancer from
Orange County, Calif., Dr. Hunter identified two genes that
were associated with an increased risk of metastasis, though
a large number of genes are probably involved in a person's
risk.
Another camp of researchers is looking at cancer cells for
genes that can set off a whole set of steps, the so-called
master regulators. A major question is how cancer cells seem
clever enough to succeed in the many steps necessary to metastasize.
Dr. Robert Weinberg, a professor of biology at the Massachusetts
Institute of Technology, is a leading proponent of a contested
theory suggesting that a tumor cell turns on an embryonic
program that allows a cancer cell to relocate. "Over
the last five years, it has become apparent that cancer cells
don’t cobble together all these different talents, but
they resurrect a previously latent behavioral program,"
Dr. Weinberg said.
He argues that a program, called the epithelial-mesenchymal
transition, or E.M.T, is turned on in embryonic cells, allowing
them to move to different parts of the body where they set
up camp and build different types of tissue. According to
Dr. Weinberg, these programs are turned off after embryonic
development, but they are sometimes briefly turned on in wound-healing
to build new tissue.
"Cancer
cells opportunistically resort to turning on these programs,
and in so doing, acquire all the traits that permit them to
disseminate through the body," Dr. Weinberg said. "What
remains unclear is whether or not all malignant carcinoma
cells must undergo an E.M.T. in order to invade and metastasize."
Dr. Welch of Alabama added, "The problem is experimentally
proving there is a turning on of E.M.T. and then a turning
off of E.M.T. when the cell lands at the distant site."
Others are looking at cancer stem
cells. Adult stem cells have the ability to renew themselves
and generate new cells, but they can also become cancerous.
Some experts believe that cancer stem cells are at the core
of every metastasis. This would help explain why millions
of cells can reach distant organs, but only a select few -
presumably those with stem cell capacities - can initiate
a tumor and colonize.
To date, cancer stem cells have been isolated from a small
number of tumor types, and more research is needed to elucidate
whether stem cells initiate metastases and where and how they
acquire their renewal capacities. Most experts are looking
at smaller pieces of the puzzle, many of them involving colonization,
the final stage of metastasis. Upon diagnosis of cancer, experts
suspect that many people already have micrometastases throughout
their body. "The horse is out of the barn," Dr.
Welch said.
Because
colonization is the least efficient step in the spread of
cancer, it seems like the Achilles' heel. A vast majority
of cells that land in a distant tissue never succeed in growing
and forming a macroscopic metastasis, Dr. Weinberg emphasized.
A
number of laboratories have identified more than a dozen metastatic
suppressor genes, which prevent micrometastases from colonizing
but do not affect primary tumors. In metastatic cells, these
genes - including NM23, Kiss1, MKK4, and RhoGDI2 - are either
defective or inactive.
In
several studies of mice, researchers have repaired defective
metastatic suppressor genes and found that the tumor cells
spread but did not colonize. In epidemiological studies, some
of these genes that have been identified have been shown to
be predictive of patient survival and metastasis, Dr. Welch
said. Labs are now beginning to test agents that can activate
the gene or repair it.
Other
researchers are focusing on trying to halt the development
of blood vessels that feed the micrometastasis in the process
of angiogenesis. One of the first things a micrometastatic
cell must do to thrive is call in new blood vessels, said
Dr. Matrisian of Vanderbilt.
Drugs
that inhibit angiogenesis have not proved that successful
when used alone, but they appear to have lengthened some lives
when combined with chemotherapy, said Dr. Lee M. Ellis, professor
of surgery and cancer biology at the M. D. Anderson Cancer
Center in Houston.Underlying these advances has been the shift
in the understanding of metastasis - as many different processes
rather than one simple mechanism, and different in each type
of cancer. Each metastasis needs to be addressed separately.
"There
are commonalities, from tissue to tissue, but what we're finding,
unfortunately, is that we need to develop therapies for each
specific site," said Dr. Steeg, of the cancer institute's
Center for Cancer Research. "We used to think we only
needed one pipeline to metastasis," she said. "Pharmaceutical
companies now realize that they have to look at subsets of
cancer, rather than at all of breast cancer."
"One
advance can save many lives, but it's only one bite,"
Dr. Massagué, the Sloan-Kettering researcher, added,
"because the next tumor type forming metastasis in the
next organ needs to be addressed."
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Cancer:
Background and Basics
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Cancer
is the second among fatal diseases, next to cardiovascular
diseases, in the industrialized countries and third fatal
disease in India. It is estimated that in the next quarter
of a century the number of new cancer cases globally is going
to double, half of them in the developing countries. World
Health Organization (WHO) has launched a campaign against
cancer, with a three-fold strategy: prevent all the preventable
cancers, cure all that can be cured, and reduce pain and discomfort
where cure is not possible. In this context it may be worthwhile
to examine the basic cellular changes leading to cancer development
and to discuss some of the areas where strategies for prevention
can be implemented.
Cancer
is a broad term used for identifying a large number of diseases.
Perhaps the only common feature of these diseases is the ability
of uncontrolled cell proliferation that cannot be checked
by the normal cell kinetics regulators. A normal cell suddenly
turns into a rogue cell and start dividing continuously without
check, leading to the development of solid lumps (tumors)
or an abnormal rise in the number of dispersed cells like
the blood corpuscles.
Cancer
can occur in any part of the body and in any organ or tissue.
Even though most of the cancers are generally associated with
old age, no age group is immune to his disease. Cancer originates
in our own cells, but several factors, both intrinsic and
external to the body, which influence our daily life, can
add to the life time cancer risk. While cancer, as such, is
not infectious, some infections can act as a stimulus to induce
and promote cancer development. In addition, environmental
pollutants like many chemicals, industrial effluents, some
therapeutic drugs, and mutagenic agents, including ionizing
radiation, can increase the incidence of cancer. About 50%
of all cancers are attributed to life style, e.g.. diet, tobacco
habits and alcohol consumption, and exposure to industrial
toxins.
The
Process of Carcinogenesis
Cancer development is understood to be a multistep process.
The concept of multi-stage carcinogenesis was first proposed
in 1948 and supported by later studies. Present day oncology
recognizes three main phases: initiation, promotion and progression.
Initiation: Neoplasia initiation is essentially irreversible
changes in appropriate target somatic cells. In the simplest
terms, initiation involves one or more stable cellular changes
arising spontaneously or induced by exposure to a carcinogen.
This is considered to be the first step in carcinogenesis,
where the cellular genome undergoes mutations, creating the
potential for neoplastic development, which predisposes the
affected cell and its progeny to subsequent neoplastic transformation.
The human DNA sequences responsible for transformation are
called oncogenes. Many of the active oncogenes have been isolated
by molecular cloning, e.g.. human bladder carcinoma, Burkitt's
lymphoma, lung carcinoma, carcinoma of the breast and several
others.
Although
the activation of more than one oncogene appears to be necessary
for neoplastic transformation, the data imply that initiation
may be induced with one hit kinetics. For example, in the
human bladder carcinoma, a single point mutation converting
the Ha-ras proto-oncogene into a potent oncogene was the first
identified mutation in a human oncogene. Such tumor gene mutations
can have profound effects on cellular behavior and response,
and can lead to dysregulation of genes involved in biochemical
signaling pathways associated with control of cell proliferation
and/or disruption of the natural processes of cellular communication,
development and differentiation.
Normal
cells may bear the seeds of their own destruction in the form
of cancer genes. The activities of these genes may represent
the final common pathway by which many carcinogens act. Cancer
genes may not be unwanted guests but essential constituents
of the cell’s genetic apparatus, betraying the cell
only when their structure or control is distributed by carcinogens.
However,
the full expression of such neoplasia initiating mutations
invariably requires interaction with other later arising gene
mutations and/or changes to the cellular environment, but
the initiating mutation creates the stable potential for pre-neoplastic
cellular development in cells with proliferative capacity
. The transformed cell undergoes continuous division with
fidelity to the transformed karyotype and, possibly, with
further mutations, before a malignant lesion is manifested.
Mechanisms
of Oncogene Activation
Each
oncogene is closely associated with a normal DNA sequence
present in the cellular genome, the proto-oncogene. At least
five different mechanisms are considered for the conversion
of proto-oncogenes to active oncogenes:
(1) Overexpression of proto-oncogene following acquisition
of a novel transcriptional promoter. The oncogene then acquires
activity because their transcripts are produced at much higher
levels than those of the related normal proto-oncogene.
(2) Over-expression due to amplification of the proto-oncogene
or oncogene.
The
increased gene copies cause corresponding increases in transcript
and gene product.
(3) Influences on the levels of transcription and, in turn,
the amount of gene product.
(4)Juxtaposition of the oncogene and immunoglobulin domains,
following chromosomal translocations, that appears to result
in
deregulation of the gene.
(5) Alteration in the structure of the oncogene protein. This
is the most well documented mechanism in the case of the oncogene
proteins encoded by the ras genes. The fourth and fifth mechanisms
seem to be inter-related.
A
translocation can disturb the regulation of an oncogene by:
a)
providing a new promoter region or some other control element
that would activate the
oncogene; or
b)
altering the coding sequence of a gene, changing its protein
product from a benign to a malignant
form.
A
close association between specific chromosomal translocations
and certain human neoplasms has been demonstrated. Promotion:
The transformed (initiated) cell can remain harmless, unless
and until it is stimulated to undergo further proliferation,
upsetting the cellular balance. The subsequent changes of
an initiated cell leading to neoplastic transformation may
involve more than one step and requires repeated and prolonged
exposures to promoting stimuli.
Thus,
in contrast to initiation which is induced at a rate of 0.1-1.0
per cell/Gy of radiation, the subsequent transforming event
in the initiated cells occurs at a rate of only 10-6 to 10-7
per cell generation.
Neoplastic
development is influenced by the intra- and extracellular
environment. Expression of the initial mutation will depend
not only on interaction with other oncogenic mutations but
also on factors that may temporarily change the patterns of
specific gene expression, e.g.. cytokines, lipid metabolites,
and certain phorbol esters. This may result in an enhancement
of cellular growth potential and/or an uncoupling of the intercellular
communication processes that restrict cellular autonomy and
thereby coordinate tissue maintenance and development.
Progression:
is the process through which successive changes in the neoplasm
give rise to increasingly malignant sub-populations. Molecular
mechanisms of tumor progression are not fully understood,
but mutations and chromosomal aberrations are thought to be
involved. The process may be accelerated by repeated exposures
to carcinogenic stimuli or by selection pressures favoring
the autonomous clonal derivatives. The initiated cells proliferate
causing a fast increase in the tumor size. As the tumor grows
in size, the cells may undergo further mutations, leading
to increasing heterogeneity of the cell population.
In
the first phase of progression, sometimes referred to as neoplastic
conversion, the pre-neoplastic cells are transformed to a
state in which they are more committed to malignant development.
This may involve further gene mutations accumulating within
the expanding pre-neoplastic cell clone. The dynamic cellular
heterogeneity, a feature of malignant development, may, in
many instances, be a consequence of the early acquisition
of gene-specific mutations that destabilize the genome. Examples
are mutations of the p53 gene or DNA mismatch repair gene.
Many tumor types develop transforming sequences in their DNA
during their progression from the normal to the cancerous
state.
An
elevated mutation rate established relatively early in tumor
development may, therefore, provide for the high-frequency
generation of variant cells within a premalignant cell population.
Such variant cells, having the capacity to evade the constraints
that act to restrict proliferation of aberrant cells, will
tend to be selected during tumorigenesis.
Tumor
metastasis: As the tumor progression advances, the
cells lose their adherence property, detach from the tumor
mass and invade the neighboring tissues. The detached cells
also enter the circulating blood and lymph and are transported
to other organs/tissues away from the site of the primary
growth and develop into secondary tumors at the new sites.
These form the distant metastases, resulting in widely spread
cancers.
Cancer
metastasis consists of a number of steps; the main steps are
common for all tumors. The progress of the neoplastic disease
depends on metastatic changes that facilitate:
(a) invasion of local normal tissues,
(b) entry and transit of neoplastic cells in the blood and
lymphatic systems, and
(c) the subsequent establishment of secondary tumor growth
at distant sites. Many of the steps in tumor metastasis involve
cell - cell and cell - matrix interactions, involving specific
cell surface molecules. Malignant cells are thought to have
reduced ability to adhere to each other, so that they detach
from the primary tumor and invade the surrounding tissues.
The
behavior of tumor is influenced by the cell adhesion molecules,
one of the most important of which are cadherins. Animal studies
have shown that a down-regulation of E-cadherin expression,
resulting in lower levels, correlated with metastatic behavior
in vivo, suggesting that cadherins function as invasion suppressor
gene products.
It
is the metastatic process and tumor spreading that are mainly
responsible for the lethal effects of many common human tumors.
In many cases gene mutations are believed to be the driving
force for tumor metastasis, with the development of tumor
vasculature playing an important role in the disease progression
.
Tumor
angiogenesis: Tumor growth depends on the supply
of growth factors and efficient removal of toxic molecules,
which comes through an adequate blood supply. In solid tumors,
efficient oxygen diffusion from capillaries occurs to a radius
of 150-200(m, beyond which the cells become anoxic and die.
Therefore, increase in tumor mass to more than 1-2 mm will
depend on adequate blood supply through development of blood
capillaries (angiogenesis). P. Schubik was the first to coin
the term 'tumor angiogenesis'. But it was Judah Folkman who
hypothesized the importance of tumor angiongenesis in the
development and metastasis of solid tumors. His theories are
widely accepted today. Folkman and colleagues established
that tumor growth beyond about 2mm size could proceed only
if a vascular supply is established. A number of tissue factors
have been identified, which stimulate endothelial cell proliferation.
These include the tumor angiogenesis factor, the vascular
endothelial growth factor, angioproteins - ang-1 and ang -
2, transforming growth factors (TGFs), interleukin - 1, and
platelet-derived endothelial cell growth factor.
Although
the blood vessels that supply the developing tumors are derived
from the host vasculature, their architecture differs considerably
from that in the normal tissue. Tumor vessels are often dilated,
saccular and tortuous and may contain tumor cells within the
endothelial lining of the vessel (Jain 1989). Therefore, the
blood flow in the tumor may be sluggish compared to that in
the adjacent normal tissues and the tumor microvasculature
may show hyperpermeability to plasma proteins.
Cancer
Genes
Somatic gene mutations are widely accepted as the basic event
in the conversion of a normal cell into cancer cell. Many
different genes are demonstrated to be involved in carcinogenesis.
The gene mutation theory of oncogenesis maintains that carcinogens
interact with DNA resulting in irreversible changes in the
gene (point mutations), which predispose the cells to malignant
transformation. The somatic genetic changes in cells that
contribute to multistage tumor development potentially involve
sequential mutation of different classes of genes, i.e. Proto-oncogenes,
tumor suppressor genes, genes involved in cell cycle regulation,
and genes that play roles in maintaining normal genomic stability.
Biochemical interactions between tumor gene mutations may
destabilize the genome, compromise control of cell signaling,
proliferation, and differentiation, and interfere with the
normal interaction of cells in tissues.
Two
classes of regulatory genes are directly involved in carcinogenesis,
the oncogenes and the antioncogenes.
Oncogenes:
They are positive regulators of carcinogenesis. In non-transformed
cells, they are inactive (proto-oncogenes). Gene mutations
can activate proto-oncogenes, resulting in a gain of function.
Several proto-oncgenes were first identified through viral
transformation of cellular genome, e.g.. c-erbB, cmos, c-myc,
c-myb, C-H-ras. A large number of mutations in specific oncogenes
- e.g.. ras, myc, etc. - have been found to be closely associated
with different types of cancers.
Anti-oncogenes
or tumor suppressor genes: They are negative growth
regulators. Many human tumors, e.g. retinoblastoma, Wilm’s
tumor, colon carcinoma, result from recessive mutation, which
cause cancer when present on both homologues. These genes
function as anti-oncogenes or tumor suppressor genes. In normal
cells they regulate cell proliferation by checking cell cycle
progression. Mutation in these genes results in a loss of
gene function (the protein product will not be produced),
which promotes carcinogenesis. Such gene mutations have been
detected in several solid tumors, e.g.. cancers of breast,
lung, rectum, etc., but only few such mutations have been
seen in leukemias.
The
two most widely studied tumor suppressor genes are the Rb
gene and p53 gene. The proteins encoded by these genes inhibit
cell cycle progression by blocking transcription of gene products
necessary for transition from G1 to S phase. Mutation in the
Rb gene could lead to loss of normal inhibitory control of
cell cycle progression and, thereby, increase cell proliferation.
This effect, coupled with genetic changes that cause loss
of apoptotic signals, would enhance malignant transformation.
p53
has a major role in maintaining the genomic stability and
cellular equilibrium. In normal cells, this gene promotes
apoptosis, regulates cell cycle through G1 - S checkpoint
control and induces cell differentiation. p53 participates
in a cell cycle checkpoint signal transduction pathway that
causes either a G1 arrest or apoptotic cell death after DNA
damage. Mutations in p53, resulting in loss of function, will
cause suppression of apoptosis, promote cell division by releasing
the G1-S block and prevent differentiation of the cells, leading
to neoplasm development. Mutations in the p53 gene are the
most common genetic change observed in a large number of human
malignancies; at least 50% of all human cancers have been
found to contain p53 abnormality. Mutations in this gene have
been observed in a wide range of human cancers like cancers
of the breast, lung, colon, skin, urinary bladder, ovary and
lymphoid organs. More than 500 mutations of this gene have
been documented in breast cancer.
Theories
of Carcinogenesis
Gene
mutation theory:
This
theory maintains that somatic gene mutations form the basis
of neoplastic transformation and their clonal expansion leading
to carcinogenesis. It is the most widely accepted and is supported
by a large volume of experimental data. However, it does not
explain tumor heterogeneity and aneuploidy and also the long
latent periods between exposure to carcinogens and the development
of tumors.
Aneuploidy
theory:
Another
theory that is currently gaining momentum is the aneuploidy
hypothesis. According to this hypothesis, a carcinogen initiates
carcinogenesis by a preneoplastic aneuploidy, which destabilizes
mitosis. This initiates an autocatalytic karyotype evolution
that generates new chromosomal variants, including rare neoplastic
aneuploidy. The aneuploidy hypothesis provides a plausible
explanation for the long latent periods from carcinogen treatment
to cancer development and the clonality.
Epigenetic
theory:
It
has been recognized that non-mutational stable changes occur
in cellular genome, which can contribute to carcinogenesis
(Feinberg 1993 Cross and Bird 1995). Such events are broadly
termed epigenetic and are thought to involve DNA methylation,
genome imprinting and changes in DNA - nucleoprotein structure.
Increased levels of methylated cytosine (one of the pyrimidine
bases in DNA) results in the elevation of spontaneous mutation
rates in the affected genome.
While
each theory has its own merits, it may not be possible to
assign an exclusive role to a single process alone in carcinogenesis.
In many cases, a combination of the two or all process may
work in cooperation.
An
initiating somatic gene mutation can destabilize the genome
and lead to aneuploidy and chromosome heterogeneity, characteristic
of solid tumors, while epigenetic events can contribute to
the neoplastic cell transformation and also facilitate promotional
changes.
Factors
Influencing Cancer Development
A
number of intrinsic (biological) and external factors are
associated with the development of cancers. The intrinsic
factors include the age and hormonal status of the individual,
familial history and genetic predisposition. The extraneous
factors include diet and life style, individuals habits like
smoking and alcohol use, exposure to toxic chemicals and radiation,
some infections, etc. Several external factors, including
asbestos, many chemicals, dyes, food additives, vehicular
emissions, act as promoters in carcinogenesis.
Biological
factors:
Age
and hormonal status: Cancer is considered to be an
old age disease. Some types of cancers are almost entirely
found in people above 50-55 years, e.g. prostate cancer. Similarly
cervix cancer in women are more commonly detected at the peri
- or post - menopausal ages. However, no age group is immune
to this disease.
Hormonal
factors play an important role in the development of gender-specific
cancers, e.g. estrogen in cancers of ovary and uterus in female.
Family
history: Some cancers are indicated to have a link
with familial occurrence. For example, women whose close relatives
like grandmother, mother, maternal aunt or sister has suffered
from breast cancer, are found to run about 3 times higher
risk of developing breast cancer than those who do not have
such a family history. Similarly, cancers of the uterine cervix
(females) and of prostate (males) are also thought to have
a familial connection.
Genetic
predisposition: Certain genetic conditions are known
to predispose the individual to cancer. For example, individuals
with genetic conditions like xeroderma pigmentosum, ataxia
telangiectasia, Bloom’s syndrome, and Fanconi’s
anemia are found to be highly susceptible to different types
of cancer.
External
factors: Diet, alcohol, and tobacco use: More than
50% of all cancers are related to the diet and individual
habits like alcoholism, tobacco chewing and smoking. High
fat diet and obesity are associated with breast cancer. A
positive correlation has been reported between age-adjusted
breast cancer mortality rates and the average per capita fat
consumption in a given nation on a daily basis. Similarly,
deep-fried and burnt food and preserved (high salt) food are
associated with increase in gastric cancer incidence. Regular
consumption of food low in fiber content and rich in animal
fat increased the risk of cancers of stomach and esophagus.
High intake of red meat and low fiber diet has been considered
to be the cause of the high incidence of gastric cancer in
the USA. The role of cigarette smoking in lung cancer is established.
Tobacco smoke contains a chemical, nitrosamine, which can
induce neoplastic changes in the lung cells. Non-smoking tobacco
habits, like chewing, are found to greatly increase the cancers
of the upper alimentary tract and buccal mucosa. India has
the highest incidence of oral cancers in the world, which
is correlated with the tobacco chewing habit.
Alcoholism
is found to increase the risk of liver and bladder cancers.
Smoking combined with alcohol consumption poses a higher risk
of cancers of the breast, esophagus, liver, stomach and urinary
bladder. Alcoholism along with hepatitis B virus infection
is a more serious risk factor in liver cancer.
Radiation
and cancer:
Ionizing
radiation is an established carcinogen, having both initiating
and promoting effects. The positive correlation between ionizing
radiation and carcinogenesis has been established from the
studies on the early radiologists, radium dial painters and
atom bomb victims of Japan. A positive association has been
seen in the increase in childhood cancers and obstetric X-ray
exposures of the mother. Tumors induced by radiation have
relatively long latencies, which vary in different species
as a more or less constant function. Within a given species
the latency varies also with age at the time of irradiation
and with the type of neoplasm induced. The age differences
in latencies appear to be related to similar age differences
in the rates of corresponding spontaneous leukemias. The risk
of adult type of malignancies tend to increase progressively
with time after irradiation, in parallel with the age-dependent
increase in the underlying base-line incidence.
Viruses
and cancer:
Oncoviruses
play an important role in specific human cancers, e.g. human
papilloma virus in cervix cancer, and certain skin cancer;
Epstein-Barr virus in Burkitt lymphoma and nasopharyngeal
carcinoma; hepatitis B virus in hepatocellular carcinoma;
human T-cell leukemia virus in leukemia. The viruses are of
two types: DNA viruses which incorporate into the cellular
genome and the retroviruses (RNA viruses) which cause transformation
of cellular genome, leading to malignant changes in the infected
cell.
Role
of free radicals:
Reactive
oxygen species (ROS) and other free radicals are produced
in the body, both during the normal metabolic process as well
as by interaction with external toxic agents, for example,
radiation and toxic chemicals. They include superoxide anions,
hydroxyl radicals, peroxy radicals and hydroperoxides. These
interact with DNA and produce gene mutations and chromosomal
aberrations, leading to cell transformation. Free radicals
are considered to have a major role in the induction of cancers
by chemicals and radiation. Several factors of our modern
life style, e.g. excess alcohol consumption, tobacco chewing
and smoking habits, exposure to toxic chemicals and radiations,
all add to the free radical production in the body and increase
the risk of cancer.
Cellular
Defense Mechanisms in Relation to Cancer Prevention and Carcinogenesis
Normal
cells are naturally equipped with efficient defense mechanisms
that work at different levels.
Antioxidants:
The
cells synthesize their own defense molecules, which include
the non-protein thiol gluthathione, and antioxidant enzymes
like superoxide dismutase, catalase, glutathione peroxidase,
reductase and S-transferases. These scavenge the ROS before
they can reach the target molecules in the cell and thus protect
against their attack on the vital molecules like DNA. Thus
they serve as the biological watchdogs in safeguarding against
free radical induced initiating changes, mutations and chromosomal
aberrations. Many dietary ingredients like green vegetables,
fruits, tea, spices and some diet supplements contain antioxidants.
These include the vitamins A, C, and E, beta-carotene, alpha-tocopherol,
ascorbic acid, flavonoids, lycopenes, curcumins and enzymes
like caspasine. They act as chemo-preventers by scavenging
free radicals and enhancing cellular defense through their
adaptogenic properties.
DNA
repair:
Damage
to cellular DNA is the crucial early event in the neoplastic
transformation of a cell. The DNA lesions may include altered
bases, co-valent binding of bulky adducts, inter - and intra
- strand crosslinks and generation of strand breaks. A range
of alkylated products is formed in DNA by exposure to nitroso-compounds
and other alkylating agents. Ionizing radiation and many genotoxic
chemicals generate free radicals, which interact with DNA
and produce different lesions ranging from base damage, deletions
and complex and multiple lesions. Most normal cells possess
a high capacity for repair of DNA damage. However, efficient
repair depends on the type of damage, its severity and the
time available for repair. The base damage and single strand
breaks are repaired fast and without error, restoring the
molecular structure. But double strand breaks and multiple
breaks and local cluster lesions are not properly repaired
and often contain errors (error-prone repair or misrepair),
leading to cell death or cell survival with abnormal gene
functions and chromosomal abnormalities which are associated
with malignant cell transformation. DNA repair involves a
number of genes, the products of which operate in a co-ordinated
manner to form repair pathways that control restitution of
DNA structure.
Apoptosis
or programmed cell death is an important mechanism of cellular
defense in reducing the risks of error-prone repair. Cells
with DNA damage undergo apoptosis, thus preventing these cells
from surviving and entering the proliferating cell pool and,
thereby, preventing the possibility of tumor development.
Apoptosis is a genetically controlled process involving p53,
bcl2 and other genes. Mutations in p53 can block the tumor-suppressive
effect by eliminating apoptosis, and, thus, allowing the damaged
cells to survive and undergo proliferation. Some of the gene
products that control cell cycle also influence apoptotic
tendencies, e.g.
c-myc, pRb, Tp53.
Role
of Diet in Cancer Control
Researchers Doll and Peto (1981) were the first to point out
an association between dietary constituents and cancer. A
vegetarian diet is considered to be beneficial in reducing
cancer incidence. Epidemiological studies have suggested that
diets rich in vegetables, and fruits reduces the risk of certain
cancers. For example, diets rich in fiber, vitamins A,C, and
E, beta-carotene, retinols, alpha-tocopherol, polyphenols,
and flavonoids, and minerals like selenium and zinc, have
cancer chemopreventive effect. Fruits and vegetables are rich
sources of chemopreventive chemicals. These include inhibitors
of carcinogen formation, blocking agents (block conversion
of procarcinogens to carcinogens), stimulators of detoxifying
system, trapping agents (trap and eliminate potential carcinogens)
and suppressing agents (suppress the different steps of the
metabolic pathway leading to cancer).
A
study in China showed a high incidence of esophageal and gastric
cancers in a population whose diet is deficient in beta-carotene
and vitamins C and E. An interventional program, where the
diet was supplemented with beta-carotenes, vitamin E and selenium,
produced a 20% reduction in the stomach cancer mortality over
a period 5 years. WHO has recommended dietary intervention
in the cancer control strategy for the new millennium.
Dietary
intervention follows two approaches:
-
Intervention through supplementing with vitamins, antioxidants
and other dietary factors.
- Intervention
through dietary modification in which target levels are
established for consumption of meat, fat, fiber, fruits
and vegetables
Conclusions
Cancer is a broad term to describe a large variety of diseases,
the common feature of which is uncontrolled cell division.
The process of carcinogenesis consists of three major steps:
initiation, where an irreversible change is affected in the
cellular genes; promotion, where the initiated cells expand
by self-proliferation leading to abnormal growth and further
mutations; and progression, where the cells detach from the
primary tumor and invade other organs and tissues, forming
metastatic growths. Angiogenesis plays an important role in
the tumor metastasis.
Different
types of cancer genes - oncogenes and antioncogenes (tumor
suppressor genes) - are involved in cancer development. Gain
of function mutations in the oncogenes, leading to abnormal
cell proliferation, and loss of function mutations in the
anti-oncogenes leading to suppression of cell differentiation
and apoptosis, are the major events leading to cancer development.
Chromosomal aneuploidy and epigenetic events are also thought
to be important. Several factors like age, sex, genetic predisposition,
along with extrinsic factors like diet, environmental pollutants,
alcoholism and tobacco habits have a major role in determining
the cancer risk. Dietary intervention as a cancer preventive
measure is a primary agenda on the WHO program.
What
is Cancer?
Cancer is the uncontrolled growth of malignant cells, which
if left unchecked, can destroy organs or their functions.
Oncology, the study of cancer and its treatment, is very complex,
as more than 200 distinct forms of cancer have been identified
and hundreds of chemotherapeutic agents are approved for the
treatment of cancer. (By MaryAnn Foote, PhD
Director, Global Regulatory Writing, Amgen Inc.)
The National Cancer Institute (NCI) has estimated that 1,334,100
people living in the US were diagnosed with some form of cancer
in 2003 and that 556,500 deaths were attributed to cancer
that year.1 The popular media are replete with reports of
cancer prevention through diet, lifestyle modification, or
early detection.
Cancer
remains a frightening and mysterious disease that appears
to strike indiscriminately. As biomedical communicators, we
must understand the facts and avoid being swayed by sensationalism
or rumors. Thus, it is important for biomedical communicators
to understand the complex subject of oncology.
Definition
of Cancer
The word "cancer" is derived from the Latin word
for "crab." Because many tumors, or clusters of
cancer cells, are capable of wildly uncontrolled cell division,
malignant tumors often are thought to have the silhouette
of a crab, with many appendages radiating from a central body.
(Normally, cells form orderly layers or sheets of tissue.)
Other names for a tumor are lesion, malignancy, mass, or neoplasm.
Cancer cells are able to divide more rapidly than normal cells
and can displace normal neighboring cells. Intrinsic changes
in cancer cell composition allow them to multiply without
the usual restraints placed on cells (i.e., most cells must
"obey" territorial limits placed on them by their
neighboring cells, but cancer cells do not); cancer cells
appear to divide more rapidly than normal cells and fewer
daughter cells undergo apoptosis.
When
cells divide rapidly but keep within their normal territory
and do not invade the surrounding tissues, the cell cluster
is referred to as a benign tumor. Usually, benign tumors pose
no threat, but if they are contained in an enclosed space,
such as the cranial cavity, they can continue to increase
in size and put pressure on an organ. For this reason, benign
tumors are often removed.
Malignant
cancers are capable of spreading through the body by 2 mechanisms:
invasion and metastasis.
Invasion
is the direct migration and penetration by cancer cells into
neighboring tissues. Metastasis refers to the ability of cancer
cells to penetrate into lymphatic and blood vessels, circulate
through the bloodstream, and invade normal tissues elsewhere
in the body.
Almost
all cells in the body are susceptible to cancer, and more
than 200 distinct varieties of cancers have been described.
Most varieties of cancer are rare, and deaths due to cancer
are mainly attributable to only a few common ones such as
lung, breast, colon, skin, and blood cancers. Cancers are
classified according to the type of tissue and type of cell
in which they originate. For example, if the disease is believed
to have originated in the tissues of the breast, the diagnosis
may be breast cancer. The cancer may spread to other organs
such as the lung, and the diagnosis would be primary breast
cancer with lung metastases.
All
cancers can be placed into 1 of 6 broad categories: carcinoma,
sarcoma, leukemia, lymphoma, melanoma, and glioma. The different
types of cancers are defined by the organ of the body in which
the cancer started. Carcinomas originate in epithelial issues,
such as the liver, lungs, glands (e.g., prostate or thyroid),
bladder, kidney, breast, ovary, uterus, testes, colon, skin,
and brain. Approximately 80% of all cancer cases are carcinomas.
Sarcomas originate in bone, muscle, cartilage, fat, and fibrous
tissue. Sarcomas are rare, representing approximately 1% of
all cancers. Leukemias originate in the bone marrow; myeloma
is a subset of leukemia and is a cancer of plasma cells. When
cancers affect the blood or blood-forming organs, they are
called myeloid; when the cancer involves other tissues that
do not directly affect the formation of blood cells, it is
referred to as nonmyeloid. Lymphomas originate in the lymphatic
system, i.e., the lymph nodes.
Melanomas
are cancers that originate in skin cells called melanocytes
(although melanomas can be found in organs other than skin),
and gliomas are cancers of the nervous tissue, i.e., the brain
and spinal cord. Most organs of the body are composed of several
types of tissue, which means that each organ can be the site
of different types of cancers. For example, most cases of
uterine cancer are carcinomas and are found in the endometrium
of the uterus. Some uterine cancers, however, are found in
the muscle of the uterus, classifying them as sarcomas.
Symptoms
of Cancer
Symptoms of cancer can be silent, particularly in the early
stages of development. Some symptoms are specific to certain
types of cancer, such as difficult urination for prostate
cancer or flu-like symptoms and easy bruising for acute leukemias.
Sudden weight loss, a thickening or lump, unexplained bleeding,
coughing, or a wound that will not heal are some of the many
symptoms that may be related to cancer. Often, symptoms are
nonspecific; that is, common to many other conditions.
Diagnosis
of Cancer
Cancers are diagnosed a variety of ways, again depending on
the primary source of the cancer. The biopsy, which involves
surgically obtaining a small tissue sample and examining it
under a microscope, is often used to help identify the primary
cancer. A biopsy can be done on all tissues including the
bone marrow. When examined microscopically, cancer tissue
has a distinctive appearance, including a large number of
dividing cells, variation in the size and shape of cells and
nuclei, loss of specialized cell features and normal tissue
organization, and poorly defined tumor boundary. Microscopic
examination of a biopsy specimen will sometimes detect a condition
called hyperplasia.
The
cell structure and orderly arrangement of cells within the
tissue remain normal, and the process of hyperplasia is potentially
reversible. Microscopic examination of a biopsy specimen can
detect another type of noncancerous condition called dysplasia,
an abnormal type of excessive cell proliferation characterized
by loss of normal tissue arrangement and cell structure. Often
such cells revert to normal behavior, but occasionally they
gradually become malignant. Because of their potential for
becoming malignant, areas of dysplasia should be closely monitored
and sometimes require treatment. The most severe cases of
dysplasia are sometimes referred to as carcinoma in situ ("cancer
in place"), which refers to an uncontrolled growth of
cells that remains in the original location. Carcinoma in
situ may develop into an invasive, metastatic malignancy and,
therefore, is usually removed surgically, if possible.
Microscopic
examination also provides information regarding the likely
behavior of a tumor and its responsiveness to treatment. Cancers
with highly abnormal cell appearance and large numbers of
dividing cells tend to grow more quickly, spread to other
organs more frequently, and be less responsive to therapy
than cancers whose cells have a more normal appearance.
Based
on these differences in microscopic appearance, oncologists
assign a numerical grade to most cancers. In this grading
system, a low number grade (grade I or II) refers to cancers
with fewer cell abnormalities than those with higher numbers
(grade III or IV). Disease progression is determined by the
size of the tumor and its invasion into surrounding tissues,
and metastases to regional lymph nodes or other regions of
the body. Based on these criteria, the cancer is assigned
a stage. A patient's chances for survival are better when
cancer is detected at a lower stage number.
Another
diagnostic tool is the endoscope, which can be used to examine
major organs and the entire digestive system. Endoscopy is
routinely used to screen for the presence of colon cancer.
Radiographs (i.e., x-rays) ultrasonography, computed axial
tomography (CAT; often called computed tomography or CT) scan,
positron emission tomography (PET) scan, and magnetic resonance
imaging (MRI) are other ways that tumors can be detected.
Additionally, blood tests may help to diagnose cancers. Some
tumors have tumor markers that include genetic markers, cellular
and tissue markers, and circulating markers that can be detected
in the blood.
A
blood test for prostate cancer measures the amount of prostate-specific
antigen (PSA), a tumor marker. Higher-than-normal concentrations
of PSA may indicate cancer. Recently, a blood test for ovarian
cancer, known as CA-125, has become available. It should be
stressed that blood tests by themselves, however, are inconclusive
because more than 300 markers have been identified but their
relationships to cancer are not fully elucidated.
Presence
of a tumor marker is not conclusive proof that a tumor exists.
-
Change in bowel or bladder habits
- Sore
that will not heal
- Unusual
bleeding or discharge
- Thickening
or lump in the breast or other part of the body
- Indigestion
or difficulty in swallowing
- Obvious
change in a wart or a mole
- Persistent
cough or hoarseness
The
biggest risk for the development of cancer is aging. The longer
a person lives, the more likely it is that some form of cancer
will develop. Some types of cancer are preventable (e.g.,
lung cancer from tobacco), while others types of cancer are
caused by environmental factors (e.g., lung cancer in heavy
smokers who use beta carotene supplements) or by genetic factors
(e.g., MYC marker in lung cancer). Because cancer usually
requires a number of genetic mutations, the chances of developing
cancer increases as a person gets older because more time
has been available for mutations to accumulate.
In
addition to chemicals and radiation, bacteria and a few viruses
can trigger the development of cancer. The bacterium Helicobacter
pylori, which can cause stomach ulcers, has been associated
with an increased risk for the development of gastric cancer.
In the case of cancer viruses, some of the viral genetic information
is inserted into the chromosomes of the infected cell, causing
the cell to become malignant.
Very
strong evidence suggests that the human papilloma viruses
(HPV) are associated with most types of cervical cancer (squamous
and adenocarcinomas), and results of several large studies
suggest that HPV infection precedes the development of cervical
cancer by 10 to 15 years. The use of tobacco products has
been implicated in nearly 30% of cancer-related deaths, making
it the largest single cause of death from cancer. Cigarette
smoking is responsible for nearly all cases of lung cancer,
and smoking has been implicated in cancer of the mouth, larynx,
esophagus, stomach, pancreas, kidney, and bladder. Tobacco
is the main environmental risk factor for lung cancer, and
it has been estimated that each cigarette smoked shortens
the smoker’s life by 14 minutes.
Skin
cancer caused by exposure to sunlight is the most frequently
observed type of human cancer. Because skin cancer is often
easy to cure, the danger posed by sunlight is perhaps not
taken seriously enough. Mortality may be low, but morbidity
can be high if the lesions must be excised from a cosmetically
sensitive area (i.e., the face). Chronic exposure to radiation
in sunlight and fair skin that is susceptible to sunburns
appear to be the most important risk factors, with increasing
frequency of exposure, age, immune status, male gender, and
DNA repair disorders (such as xeroderma pigmentosum) as other
risk factors.
Drinking
excessive amounts of alcohol is linked to an increased risk
for several kinds of cancer, especially those of the mouth,
throat, and esophagus. The combination of alcohol and tobacco
appears to be especially dangerous: in heavy smokers or heavy
drinkers, the risk of cancer of the esophagus is approximately
6 times greater than that for nonsmokers/nondrinkers. For
people who both smoke and drink, the risk of cancer is 40
times greater than that for nonsmokers/nondrinkers. Alcohol
cannot cause cancer but can convert damaged cells into malignant
cells.
Studies
suggest that differences in diet may play a role in determining
cancer risk. In contrast to the clear-cut identification of
tobacco, sunlight, and alcohol, the exact identity of the
dietary components that influence cancer risk has been difficult
to determine. Limiting fat consumption and calorie intake
appears to be one possible strategy to decrease the risk of
some cancers because people who consume large amounts of meat
(rich in fat) and large numbers of calories have an increased
risk for cancer, especially for colon cancer.
Causes
of Cancer
Cancer
is a multifaceted disease, sometimes the result of the unlucky
convergence of genetics and environment. The etiology of cancer
is different from the risk of cancer. Avoidance of the causes
(etiology) of cancer may greatly reduce a person's risk of
cancer. For example, smoking is a cause of cancer; not smoking
reduces one's risk of cancer, even if he or she has a genetic
defect that is a predisposition to cancer.
Genes
and Cancer: Is Cancer Hereditary
All cancers are caused by a defect in a gene that allows the
cell to proliferate wildly. The genetic effect occurs through
small mutations in the DNA, little "hits" over many
years. (Dr. Alfred Knudson developed the "2-hit"
theory of cancer; he was the McGovern Award recipient at the
1999 AMWA meeting in Philadelphia.) Not all cancers are hereditary—actually
only 5% of cancers are due to genetic inheritance. People
born with the defective gene must still be subjected to prolonged
or repeated exposure to a carcinogen.
Chemicals
(e.g., from smoking), radiation, viruses, and heredity all
contribute to the development of cancer by triggering changes
in a cell's genes. The chemicals that trigger changes are
called initiators. Chemicals and radiation act by damaging
genes, viruses introduce their own genes into cells, and heredity
passes on alterations in genes that make a person more susceptible
to cancer. Genes are altered, or "mutated," in various
ways as part of the mechanism by which cancer arises.
Several
groups of genes have a role in carcinogenesis. The first group
of genes implicated in the development of cancer are damaged
genes, called oncogenes. Oncogenes are genes whose presence
in certain forms and/or overactivity can stimulate the development
of cancer. Cell growth and division is normally controlled
by proteins called growth factors, which bind to receptors
on the cell surface. This binding activates a series of enzymes
inside the cell, which in turn activate special proteins called
transcription factors inside the cell's nucleus. The activated
transcription factors turn on genes required for cell growth
and proliferation.
Oncogenes
in normal cells can cause the cells to become malignant by
instructing cells to make proteins that stimulate excessive
cell growth and division. By producing abnormal versions or
quantities of cellular growth-control proteins, oncogenes
cause a cell's growth-signaling pathway to become hyperactive.
A cancer cell may contain 1 or more oncogenes, which means
that 1 or more components in this pathway will be abnormal.
Oncogenes are related to proto-oncogenes, a family of normal
genes that code primarily for proteins involved in a cell's
normal growth. A second class of genes implicated in cancer
are tumor suppressor genes.
Tumor
suppressor genes are normal genes whose absence can lead to
cancer. Tumor suppressor genes instruct cells to produce proteins
that restrain cell growth and division. Because tumor suppressor
genes code for proteins that slow down cell growth and division,
the loss of such proteins allows a cell to grow and divide
in an uncontrolled fashion. One particular tumor suppressor
gene codes for a protein called p53 that can trigger apoptosis.
In cells that have undergone DNA damage, the p53 protein halts
cell growth and division. If the damage cannot be repaired,
the p53 protein eventually initiates cell suicide, thereby
preventing the genetically damaged cell from growing out of
control. If a pair of tumor suppressor genes are either lost
from a cell or inactivated by mutation, their functional absence
can cause cancer.
Individuals
who inherit an increased risk for the development of cancer
often are born with one defective copy of a tumor suppressor
gene. Because genes come in pairs (one inherited from each
parent), an inherited defect in one copy will not cause cancer
because the other normal copy is still functional. If the
second copy undergoes mutation, cancer may then develop because
there no longer is any functional copy of the gene.
A
third class of genes implicated in cancer are called mismatch
repair genes. Mismatch repair genes code for proteins whose
normal function is to correct errors that arise when cells
duplicate their DNA before cell division. Mutations in mismatch
repair genes can lead to a failure in DNA repair, which in
turn allows subsequent mutations in tumor suppressor genes
and proto-oncogenes to accumulate.
People
with a condition called xeroderma pigmentosum have an inherited
defect in a mismatch repair gene. As a result, the DNA damage
that normally occurs when skin cells are exposed to sunlight
cannot be effectively repaired, and so the incidence of skin
cancer is abnormally high for people with this condition.
Certain forms of hereditary colon cancer also involve defects
in DNA repair.
Cancer
often arises because of the accumulation of mutations involving
oncogenes, tumor suppressor genes, and mismatch repair genes.
Colon cancer can begin with a defect in a tumor suppressor
gene that allows excessive cell proliferation. The proliferating
cells acquire subsequent mutations involving a mismatch repair
gene, an oncogene, and several other tumor suppressor genes.
The accumulated damage yields a highly malignant, metastatic
tumor.
Another
type of gene involved in the development of cancer is the
telomerase gene. The end |