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The study of tumor metastasis is the primary focus of study
in our laboratory. Metastasis is the process by which tumors
spread from the primary organ in which they arose to other sites
in the body. In most cases, tumors that stay confined to one
organ will not be fatal, and surgical removal or radiation of
these tumors will often result in complete cure. Tumors that
have spread to the other organs by the time at which a patient
is first diagnosed with cancer have a greater potential for
causing harm. <top>
Why are metastatic tumors more
dangerous than primary tumors?
In most cases, a single primary tumor arises in an organ. If
there is only one tumor, and it can be detected and removed, the
cancer is completely eradicated. In addition, some primary
tumors form in organs that are not essential for survival such
as the prostate and breast. Even if there are several primary
tumors in those organs, the entire organ could be removed
without threatening the life of the patient. Single primary
tumors are only fatal if they arise in an essential organ such
as the brain or pancreas and rapidly invade throughout that
organ. When tumors metastasize, they often do so over an
extended period of time and each single tumor cell that reaches
another organ can give rise to a new tumor. It is common to see
hundreds of metastatic colonies arise in an organ that is
distant from the primary site. As these multiple colonies each
grow larger, they can take over the function of the entire organ
and render it useless. The three most common sites of tumor
metastasis are the lungs, liver and bone marrow - all essential
organs which must function for a person to survive.
<top>
How do tumor cells metastasize?
Carcinoma In Situ. The process
by which metastases form is now well understood. Most human
tumors are carcinomas which originate in the epithelial layer of
a given organ. The first stage of tumor growth is generally the
formation of a small sphere of tumor cells. When this sphere
reaches a size of 1-2 millimeters in diameter the cells on the
inside begin to die because they cannot get sufficient nutrients
from the environment. Because the cells on the outside of the
sphere continue to divide while the cells on the interior are
dying, the tumor sphere can remain at the same size and in the
same place (carcinoma in situ) for months or years without
changing. We now know that most 'healthy' people have numerous
small tumors of this type in organs such as the thyroid, breast
, prostate and cervix that never grow large and never harm the
individual.
Primary Tumor
Local Invasion and Angiogenesis.
To grow beyond a small sphere, tumor cells must be able to
invade across a barrier called the basement membrane and into
the local tissue. At this point they also must be able to
produce factors that recruit new blood vessel formation (angiogenesis)(Zetter
BR. Angiogenesis and Tumor Metastasis, Ann Rev Med. 1998:). The
most potent tumor angiogenesis factors are fibroblast growth
factor (FGF) and vascular endothelial growth factor (VEGF). This
results in a large vascular network that surrounds the tumor and
promotes the expansion of the tumor to a larger size. In
addition to allowing the tumor to grow larger, these new vessels
also support tumor metastasis. The vessels promote metastatic
spread (dissemination) by providing the route of exit for cells
to leave the primary tumor and circulate in the blood stream for
travel to distant sites. It has been estimated that a tumor the
size of a grape (1 centimeter in diameter) can shed as many as
2,000,000 cells into the circulation in a 24 hr period by means
of the new angiogenic blood vessel network.
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Invasion
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Angiogenesis
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Intravasation
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Circulating Tumor Cells. The
tumor cells that enter the new tumor blood vessels will
circulate in the blood stream until they are either killed,
trapped in a capillary bed in another organ, or pass across the
blood vessel wall (extravasate) into the tissue in a distant
organ. It is only these latter cells that take exit the
bloodstream and enter a new tissue that can ever form metastatic
colonies. Cells that stay in the bloodstream or get trapped
inside small vessels will die fairly rapidly (often within
hours). Only a small percentage of the cells that reach the
bloodstream ever form metastatic colonies (as few as 1 in
100,000) but because the process takes place over and over each
day, there can eventually be several hundred metastatic colonies
in a single organ.
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Adhesion to Blood Vessel Wall in Distant Organ
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Extravasation and Migration
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Lymphatic Metastasis. In many
cases the first metastases detected in cancer patients consist
of tumor cells that have spread to regional (local) lymph nodes.
Lymphatic metastases indicate that the tumor has acquired the
ablility to leave the primary site and often suggests that
distant metastases will later be found. Thus the prognosis for
patients with no lymphatic metastases is better than for those
who have one or pore postivie lymph nodes. It is important to
realize, however, that lymphatic metastases are rarely
themselves the cause of death in cancer patients. As mentioned
earlier, cancers are most dangerous when they spread large
numbers of metastatic colonies to critical distant organs such
as the liver, lung, bone or brain. Thus the prognosis for
patients with known distant metastases is often worse than for
those patients who display only regional lymphatic metastases.
Micrometastases and Tumor Dormancy. The single cells that
initiate the formation of tumor metastases often start out by
producing small colonies, consisting of several cells that wrap
around a small blood vessel in the new organ site. Again these
colonies are limited by diffusion to 1-2 millimeters in
diameter. In some cases, the colonies quickly progress to a
large size and rapidly take over the organ. In other cases, the
tumors remain small for months or even years. A patient can live
their entire life expectancy with multiple small metastases in
place as long as none of them exceed this small size. However,
in some cases, a metastatic colonies may stay small and dormant
for several years and then rapidly start to expand and result in
the death of the patient. Current thinking holds that new
therapies could be designed to keep metastatic colonies small
and dormant without actually eliminating every tumor cell in the
body. One approach is to use long-term treatment with anti-angiogenic
drugs to keep the metastatic colonies avascular (no new blood
vessels) which may keep them small and harmless.
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Micrometastasis
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Metastasis
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How do tumor cells become capable of
metastasis? The notion of tumor progression.
One of the main interests in our lab is the process of tumor
progression. This refers to the development of the properties
required for a tumor to produce metastatic colonies in distant
organs. It is generally agreed that tumor progression occurs
over a long period of time and is generated primarily by
mutations in the tumor cell DNA that accumulate with time. It is
clear that the mutation rate is significantly higher in tumor
cells than in normal cells. Some of the increase in mutation
rate is due to congenital (hereditary) or spontaneous defects in
DNA repair enzymes leading to unfaithful DNA copying. Although
certain events in the metastatic process must precede others
(for example, angiogenesis precedes tumor cell escape from the
primary tumor), it is generally thought that the mutations
responsible for this process accumulate randomly. Consequently,
the development of any particular part of the metastatic process
(invasion, migration, angiogenesis, etc.) must await the
accumulation of the appropriate mutations that can permit that
event to happen. <top>
Cancer Diagnosis and Prognosis
Despite the fact that most mutations do occur randomly as
tumors progress to the metastatic state, some mutations are
indeed associated with a particular stage in the metastatic
process. For example, changes in cell proliferation often are
among the earliest changes found in new tumors, long before the
tumors become metastatic. Alterations in cell-cell adhesion, and
protease production often are seen after the changes in
proliferation but before metastasis is observed because they are
required for cell invasion across the basement membrane and into
the tissue stroma. Other mutations may be seen later in tumor
progression as the cells are becoming or have become capable of
metastasis.
Could the distinction in the time of appearance of a
particular mutation be useful clinically? We believe that it is.
For example, if we wish to know if a particular patient has or
does not have cancer, we should use a marker that comes up very
early and is expressed continuously by the tumor. In this way,
all patients with that cancer will be detected by screening for
that marker. In contrast, a marker that comes up when a tumor is
converting from non-metastatic to metastatic may be useful in
tumor prognosis. A patient without evidence of that marker may
have tumor that is still confined to the primary site and can be
eliminated by radiation or surgery. In contrast, a tumor that
produces a metastatic marker may have already produced
micrometastases at a distant site and require systemic treatment
with chemotherapy or anti-angiogenic agents. Markers produced by
aggressive tumor cells may also be used to immunize patients
(tumor vaccines) and use the body's immune system to attack the
aggressive tumor cells.
In our own lab, we have found that certain molecules that
regularly appear later in metastatic progression can be used to
predict the course of prostate cancer in patients. The PSA test,
which can be used to diagnose prostate cancer is not as useful
for telling whether a patient will go on to develop metastatic
disease. In contrast, we have developed a panel of markers that
appear to be able to predict which tumors are likely to go on to
metastasize or have likely already produced metastatic colonies.
The prototype for this type of molecule is thymosin Beta-15. A
molecule that stimulates cell migration and promotes metastasis
in prostate cancer cells. We and others have now shown that
tumors in which thymosin Beta-15 cannot be detected are unlikely
to develop metastases and may not warrant aggressive treatment.
In contrast, tumors expressing thymosin Beta -15 are more likely
to have disseminated metastases and are candidates for
aggressive systemic therapy. A more complete description of this
molecule can be found in the section of this web site devoted to
prostate cancer. |
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