|
The Metastasis Research Society
is dedicated to understanding the process of tumor
metastasis on a cellular, molecular and biochemical basis;
to the identification of potential therapeutics that would
halt the metastatic process and their preclinic
evaluation; and to working with clinicians to design and
implement clinical trials to bring these new therapeutic
strategies forward.
Tumor metastasis (from the Greek
“change of place”) is the movement of tumor cells from the
site where the cancer began, to grow in other sites of the
body. It is a complex process that is only partially
understood today at the biochemical and molecular levels.
When a cancer patient wakes from surgery and asks “Has it
spread?” , they are asking if the tumor has metastasized.
For many cancers, surgery and radiation therapy remove or
destroy the the primary tumor. It is the spread of cancer
cells to other (secondary) sites and their growth in these
sites that can contribute to some cancer patients’
sickness (morbidity) and deaths (mortality).
The tumor metastatic process has been
compared to a marathon. Tumor cells have to invade the
solid tissues around the primary tumor site. The tissue in
which the tumor arose is complex, containing other cells
such as fibroblasts, a protein filled matrix that provides
a solid support and immune cells and lymphatic drainage.
Tumors have to invade past these barriers. To do so
they develop the ability to move. Tumor cells do not float
out of a tissue, they crawl. Basically, tumor cells react
to factors in their environment, they put out a “finger”
of the cell toward the attractant and ratchet the cell
forward. To move, tumor cells must alter their adhesion to
other cells and to the protein matrix in a very dynamic
fashion. They may also have to create a pathway amongst
the tissue, by degrading the protein matrix using enzymes
(proteases).
Tumor cells can spread around the body
using one of two major “highways”. All tissues are served
by blood vessels (which provide oxygen and nutrients) and
also lymphatic vessels which drain excess fluid to nearby
lymph glands. For many cancer cells, their first
opportunity to escape is to use the lymphatic drainage
system. This is why for many cancers lymph nodes are
biopsied or removed at surgery to see if the cancer has
spread, and oncologists us the information to determine
the “stage” of the cancer. Cancer cells can enter the
bloodstream either indirectly via the lymphatics, or
directly from a vessel in the primary tumor. The
bloodstream is a very harsh environment with a high
velocity of flow and full of immune cells. Moreover,
cancer cells are used to being attached to the
proteinaceous matrix, many tumor cells die when detached
from their support and have to swim ( detachment mediated
death is called anoikis, another Greek word describing the
death of leaves from as they detach from trees in the
Fall). The majority of tumor cells get stuck (arrest) in
the first capillary bed that they float into. This is why
colon cancer tends to metastasize to the liver, etc. This
is not always the case, however, and some tumor cells end
up in distant organs. How do tumor cells get out of the
bloodstream? In essence, they attach to the endothelial
cells lining the blood vessels and the endothelial cells
retract, they move apart, to permit the tumor cells to
enter the tissue. This may be a normal reaction of
endothelial cells to immune cells, cells of our immune
systems migrate in and out of the bloodstream all the time
to maintain surveillance. In fact, tumor cells can
disguise themselves as lymphocytes by expressing similar
molecules on their surface that fool the endothelial
cells. These molecules may also determine their apparent
ability to “home” to specific organs preferentially, as
they may respond to gradients of chemicals differentially
expressed there.
Growth in the distant site is called
metastatic colonization. We know less about this process
than the previous steps . While a tumor, by definition,
can grow, growth in the primary tumor site is not always
identical to growth elsewhere. In the primary tumor site,
growth may have been aided by specific factors in the
matrix or by interactions with specific neighboring cell
types. About 100 years ago, a British pathologist named
Dr. Stephen Paget described metastasis by a “Seed and
Soil” hypothesis. He proposed that flowers send seeds
everywhere (just as tumor cells disseminate everywhere),
but that seeds only grow in congenial soil. Thus
metastatic tumor cells need to have an environment which
supports their growth. This can result from some very
general factors in the blood stream that could aid growth
virtually anywhere (examples are cytokines such as TGF-b
and phospholipids such as LPA). Tumor cells must
establish a blood supply (angiogenesis) to continue to
grow. Alternatively, there are many tissue specific
environments that may promote tumor colonization. One of
the best studied is in bone metastasis. Here a “vicious
cycle” has been described where tumor derived factors
stimulate the osteoclasts in the bone to degrade the bone
matrix; when degraded, the bone matrix releases factors
that stimulate tumor cell growth, providing a never ending
cycle.
The metastatic colonization process can
be halted or retarded by a poorly understood process
called tumor dormancy. Essentially, tumor cells can stay
alive, but stop dividing; alternatively they can die
(apoptosis) at rates equal to their proliferation, so that
the small tumor fails to increase in size. There are
probably many reasons for tumor dormancy. For instance, a
lack of angiogenesis may cause dormancy, where a lack of
an adequate blood supply may fail to provide sufficient
oxygen and nutrients for growth. The environment of the
metastatic site (matrix and other cells) may also enforce
dormancy, or localized host defences and immune responses
may also contribute. We have a very incomplete
understanding of the conditions that promote dormancy or
bring a tumor cell out of this state. The breaking of
dormancy is why some cancers recur 20-30 years after they
were initially treated.
Fortunately for us, the metastatic
process is very inefficient. Researchers using
experimental models estimate that 0.01% of the tumor cells
that enter the bloodstream eventually form a metastasis.
|
