http://www.cancer.gov/newscenter/pressreleases/ crossposted to
sci.med.diseases.cancer
New Research Results Explain How Dormant Tumor Cells Become Active in
Later Years

Scientists using a three-dimensional cell culture system have identified a
mechanism by which dormant, metastatic tumor cells can begin growing again
after long periods of inactivity. The new findings indicate that the
switch from dormancy to proliferative, metastatic growth may be regulated,
in part, through signaling from the surrounding microenvironment, which
leads to changes in the skeletal architecture of dormant tumor cells.
Targeting this mechanism may also provide strategies for inhibiting the
switch from dormancy to proliferation. The results of this study by
National Cancer Institute (NCI) scientists and their collaborators,
appears in the August 1, 2008, issue of Cancer Research. NCI is part of
the National Institutes of Health.

The recurrence of breast cancer often follows a long latent period in
which there are no signs of cancer, and metastases may not become
clinically apparent until many years after removal of the primary tumor
and follow-up therapy. According to NCI's Jeffrey E. Green, M.D., one of
the lead researchers of this study, "Recent evidence suggests that, in
many cases, tumor cells have already seeded metastatic sites even when the
primary tumor is diagnosed at an early stage." Approximately 30 percent of
breast cancer patients diagnosed with early-stage disease have been found
to have breast cancer cells in their bone marrow. However, these cells
seem to exist primarily as micrometastases that do not manifest themselves
clinically in any way.

Although many of these disseminated tumor cells may not survive for
extended periods of time, a subset of them may represent dormant but
viable cells that could begin to proliferate years later. These dormant
cells are resistant to conventional therapies such as chemotherapy that
target actively dividing cells. Such cells could account for disease
recurrence after apparently successful treatment of primary tumors.

It has been proposed that tumor cells can switch from a dormant state to
become active micrometastases, but the size of the resulting tumors may be
limited by the availability of an adequate blood supply, which is needed
to provide oxygen and nutrients for cell growth. Discerning the mechanisms
that either maintain prolonged cellular dormancy or activate dormant tumor
cells to a proliferative stage has been a goal of scientists for many
years. The development of therapeutic approaches to eliminate these
inactive micrometastatic tumor cells has been hampered by the absence of
models in living systems that mimic cellular dormancy and the emergence of
clinical metastatic disease.

The tumor microenvironment has been increasingly recognized as a critical
regulator of cancer progression. The extracellular matrix (ECM), a key
component of the microenvironment, is in immediate contact with tumor
cells. The ECM significantly affects tumor biology and progression by
providing factors for cell growth and survival and for stimulating the
growth of new blood vessels to feed the tumor. Also, cell adhesion to the
ECM triggers signaling pathways that can regulate various phases of cell
growth.

In this study, NCI investigator Dalit Barkan, Ph.D., and colleagues
characterized a novel application of a three-dimensional culture system in
which the growth of several different types of tumor cells in the ECM
correlated with the dormant or proliferative behavior of the tumor cells
at metastatic, secondary sites in a living system. A three-dimensional
system can be used to culture a variety of different cells and tissues in
the laboratory for prolonged periods of time. The results revealed that a
stage of prolonged tumor cell inactivity, presumably preceding a later
stage that is dependent on blood vessel formation for metastatic growth,
exists due to a brake being applied to the cell division cycle, which is
the regulated series of steps that a cell goes through when it replicates.
The researchers were also able to demonstrate that the switch from
inactive to proliferative, metastatic growth is strongly influenced by
interactions with the ECM.

Specifically, the interactions that the researchers identified affect the
activity of an enzyme called MLC kinase. Inhibition of this particular
enzyme causes a chain reaction that limits alterations of the skeletal
architecture in dormant tumor cells and thus inhibits proliferative growth
in the living system model.

"We hope that, with additional studies, we can begin to discover new ways
to therapeutically keep the dormant-to-active switch in the 'off'
position, thus limiting the chance that micrometastases become active in
later life," said Green.

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Reference: Barkan D, Kleinman H, Simmons JL, Asmussen H, Kamaraju AK,
Hoenorhoff MJ, Liu Z, Costes SV, Cho EH, Lockett S, Khanna C, Chambers AF,
Green JE. Inhibition of metastatic outgrowth from single dormant tumor
cells by targeting the cytoskeleton. Cancer Research. August 1, 2008.

For more information on Dr. Green's research, please go to
http://ccr.cancer.gov/staff/staff.asp?profileid=13662