Source: NIH News Release (www.nci.nih.gov)
Author: news release

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 can be 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. Thus,
interactions between tumor cells and the ECM are critical modulators of the
metastatic potential of tumor cells.

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.

“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.