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. Lysophospholipids activate ovarian and breast cancer cells. / Xu, Y.; Fang, X. J.; Casey, G.; Mills, G. In: Biochemical Journal, Vol. Metastases cause the vast majority of cancer deaths, but their tiny seeds are so difficult to track. Now, scientists described studying individual metastatic cells from human breast cancer tumors implanted into mice as the cells escaped into the blood stream and began to form tumors elsewhere in the body. 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. For more information on Dr. Green’s research, please go to. For more information about cancer, please visit the NCI website at, or call NCI’s Cancer Information Service at 1-800-4-CANCER (1-800-422-6237). About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit. NIHTurning Discovery Into Health ®. High levels of an enzyme known to suppress the immune system may put patients diagnosed with the most common form of leukemia at the risk of early death, say researchers including one of Indian-origin. High levels of this enzyme, indoleamine 2,3 dioxygenase, or IDO, at diagnosis can also identify those who might benefit most by taking an IDO inhibitor along with their standard therapy, said the study published in the journal Scientific Reports. “We want to help people who are not responding to treatment and are dying very soon after their diagnosis,” said Ravindra Kolhe from Medical College of Georgia at Augusta University in the US. The researchers found that increased IDO expression in the bone marrow biopsy of patients with acute myeloid leukemia, or AML, correlated with lower overall survival rates and early mortality. It also indicates that IDO expression should routinely be measured when the diagnostic bone marrow biopsy is performed, Kolhe said. An early phase clinical study is already underway to begin to explore the IDO inhibitor’s clinical potential in these patients, the researchers said. “We wanted to look at what makes this leukemia so aggressive that initial induction chemotherapy is not working,” Kolhe said.
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March 2018
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