BETHESDA, Md.—Using a three-dimensional cell culture system, a team of National Cancer Institute (NCI) scientists has identified a mechanism by which dormant tumor cells can begin growing again after long periods of inactivity—a system that could be used to discover additional therapeutic targets to inhibit a tumor cell's switch from dormancy to proliferation.
The discovery, detailed in a study published in the Aug. 1 edition issue of the American Association for Cancer Research (AACR) journal Cancer Research, indicates the switch from dormancy to 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, according to NCI investigator Dr. Dalit Barkan.
"It is well known that cancer cells detach from the primary tumor and travel throughout the body," Barkan says. "Very few of these cells will ultimately survive in another organ site. However, those that do survive in this foreign and hostile environment can remain dormant for years and then proliferate to clinical metastases. We therefore tried to reproduce the immediate microenvironment encountered by tumor cells once they reach the metastatic site."
The cells were placed in a 3-D, specialized matrix called the basement membrane that has previously been used to address experimental questions related to development and tumor progression. The tumor cells were placed in the 3-D system as single cells to mimic the few metastatic cells that successfully reach the distant site, then subjected to partial depravation of nutrients and growth factors, recreating in part the hostile microenvironment they encounter at the metastatic site.
The results revealed that a stage of prolonged tumor cell inactivity exists due to a brake being applied to the cell division cycle, the regulated series of steps a cell goes through when it replicates. The researchers were also able to demonstrate the switch from inactive to proliferative, metastatic growth is strongly influenced by interactions with the extracellular matrix, a key component of the microenvironment that significantly affects tumor biology and progression by providing factors for cell growth and survival and stimulating the growth of new blood vessels to feed the tumor.
"This study demonstrates the critical roles of the extracellular matrix and cellular cytoskeletal dynamics in determining whether metastatic cells remain dormant or proliferate," Barkan says. "We found that the switch from dormancy to metastatic growth may be regulated, in part, through re-modeling of the extracellular matrix by the tumor cells. Altered signaling from the microenvironment could then induce a reorganization of the cytoskeletal architecture of the tumor cells. Blocking the interaction of the cells with the remodeled environment or directly inhibiting the enzyme that changes the cytoskeletal architecture, using a drug or through genetic means, prolonged the dormant state of the cells in the 3-D system and also in a living model routinely used to study metastasis."
The model system proposed in the study can be used to begin to address fundamental questions regarding tumor dormancy, Barkan says.
"For example, what keeps these tumor cells alive for so long, and what triggers their transition from dormancy to clinical metastasis?" he says. "Our results also suggest that targeting pathways regulating the cytoskeleton may provide an effective means of inhibiting the switch from tumor cell dormancy to clinical metastatic disease. This approach, perhaps in combination with immunotherapeutic strategies, may reduce the incidence of tumor recurrence from disseminated, dormant tumor cells."
The discovery, detailed in a study published in the Aug. 1 edition issue of the American Association for Cancer Research (AACR) journal Cancer Research, indicates the switch from dormancy to 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, according to NCI investigator Dr. Dalit Barkan.
"It is well known that cancer cells detach from the primary tumor and travel throughout the body," Barkan says. "Very few of these cells will ultimately survive in another organ site. However, those that do survive in this foreign and hostile environment can remain dormant for years and then proliferate to clinical metastases. We therefore tried to reproduce the immediate microenvironment encountered by tumor cells once they reach the metastatic site."
The cells were placed in a 3-D, specialized matrix called the basement membrane that has previously been used to address experimental questions related to development and tumor progression. The tumor cells were placed in the 3-D system as single cells to mimic the few metastatic cells that successfully reach the distant site, then subjected to partial depravation of nutrients and growth factors, recreating in part the hostile microenvironment they encounter at the metastatic site.
The results revealed that a stage of prolonged tumor cell inactivity exists due to a brake being applied to the cell division cycle, the regulated series of steps a cell goes through when it replicates. The researchers were also able to demonstrate the switch from inactive to proliferative, metastatic growth is strongly influenced by interactions with the extracellular matrix, a key component of the microenvironment that significantly affects tumor biology and progression by providing factors for cell growth and survival and stimulating the growth of new blood vessels to feed the tumor.
"This study demonstrates the critical roles of the extracellular matrix and cellular cytoskeletal dynamics in determining whether metastatic cells remain dormant or proliferate," Barkan says. "We found that the switch from dormancy to metastatic growth may be regulated, in part, through re-modeling of the extracellular matrix by the tumor cells. Altered signaling from the microenvironment could then induce a reorganization of the cytoskeletal architecture of the tumor cells. Blocking the interaction of the cells with the remodeled environment or directly inhibiting the enzyme that changes the cytoskeletal architecture, using a drug or through genetic means, prolonged the dormant state of the cells in the 3-D system and also in a living model routinely used to study metastasis."
The model system proposed in the study can be used to begin to address fundamental questions regarding tumor dormancy, Barkan says.
"For example, what keeps these tumor cells alive for so long, and what triggers their transition from dormancy to clinical metastasis?" he says. "Our results also suggest that targeting pathways regulating the cytoskeleton may provide an effective means of inhibiting the switch from tumor cell dormancy to clinical metastatic disease. This approach, perhaps in combination with immunotherapeutic strategies, may reduce the incidence of tumor recurrence from disseminated, dormant tumor cells."
