Role of Mesenchymal-Derived Stem Cells in Stimulating Dormant Tumor Cells to Proliferate and Form Clinical Metastases
Technical Report,15 Jun 2014,14 Jun 2017
The Geneva Foundation Tacoma United States
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Tumor metastasis is a complex and often fatal complication of most cancers. One of the biggest challenges to treatment is that prior to diagnosis or during treatment tumor cells can disseminate and remain dormant in distant tissue sites. These cells can become proliferative and lead to metastatic disease late after completion of therapy. The biology of this outbreak of dormant tumor cells that leads to relapsed metastatic disease is the major focus of this grant. Using a fibrosis model of tumor dormancy we have determined the break in dormancy is dependent on collagen and other fibrotic extracellular matrix components for the induction of a proliferative state in these dormant D2.0R breast cancer cell lines. Performing gene expression array on these dormant D2.0R cells exposed to collagen to induce a break from dormancy compared to dormant D2.0R cells revealed a set of genes that overlap with published dormancy gene sets. We also have performed immunophenotyping of the microenvironment of proliferating D2.0R cells in the fibrosis model of tumor dormancy and have identified an expansion and alteration of mesenchymal stem cells coincident with this metastatic outgrowth. We have performed studies to analyze the key chemokinecytokines released from the tumor cells transitioning from a dormant to proliferative state that may recruit these mesenchymal cells. We have delved into the crosstalk between these mesenchymal cell populations and the tumor cells to delineate the molecular pathways, which inform this complex biology. We use both our in vivo and in vitro models with conditional gene deletion in the specific cell populations to determine the functional role of each key molecular component in the break from tumor dormancy. These findings are aiding in the identification of potential new therapeutic approaches to inhibit metastatic progression.
- Medicine and Medical Research