Investigating the Role of Stem Cell Niche Signaling on Cancer

Objectives: Previously we have demonstrated that disseminated prostate cancer (PCa) cells target the endosteal hematopoietic stem cell (HSC) niche during metastasis to the bone marrow. Given that HSC homing, quiescence and reactivation from quiescence is tightly regulated within the niche by several protein/receptor axises including Ang-1/Tie-2, Jagged-1/Notch-1, osteonectin, and GM-CSF/GM-CSFR, we wondered if molecules which regulate HSC reactivation from quiescence also regulate disseminated tumor cell (DTC) reactivation from dormancy and which can lead to their emergence as malignant outgrowths in the bone marrow niche. The aim of this study is to identify niche-derived molecules that either stimulate or inhibit DTC dormancy/reactivation in the bone marrow.
Methods: To determine the role of Ang-1, Jagged-1, osteonectin, and GM-CSF on DTC reactivation from dormancy, The proliferation was performed by XTT assays in human PCa cells (PC3 and DU145 ) in vitro. Data are reported as O.D. values (mean ± S.D. where significance was determined by ANOVA for n= x repeats.
Results: Following 96 hours in culture, Jagged-1 (vehicle vs. Jagged-1, 0.28±0.013 vs. 0.307±0.016, p-value < 0.05) and GM-CSF (vehicle vs. GM-CSF, 0.28±0.013 vs. 0.32±0.018, p-value <0.001) induced PC3 proliferation. Like PC3 cells, Jagged-1 stimulated the proliferation of DU145 cells (vehicle vs. Jagged-1, 0.40±0.012 vs. 0.51±0.061, p-value <0.01). Ang-1 and osteonectin, under the conditions and doses tested, did not significantly alter proliferation of either cell type, although osteonectin slightly decreased PCa proliferation.
Conclusions: Interactions between the HSC niche and DTC play a critical role in regulating DTC reactivation from dormancy, which can lead to malignant outgrowths in bone marrow during metastasis. Our findings suggest that Jagged-1 and GM-CSF may play a role in regulating PCa proliferation in the context of the marrow and suggest that interventions targeting these proteins may have a therapeutic benefit.