New research helps explain how multiple myeloma (MM) cells manipulate the bone marrow (BM) environment to promote disease progression.
The researchers knew that mesenchymal stem cells (MSCs) are often altered in MM in a way that favors disease progression, but the mechanisms behind this phenomenon weren’t well understood.
So the team set out to determine how and when normal MSCs evolve into tumor-promoting MSCs.
Mahmoud Dabbah, of Meir Medical Center in Kfar Saba, Israel, and his colleagues conducted this research and reported the results in the Journal of Leukocyte Biology.
The researchers cultured the MM cell lines U266 and ARP1 with MSCs from healthy donors, looking for changes in the MSCs. The team observed changes in migration and protein translation initiation.
Specifically, they found that co-culturing MSCs with MM cell lines induced an elevation in translation initiation factors eIF4E and eIF4GI as well as their regulators and targets. But these changes were reversible.
MM-conditioned MSCs had significantly elevated levels of peIF4E, total eIF4E, peIF4GI, and total eIF4GI after 3 days of co-culture with both MM cell lines (all increased about 200%, P<0.05).
In fact, levels of peIF4GI and peIF4E were significantly elevated in the MSCs within 1.5 hours of co-culture (both increased more than 250%, P<0.05).
However, when the MSCs were removed from co-culture, the levels returned to baseline within 3 to 6 hours.
MM-conditioned MSCs also showed a significant increase in migration. When cultured for 16 hours, MSC migration increased more than 400% (P<0.05).
Accordingly, the MM-conditioned MSCs expressed lower levels of microRNAs with established roles in cell migration.
The MSCs showed decreased levels of MIR-125a-5p and MIR-199b-3p after 12 hours of co-culture (a decrease of 160% to 250%, P<0.05). And this effect was maintained as long as the co-culture continued.
The researchers said their findings suggest a dynamic interaction between MM cells and the BM niche that causes profound changes in non-malignant BM constituents. They hope that future studies will reveal clinically relevant means of blocking this crosstalk to improve MM therapy.
“Our research should help identify therapeutic targets that may be used to minimize the collateral damage,” Dabbah said. “The identification of the translation initiation phase as a dialogue platform affords a potential new therapeutic target to be explored.”
