Cancer Cells Use Bone Marrow Fibroblasts to Evade Treatment, Study

A five-year study led by researchers at Fox Chase Cancer Center has revealed that cancer cells can evade anti-cancer drugs by entering and surviving within bone marrow fibroblasts, a process the team refers to as “cell-in-cell.” This newly observed live phenomenon may help explain why patients with chronic lymphocytic leukemia (CLL) and related cancers often relapse despite initially responding to treatment.

CLL, the most common blood cancer in western countries, is typically treated with BTK inhibitors. While more than 90% of patients initially improve and their tumors shrink, only 8% to 11% reach complete remission, leaving many with residual disease that can later lead to relapse. Led by Y. Lynn Wang, the research aimed to uncover why the disease persists in spite of early therapeutic success. 

Using confocal microscopy and other techniques the team analyzed patient bone marrow samples and watched live CLL cells enter bone marrow fibroblasts after exposure to BTK inhibitors. They confirmed that these subsumed cancer cells remained alive and active inside the fibroblasts, and that they survived better than CLL cells left outside to face the drugs. Wang, senior author on the study published in Blood Neoplasia, compared this to tumor cells “retreating off the street into a house where they’re safer from the street bullies, i.e., the drugs.”

The researchers determined that BTK inhibitor exposure increases expression of CXCR4, a receptor on tumor cell surfaces. This receptor detects chemical gradients produced by fibroblasts, drawing the tumor cells toward them. Once in close proximity, the CLL cells enter the fibroblasts, effectively creating a drug-protected “safe house.”

After identifying this mechanism, the team tested whether blocking CXCR4 could prevent the cell-in-cell process. Using drugs already approved for other conditions, they successfully kept CLL cells from entering fibroblasts. This approach could make the cancer more susceptible to therapy when used alongside standard BTK inhibitors. “If we can block CXCR4, it’s like locking the door of the house where tumor cells wanted to retreat and hide,” Wang explained.

The study also found similar hiding behavior in follicular lymphoma and suggests the mechanism might occur in other cancers. Wang hopes that sharing these results will encourage further research into residual disease persistence.