A new study report that the molecular pathway known as STAT3 is the mechanism tumor-associated macrophages use to support neuroblastoma. It was also demonstrated that the use of ruxolitinib blocked the pathway. The work appeared in Oncotarget last week from researchers at the Children's Center for Cancer and Blood Diseases at Children's Hospital Los Angeles (CHLA).
"The macrophages are essentially co-opted by the tumor cells to help them grow," said Shahab Asgharzadeh, M.D., director of the Basic and Translational Neuroblastoma program at CHLA and lead investigator of the study. "We're trying to find out more about the mechanisms that enable TAMs (tumor-associated macrophages) to help cancer grow so that we can target the pathways they use and block their pro-tumor effect."
Using a mouse model, the research team observed the "recruitment and polarization" of TAMs, which enhance the ability of neuroblastoma to spread and grow. They saw that the TAMS not only nourished neuroblastoma but also evaded the "good immune cells" that were trying to kill the tumor cells.
To study the effect of TAMs on neuroblastoma cell growth and proliferation, the investigators co-cultured both mouse and human neuroblastoma cells with TAMs and found a significant increase compared to tumor cells without TAMs.
The researchers then wanted to figure out what the TAMs were secreting that caused the stimulation of tumor cells. IL-6 was known to cause proliferation in certain types of cancer, so they used a mouse model that lacked IL-6. However, they still saw increased tumor growth. From these experiments, they noted the activation of the STAT3 cell-signaling pathway—known to promote tumor growth preceding an increase of MYC—a gene that drives many types of cancer.
They then targeted the STAT3 pathway. Using ruxolitinib, which is known to block the STAT3 pathway, the scientists co-cultured both human and mouse TAMs and neuroblastoma cells and observed that the immune cells no longer supported tumor growth.
According to Asgharzadeh, the next step is to combine agents that block the STAT3 pathway with drugs that have been effective in treating neuroblastoma.