The trailblazers are bone marrow–derived cells (BMDCs) that were earlier implicated in building blood vessels in established tumors. When Kaplan saw the cells in metastases she thought it was the same story. “For a long time we thought the tumor cells got there and then brought the bone marrow cells afterwards,” she says. But careful examination showed that, both in mice and humans, the BMDCs showed up several days before the first tumor cells. Interfering with the trailblazing BMDCs prevented metastasis.
The group now thinks that growth factors from the tumors have two distinct activities. They coax BMDCs out of the bone marrow and into the circulation. And they induce fibroblasts in other tissues to proliferate and make fibronectin. These fibroblast actions in turn attract the fibronectin-binding BMDCs, which settle into their niche and start producing other factors that attract the tumor cells.
This rather complex dance “is very logical,” says Lyden. “Tissue regeneration is happening all the time: you need to make new blood vessels all the time; you need to heal wounds all the time.” The tumor, he thinks, is inducing remote sites to act as if they are wounded or inflamed, thus recruiting the BMDCs as healers. The BMDCs need to recruit yet other cells to complete the healing, yet in the process they pull the tumor cells into the mix.The molecular details thus far consist of a specific receptor (VEGFR1) and integrin (the fibronectin ligand VLA-4) on the BMDCs. Kaplan and Lyden are now defining the profile of factors made by different tumors in the hopes that this will be predictive of future metastatic sites.