Clinical issue

White blood cells are attracted to sites of infection or tumors to defend the organism. However, instead of attacking tumors, some white blood cells stimulate tumor growth and cancer spreading. Knowledge of how these cells behave in tumors could contribute to the understanding of how the cells promote cancer, but little is known about their real-time behavior.

Results

In this paper, a system is described that monitors white blood cells inside tumors of live mice for up to 12 hours. This system is built around a spinning disk confocal microscope. It uses genetically engineered mice that model the aggressive HER2-expressing human breast cancer, where the cancer cells and white blood cells have been given different fluorescent colors.

The white blood cells moved differently depending on their position in the tumor. At the tumor periphery, one cell population moved, whereas another did not. A third population, which had penetrated into the tumor, was also motionless. Since oxygen levels are lower inside tumors than at the periphery, it was tested whether moving cells would slow down when the mice were ventilated with reduced oxygen concentrations. The myeloid cells originating from the bone marrow remained unaffected. In contrast, regulatory T-lymphocytes, originating from the lymph nodes, stopped migrating when the oxygen concentration was lowered. This finding suggests that the low oxygen levels in tumors reduce the ability of some white blood cells to penetrate into the tumor, while leaving others unaffected.

To mark the blood vessels, a fluorescently labeled polysaccharide, dextran, was injected, which leaked out of the blood vessels and was ingested by stationary, alternatively activated macrophages, a myeloid cell type that promotes tumor progression. In contrast, Gr1+ myeloid cells moved, both inside tumor blood vessels and at the tumor periphery. Therefore, these two myeloid-derived cell populations behaved distinctly.

Implications and future directions

An immediate application of the live microscopy system described here is to watch cancer drugs in action. Development of live microscopy in humans or, of human tissue samples, is necessary to confirm the human relevance. Insights into the behavior of white blood cells in tumors could help solve why some of these cells promote tumor growth. This could lead to new ideas on how to treat cancer. The techniques are not limited to the study of cancer, but could help gain new understanding of how cells function in live organs, healthy or diseased.