In this image, prostate cancer cells are seen to express CXCL16, a protein (red) that recruits wound healing cells into the tumor bed. The nuclei of the tumor cells is shown in blue. (Source: Russell Taichman)Combining two biological approaches, a research team from University of Michigan broke down the molecular signaling that leads to metastasis in prostate and breast cancer tumors.

In the laboratory of Dr. Russell Taichman, a professor at the U-M School of Dentistry, researchers focus on two different areas of biology. One half of his lab looks at how very small embryonic-like cells (v-cells) help with tissue regeneration and wound healing, while the other half looks at how tumors metastasize to bone marrow.

“At one point (research assistant) Younghun Jung, who is the first author on the paper, was measuring these v-cells in numbers of tissues, and she was also working on the tumor side,” Taichman says. “We had pulled out tumors from an animal and she ran it through the assay for the v-cells – it was her idea to do it – and we found that, compared to what we had expected, the tumors had a lot of v-cells in them. That set the whole stage.”

The resulting study fused the two types of research. “We used the concept that tumors are wounds that don’t heal, which raised our suspicions that we should be looking at our wound-healing cells in the context of tumors,” Taichman says.

The research focused on the presence of wound-healing cells called mesenchymal stem cells, or MSCs. V-cells, like the type found in the initial animal tumor screened by Jung, are precursors to MSCs, Taichman says.

Wound-healing cells are called into a tumor through the production of a specific protein, CXCL16, which is used in the immune system to signal and call cells into wounded sites and to communicate immune regulation. Once those healing cells get into the tumor, they differentiate into the cell-type called cancer-associated fibroblasts.Prostate cancer cells, after interacting with normal wound healing cells have become more invasive and more able to metastasize. (Source: University of Michigan)

“We had previously studied CXCL16, so we knew it was important,” says Taichman. “But cancer-associated fibroblasts are known to produce another protein, which we had also studied.  We were just putting those two things together and ended up here.”

What Taichman observed inside the tumor cells is referred to as epithelial-to-mesenchymal transition of the healing cells. The wound-healing cells, or MSCs, are attracted to CXCL16. They sense that protein with a receptor, known as CXCR6. When CXCR 6 is activated, these cells start the conversion from a precursor cell into a cancer-associated fibroblast.

Those cells, in turn, make a protein called CXCL12, stromal cell-derived factor-1. At that point, the tumor cell changes from an epithelial-like cell to a mesenchymal-like cell.

“This process, the epithelial-to-mesenchymal transition, makes tumor cells more migratory,” Taichman says. “Then, they start looking around for even higher sources of that protein (CXCL12).The site that produces CXCL12 in really high levels is the bone marrow, so they end up migrating toward there.”

Taichman was able to observe tumor cells in the bone marrow using polymerase chain reaction (PCR), which was crucial in the detection of specific sequences of genes.

“With this technique, we were able to quantify the number of tumor cells that arrived in the bone marrow,” he says. “The beauty of this is that we were able to detect very few tumor cells that had arrived, at the earliest stage of the disseminations of tumors. That was a really key event for the paper.”

Armed with the knowledge of how and when a tumor can metastasize to bone marrow, researchers now have a new angle for running interference on the spread of cancer.

“We’d like to figure out how to either stop the host cells from coming into tumors or prevent them from turning into cancer-associated fibroblasts,” says Taichman. “Or, we could potentially use these host cells as a diagnostic tool to determine whether somebody has a tumor or not.”

The paper, “Recruitment of mesenchymal stem cells into prostate tumours promotes metastasis,” is published online in Nature Communications.