Pair of Signaling Molecules Critical to Osteosarcoma Metastases in Lungs

Blocking interleukin 6 and the chemokine CXCL8 inhibits metastatic growth in multiple disease models

The bone cancer osteosarcoma (OS) kills 80 percent of patients who develop lung metastases.

Researchers in the Center for Childhood Cancer and Blood Diseases at Nationwide Children’s, and other institutes in the U.S. and Italy, found two signaling molecules that appear to be essential for metastases to grow in the lung.

In fact, when they used drugs to block the production of these molecules, the multifunctional cytokine interleukin 6 (IL-6) and the chemokine CXCL8, metastases could not develop.

“If we can prevent lung metastasis, we can, in theory, save 80 percent of the lives lost to OS,” says Ryan Roberts, MD, PhD, a principal investigator in the center and senior author of the study, published in JCI Insight. “This study shows that’s not unreasonable.”

OS is found primarily in children and adolescents.  While a few of those affected with the disease will have lung metastases at diagnosis, many more will develop lung lesions long after completing surgery and chemotherapy.

The research team studied human tumor and lung tissue samples and cultures to try to learn why OS metastases grow almost exclusively in the lungs. They discovered IL-6 and CXCL8 were expressed at higher levels in OS lung metastases than in the same patient’s primary tumor cells. Testing in mouse models of the disease showed IL-6 and CXCL8 expression correlated with how efficiently metastases colonized lung tissue.

To further test the molecules’ importance to metastases, investigators tried blocking them with drugs. Blocking one resulted in no change. But when they blocked both, metastases were inhibited in mouse models of a number of different lines of human OS as well as a mouse model of canine OS, indicating the treatment is likely broadly applicable.

The researchers have translated the work to a clinical trial in collaboration with The Ohio State University College of Veterinary Medicine and the Cummings School of Veterinary Medicine at Tufts University. The other species that gets osteosarcoma is dogs.

They’ve finished the first phase, finding the right doses, and are starting the treatment trial on companion dogs with the disease. Cheryl London, DVM, PhD, professor of veterinary biosciences at OSU, is leading the trial. 

“If it works, we’ll seek a clinical trial with kids,” Dr. Roberts says.

The team is also expanding the work, collaborating with the Institute for Genomic Medicine at Nationwide Children’s to find more targets for therapy, he says. “We can now look at all individual genes, cell by cell, and how they are expressed. We can identify specific cells that will be in metastasis and can look gene by gene to see how signals from different cells might inadvertently help the metastases to grow.”

Citation: Gross AC, Cam H, Phelps DA, Saraf AJ, Bid HK, Cam M, London CA, Winget SA, Arnold MA, Brandolini L, Mo X, Hinckley JM, Houghton PJ, Roberts RD. IL-6 and CXCL8 mediate osteosarcoma-lung interactions critical to metastasis. JCI Insight. 2018 Aug 23:3(16).