Triple-Negative Breast Cancer Tumor Stroma Plays Big Role in Bone Metastases

In order for malignancies to establish in metastatic sites, cancer cells must acquire attributes of those sites; specifically how this occurs in many cancers is relatively unknown, but a new study implicates the stroma of certain breast cancer tumors in the development of bone metastases. Specifically, cancer-associated fibroblasts were found to influence cells into developing properties that allow them to establish lesions in bone.

“Primary tumors release large numbers of cancer cells into the circulation, yet only a small proportion of these cells survive the stress of invading distant organs and progress to metastases,” wrote investigators led by Xiang H.-F. Zhang, PhD, of Baylor College of Medicine in Houston, in the August 29 issue of Cell. They focused on a subset of triple-negative breast cancer tumors-which generally tend to metastasize in the lungs, liver, brain, and other nonskeletal tissues-that often spread to bone. These cells have a high level of Src activity.

The in vivo studies found that triple-negative tumor stroma that is rich in mesenchymal cells tends to proliferate tumor cells that are suited to “thrive on the cancer-associated fibroblast-derived cytokines CXCL12 and IGF1.” Because bone is relatively rich in those cytokines, in comparison to other potential metastatic sites, this predisposes the cancer cells to take hold in bone rather than in other tissues.

“The ability of the primary tumor stroma to drive the selection of organ-specific metastatic cells is distinct from previously described roles of stromal signals in tumor progression,” the authors wrote; specifically, stromal signals have been implicated in the development of resistance to chemotherapy, among other things. They added that these results suggest that breast cancer cases with fibroblast-rich stroma or with bone metastases already developed may benefit from therapies targeting the PI3K-AKT pathways, which are related to Src amplification.

In an accompanying editorial in Cell, Theresa A. Guise, MD, of Indiana University in Indianapolis, wrote that these findings could eventually change “the prognostic, predictive, and preventative management of women” with breast cancer that has spread to bone. Importantly, she noted, this research suggests that the “neighborhood,” or the tumor’s microenvironment, is crucial in determining what eventual metastatic sites are chosen.

“More importantly, it may dictate therapy,” she wrote, adding that if clinical trials confirm these findings then the targeting of PI3K-AKT pathway may indeed prove beneficial. Outstanding questions persist, however, including whether or not this influence of the primary tumor stroma is present in other types of breast cancer, or other types of malignancies entirely.