Hypoxia-inducible factor-dependent signaling between triple-negative breast cancer cells and mesenchymal stem cells promotes macrophage recruitment

Significance The recruitment of host stromal cells, such as macrophages and mesenchymal stem cells (MSCs), to the primary tumor is a critical step toward cancer malignancy. We have identified signals that are exchanged between breast cancer cells (BCCs) and MSCs. This signaling increases the recruitment of both MSCs and macrophages to primary tumors and increases metastasis of BCCs to lymph nodes and lungs. Reduced oxygen levels (hypoxia) in breast cancers are associated with increased risk of metastasis and decreased patient survival. We show that hypoxia stimulates signaling between BCCs and MSCs due to the activity of hypoxia-inducible factors (HIFs). Drugs that block HIF activity prevent signaling and macrophage recruitment, which suggests that they may be useful additions to breast cancer therapy.