Osteoblasts Exert a Pro-Tumorigenic Effect on Breast Cancer Spheroids Through CXCL5/CXCR2 Signaling In 2D And 3D Bone Mimetic Cultures.

Bone provides a favorable niche for breast cancer colonization and metastatic progression. Breast cancer cells are attracted to the bone microenvironment where they induce bone cells to resorb bone, which enhances tumor cell proliferation in a positive feedback loop often referred to as the vicious cycle. While this phenomenon is established, the molecular interactions between cancer cells and bone cells are not well defined. CXCL5/CXCR2 signaling has recently been shown to promote breast cancer colonization to the bone. Here, we investigate the effects of osteoblasts and osteocytes on breast cancer cell proliferation in engineered two- and three-dimensional models. We observed that osteoblasts and osteocytes induce proliferative effects on cancer cells. Specifically, bone cells increase cancer proliferation in 2D culture and osteoblasts increase cancer growth more than osteocytes in 3D models. Moreover, osteocyte interaction with cancer cells in 3D models are stiffness dependent. We show that these effects depend on the CXCL5/CXCR2 signaling axis. Taken together, we demonstrate that osteoblasts drive cancer growth in a bone metastatic niche and that this effect can be rescued with CXCL5/CXCR2 inhibition.