Cytokine Regulation of the Bone Pre- and Metastatic Niches: Implications for Breast Cancer Dormancy

Breast cancer relapse in bone is a significant clinical problem that is experienced in ~70-80% of patients with late-stage breast cancer. This condition commonly occurs 5-10+ years following surgical removal of the primary tumor. The long latency seen prior to relapse in bone is a result of tumor cell dormancy. Once disseminated to the bone, tumor cell interaction with the bone metastatic niche (endosteal niche and endovascular cells) maintains cells in a dormant state until changes to the local environment activate the niche to support outgrowth. Amassing evidence suggests that cytokines are key regulators of the bone metastatic niche, controlling bone homing and metastatic outgrowth. Pro-inflammatory cytokines including IL-1β, IL-6, IL-8, TGFβ and RANKL play crucial roles in attracting tumor cells to bone. Furthermore, these cytokines act in conjunction with IFN, VEGF, TGF, PTHrP, FGF, OPG and various chemokines to regulate expansion of the niche, facilitating tumor cell escape from dormancy and promoting the “vicious cycle of bone metastasis”. Here, we review the current literature to provide an up to date understanding of how interactions between cytokine signalling cascades regulate the bone metastatic niches to promote homing, dormancy or metastatic outgrowth of breast cancers.