Awakening of Dormant Breast Cancer Cells in the Bone Marrow

Abstract

Up to 40% of patients with breast cancer (BC) have metastatic cells in the bone marrow (BM) at the initial diagnosis of localized disease. Despite definitive systemic adjuvant therapy, these cells survive in the BM microenvironment, enter a dormant state and recur stochastically for more than 20 years. Once they begin to proliferate, recurrent macrometastases are not curable, and patients generally succumb to their disease. Many potential mechanisms for initiating recurrence have been proposed, but no definitive predictive data have been generated. This manuscript reviews the proposed mechanisms that maintain BC cell dormancy in the BM microenvironment and discusses the data supporting specific mechanisms for recurrence. It addresses the well-described mechanisms of secretory senescence, inflammation, aging, adipogenic BM conversion, autophagy, systemic effects of trauma and surgery, sympathetic signaling, transient angiogenic bursts, hypercoagulable states, osteoclast activation, and epigenetic modifications of dormant cells. This review addresses proposed approaches for either eliminating micrometastases or maintaining a dormant state.

Keywords: bone marrow microenvironment; dormancy; hematopoietic niche; micrometastases; osteoblast niche; reawakening.

Figure 1

The bone marrow hematopoietic and dormant metastatic breast cancer niches. The image depicts simplified representations of the endosteal and parasinusoidal niche containing the HSC, the dormant micrometastasis, and the supporting cellular, structural and soluble elements. Growth factors and chemokines listed in the text are depicted as a cluster of light blue dots.