Tumor Cell Dormancy and Reactivation in Bone: Skeletal Biology and Therapeutic Opportunities

Abstract

In the advanced stages of many cancers, tumor cells disseminate from the primary site and colonize distant locations such as the skeleton. These disseminated tumor cells colonizing bone can evade treatments and survive for prolonged periods in a dormant state before becoming reactivated to form overt metastases. The precise interactions between tumor cells and the bone microenvironment that promote survival, dormancy, and reactivation are currently unknown; as a result, bone metastases remain incurable. In this review we discuss the unique cellular and microenvironmental features of endosteal bone that tumor cells engage with to persist and survive, and ultimately reactivate and proliferate. Specifically, we provide a detailed summary of current perspectives on the processes of tumor cell colonization of the skeleton, and the endosteal bone cells as critical controllers of the dormant cancer cell phenotype, as well as relevant microenvironmental effects such as hypoxia. Evidence for the role of the osteoclast in controlling dormant cancer cell reactivation in bone is highlighted, preceding a discussion of therapeutics targeting the bone microenvironment, including anti‐RANK ligand and bisphosphonate therapies and their potential utility in preventing tumor cell reactivation in addition to protecting bone from tumor‐induced destruction. © 2018 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Ras and Wnt Interaction Contribute in Prostate Cancer Bone Metastasis

“…Giancotti provided a hypothesis in his review that presumes that the epithelial-mesenchymal transition (EMT) might be a possibility for reactivation from dormancy [88]. A review by Byrne et al summarizes that castration causes bone loss and increased metastasis via hypoxia induction and vascular remodeling [89]. Furthermore, Miftakhova et al reported that cyclin A1 coupled with aromatase (CYP19A1) enables PCa metastatic growth in bone marrow through manipulating androgen concentrations in the TME [90].…”

“…The dynamics of Wnt and Ras at each stage of PCa metastasis need to be clarified, and the details within each stage must be elucidated, in order to completely answer the question. Byne et al have reviewed that castration-mediated osteoporosis might link to PCa BM which bone reformation might increase BM activity [89]. Detail mechanism regarding castration-mediated osteoporosis is not well-known but recent knowledge indicates that Wnt signaling is involved in osteoblast activity instead of osteoclast activity [163].…”

Skeletal Metastases of Unknown Primary: Biological Landscape and Clinical Overview

“…Different approaches have been proposed in order to resolve the biologic complexity underlying the pathophysiologic step to bone dissemination. The first of the steps in the process of cancer spreading to the bone is the homing to the marrow microenvironment throughout the bloodstream of the tumor cells, via the neo-angiogenesis process, trough permissive bone marrow endothelial cells [33,34]. Remarkably, a prone microenvironment is involved in the cancer cycle, educating and hijacking the tumor niche that is to be colonized throughout a neoplastic permissive environment [35,36].…”

Switching Homes: How Cancer Moves to Bone

“…The bone marrow is likely the most common site where cellular dormancy occurs, since many of the mechanisms that are thought to keep cancer cells dormant, are based on molecular pathways that are usually used by haematopoietic stem cells for maintaining their own quiescence [167,168,170,172]. Undoubtedly, cellular dormancy is an extremely complex phenomenon, that reflects the complexity of the bone marrow microenvironment and the many niches that reside there.…”