The best of both worlds — managing the cancer, saving the bone

Abstract

In the context of breast cancer, the importance of the skeleton in the regulation of primary tumour development and as a site for subsequent metastasis is well characterized. Our understanding of the contributions made by the host bone and bone marrow cells increasingly demonstrates the extent of the interaction between tumour cells and normal host cells. As a result, the need to develop and utilize therapies that can impede the growth and/or function of tumour cells while sparing normal host bone and bone marrow cells is immense and expanding. The need for these new treatments is, however, superimposed on the orthopaedic management of patients’ quality of life, where pain control and continued locomotion are paramount. Indeed, the majority of the anticancer therapies used to date often result in direct or indirect damage to bone. Thus, although the bone microenvironment regulates tumour cell growth in bone, cells within the bone marrow niche also mediate many of the orthopaedic consequences of tumour progression as well as resistance to the antitumour effects of existing therapies. In this Review, we highlight the effects of existing cancer treatments on bone and the bone marrow microenvironment as well as the mechanisms mediating these effects and the current utility of modern orthopaedic interventions.

Hallmarks of Bone Metastasis

“…It is important to recall that the bone destruction resulting from tumor osteolysis as well as any tumor-induced bone formation is entirely due to tumor-derived stimulation of resident bone cells; it is not related to any direct actions of the tumor cells themselves on the skeleton [8]. Upon dissemination to the bone marrow, it is well established that breast cancer cells interact with osteoblasts (and other resident cells) to induce osteolysis.…”

“…Numerous interactions exist between bone cells and resident bone marrow cells that are necessary to maintain normal endocrine homeostasis [8, 105]. As such, a variety of putative bone-targeted treatment opportunities targeting cancer cells resident in bone exist, but are largely under-explored.…”

“…1), including our ability to replicate different features of human bone metastatic disease in vivo. The mechanics of these niches in the bone marrow drives a significant interdependence between hematopoietic stem cell differentiation and mesenchymal progenitor cells [6, 7] and the coupling of bone resorption with bone formation [8]. …”

“…In the context of breast cancer bone metastasis, the bone marrow compartment provides not only a receptive growth factor-enriched environment but also favorable niches in which circulating/disseminated tumor cells can survive [8]. Following arrival in the bone marrow, tumor cells proliferate and interact with mesenchymal and hematopoietic progenitors at multiple stages of differentiation [9].…”

“…Following arrival in the bone marrow, tumor cells proliferate and interact with mesenchymal and hematopoietic progenitors at multiple stages of differentiation [9]. These interactions provide important signals for both tumor cells and host bone and bone marrow cells during tumor colonization of bone [4, 8], frequently (and often incorrectly) referred to as the “vicious-cycle” [10]. This term was originally associated with the underlying action of parathyroid hormone-related protein (PTHrP), a well-known regulator of tumor-associated bone destruction [10, 11] as well as the hypercalcemia of many cancer types [12].…”