Signaling Between Tumor Cells and the Host Bone Marrow Microenvironment

Abstract

Tumor cells with high skeletal homing affinity express numerous cell surface receptors that bind ligands produced in bone. Upon arrival, these cells survive in the host environment, encompassed in close proximity to bone marrow cells. Interactions between tumor cells and cells of the host microenvironment are essential to not only tumor cell survival but also their activation and proliferation into environment-modifying tumors. Through the production of RANKL, PTHrP, cytokines, and integrins, activated tumor cells stimulate osteoclastogenesis, enhance bone resorption, and subsequently release matrix-bound proteins that further promote tumor growth and bone resorption. In addition, alterations in the TGF-β/BMP and Wnt signaling pathways via tumor cell growth can either stimulate or suppress osteoblastic bone formation and function, leading to sclerotic or lytic bone disease, respectively. Hence, the presence of tumor cells in bone dysregulates bone remodeling, dramatically impairing skeletal integrity. Furthermore, through complex mechanisms, cells of the immune system interact with tumor cells to further impact bone remodeling. Lastly, with alterations in bone cell activity, the environment is permissive to promoting tumor growth further, suggesting an interdependence between tumor cells and bone cells in metastatic bone disease and multiple myeloma.

Denosumab: an Emerging Therapy in Pediatric Bone Disorders

“…These are common processes in children with chronic illnesses, who have multiple risk factors related to mobility, nutrition, and exposure to bone-toxic therapies [3]. In addition, osteolytic disorders such as primary tumors and metastases result in bone destruction through localized activation of osteoclasts [4]. Therapeutic strategies to treat these disorders include targeting the bone remodeling cycle through anti-resorptive medications that inhibit osteoclasts, and/or anabolic therapies that promote osteoblast activity.…”

Multiple myeloma in the marrow: pathogenesis and treatments

“…[70][71][72][73] Decorin is one proteoglycan produced by OBs that has been demonstrated to directly inhibit growth and survival of MM cells in vitro by inducing apoptosis and subsequent arrest of MM cell cycle. 6,74,75 By contrast, OBs may also promote growth and survival of MM cells through the production of various growth factors or providing a niche to harbor quiescent MM cells, inducing chemotherapy resistance. Factors such as osteocalcin, osteopontin, FGF, and TGF-␤, which are synthesized and secreted by OBs, have been identified as factors that modulate the growth and survival of MM cells.…”

“…More remains to be examined in this realm, and three-dimensional models of OBs and MM cells may help us explore these interactions in a more physiologically relevant model than possible in two-dimensional cocultures. 6,70,74 Osteoclasts OCs, the major target of bisphosphonate therapies, are the primary mediators of bone resorption in both healthy and pathological bone turnover. 4,74 Clinically, the presence of lytic bone lesions in MM manifests with severe bone pain, pathological fractures, increased bone turnover serum markers, and hypercalcemia.…”

Navigating the bone marrow niche: translational insights and cancer-driven dysfunction

“…88,89 TGF-β (through Smad pathway signalling), hypoxia (through HIF-1α), and extracellular calcium (through Akt and MAPK pathways) alter gene expression within tumour cells in the bone microenvironment, enabling the survival and growth of these cells in the marrow cavity. 88,90,91 Many osteolytic tumour cells produce PTHrP, TGF-β, dickkopf-1, sclerostin, and RANKL; moreover, osteoblastic tumours often secrete bone morphogenic proteins and other growth factors (such as fibroblast growth factors and Wnt family members), but many of the mechanisms of osteoblastic lesion development remain undetermined. 92 Metabolic changes in tumour cells induced by their local microenvironment are also now recognized as important contributors to tumour growth and potential therapeutic targets.…”