Identification of new therapeutic targets of bone cancers by proteomic strategies

Primary bone cancers—incidence and outcomes

Malignant bone tumors include the sarcomas of mesenchymal origin: OS (derived from osteoblastic cells of mesenchymal origin) and ES (derived from bone marrow round cells).

OS affects children and adolescents predominantly [ ]. Within the epidemiology of OS there are [ ] two peaks of OS incidence observed and this has been described as a peak around 18 years and one typically occurring around 60 years, with the latter often being secondary OS following either Paget's disease or radiotherapy [ , ]. The survival rate after surgical resection and standard multiagent chemotherapy is 60%–70%, generally due to development of recurrence or lung metastases (90%). Prognosis for nonresectable, metastatic, or recurrent OS is very poor and treatment outcomes have not significantly improved over the last 30 years. There is an urgent need to discover new therapeutic targets to overcome the limitations of current treatments.

ES is the second most common bone tumor of childhood and adolescence. ES is responsible for 2% of all childhood cancers with a peak age of incidence of 15 years. Overall survival within ES is linked to the metastatic stage of the disease. In the case of localized tumors 5-year survival is 50%–60%, whereas for metastatic cancers the 5-year survival rate is only 20%. Approximately 20%–25% of ES cases are diagnosed with detectable metastases [ ].

In addition to OS and ES, primary bone cancers also include MM, which is responsible for approximately 1.3% of all malignancies and 15% of all hematological malignancies. MM is the second most common blood cancer after non-Hodgkin lymphoma [ ]. Approximately 29% of all patients diagnosed with MM in England currently survive for 10 years or more [ ].

Secondary cancers (bone metastases)

Metastasis to the skeleton is detected within 65%–75% of cases of advanced BCa, approximately 80% of cases of advanced PCa, 17%–64% of LC patients, and 70%–95% of cases of MM [ ]. Metastatic spread to bone results in skeletal complications termed SREs within patients including: bone fractures, spinal cord compression, hypercalcemia, bone pain, and the need for radiotherapy [ ]. SREs result in a significantly decreased patient quality of life as well as significant health economic costs [ ].

Primary bone cancers

Primary bone cancers (e.g., OS, ES, and MM) trigger bone degradation with the enhanced differentiation of active osteoclasts, in a manner analogous to bone metastatic cancers (see below). There is, however, still controversy within the bone sarcoma field and it is still debated whether active osteoclasts promote tumor development through increased angiogenesis, or act further downstream in tumor development to inhibit tumor development [ , ]. Within both ES and OS there is evidence of a paracrine signaling interaction between MSCs and bone sarcoma cells. MSCs secrete factors which promote the stemness of OS and ES cells, while the acidic environment promoted by OS or ES cells promotes the stemness of MSCs [ ]. Several mechanisms have been proposed to function in the communication between bone sarcoma cells and MSCS including communication via gap junctions as well as the release of mRNA- and protein-containing extracellular vesicles [ , ]. A comprehensive description of the autocrine and paracrine signaling events within the development of OS and ES is beyond the scope of this review; however, it has been reviewed elsewhere [ ].

MM promotes osteolytic bone destruction via osteoclast activation and reduced osteoblast maturation. Several mechanisms are implicated within MM bone disease. MM cells influence osteoclast activation by inducing the degradation of OPG via the Syndecan-1 system [ ]. The ability of MM cells to alter the RANKL: OPG ratio thus triggers degradation of bone, and measurement of the ratio of RANKL: OPG predicts patient outcomes within MM [ ]. MM perturbs normal bone homeostasis via additional mechanisms. MM cells express multiple receptors and ligands for the Notch signaling pathway, and intracellular signaling downstream of Notch triggers MM cells to increase their release of RANKL [ , ]. Numerous autocrine and paracrine signaling events have been implicated in MM-mediated bone degradation and a thorough review is beyond the scope of this chapter; however, this has been reviewed elsewhere [ ].