Translational biology of osteosarcoma

KEY POINTS * Osteosarcomas are rare malignancies of bone, affecting primarily children and adolescents. Patients are typically treated with surgery and intensive adjuvant chemotherapy. The

5-year survival rate for recurrent or metastatic osteosarcoma is less than 25%. * Bone has a highly specialized microenvironment. Crosstalk between osteoblasts, the cell lineage from which

osteosarcoma arises, and monocyte-derived osteoclasts, occurs via signalling molecules that, in many cases, are linked to immune biology. * Osteosarcomas are characterized by high levels of

genomic instability. Recently, novel mutation patterns have been observed, including chromothripsis and kataegis. Few recurrent, therapeutically targetable mutations have been found. *

Therapeutic strategies targeting oncogenic kinases have been disappointing, while strategies targeting the osteoclast using denosumab and bisphosphonates are being evaluated. * Immune

strategies show promise. The immune adjuvant, mifamurtide is the most substantial therapeutic advance in osteosarcoma in the past 10 years. * Evidence from preclinical studies suggests that

immune checkpoint blockade inhibitors may be useful in the treatment of this disease. ABSTRACT For the past 30 years, improvements in the survival of patients with osteosarcoma have been

mostly incremental. Despite evidence of genomic instability and a high frequency of chromothripsis and kataegis, osteosarcomas carry few recurrent targetable mutations, and trials of

targeted agents have been generally disappointing. Bone has a highly specialized immune environment and many immune signalling pathways are important in bone homeostasis. The success of the

innate immune stimulant mifamurtide in the adjuvant treatment of non-metastatic osteosarcoma suggests that newer immune-based treatments, such as immune checkpoint inhibitors, may

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THERAPY IN OSTEOSARCOMA Article Open access 08 June 2023 MULTI-OMICS ANALYSIS IDENTIFIES OSTEOSARCOMA SUBTYPES WITH DISTINCT PROGNOSIS INDICATING STRATIFIED TREATMENT Article Open access 23

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(1995). Article  CAS  PubMed  Google Scholar  Download references ACKNOWLEDGEMENTS The authors apologize to those whose work on the biology and clinical aspects of osteosarcoma have advanced

the field but could not be cited owing to space limitations. The work of the authors is funded by the National Health and Medical Research Council (NHMRC), Australia. D.M.T. is supported by

an NHMRC Senior Research Fellowship (1003929). AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Research Division, Peter MacCallum Cancer Centre, Melbourne, 3002, Victoria, Australia Maya

Kansara & David M. Thomas * Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, 3010, Victoria, Australia Maya Kansara & David M. Thomas * Immunology in

Cancer and Infection Laboratory and Cancer Immunoregulation and Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, 4006, Queensland, Australia Michele W. Teng 

& Mark J. Smyth * School of Medicine, University of Queensland, Herston, 4006, Queensland, Australia Michele W. Teng & Mark J. Smyth * The Kinghorn Cancer Centre, Garvan Institute of

Medical Research, Darlinghurst, 2010, New South Wales, Australia David M. Thomas Authors * Maya Kansara View author publications You can also search for this author inPubMed Google Scholar

* Michele W. Teng View author publications You can also search for this author inPubMed Google Scholar * Mark J. Smyth View author publications You can also search for this author inPubMed 

Google Scholar * David M. Thomas View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to David M. Thomas. ETHICS

DECLARATIONS COMPETING INTERESTS The authors declare no competing financial interests. RELATED LINKS DATABASES ClinicalTrials.gov POWERPOINT SLIDES POWERPOINT SLIDE FOR FIG. 1 POWERPOINT

SLIDE FOR FIG. 2 POWERPOINT SLIDE FOR FIG. 3 POWERPOINT SLIDE FOR TABLE 1 POWERPOINT SLIDE FOR TABLE 2 SUPPLEMENTARY INFORMATION SUPPLEMENTARY INFORMATION S1 | EXAMPLES OF MICRORNAS

IDENTIFIED TO BE DEREGULATED IN OSTEOSARCOMA (PDF 171 KB) SUPPLEMENTARY INFORMATION S2 | COMMONLY USED OSTEOSARCOMA CELL LINES (PDF 154 KB) SUPPLEMENTARY INFORMATION S3 | MOUSE GENOTYPES

THAT PREDISPOSE TO OSTEOSARCOMA (PDF 158 KB) GLOSSARY * Metaphyseal growth plate The wide portion of the long bone between the narrow diaphysis and the epiphysis that grows during childhood.

* Osteoid This is the organic un-mineralized portion of the bone matrix composed primarily of type I collagen that is secreted by osteoblasts prior to maturation of bone tissue. *

Conventional Conventional osteosarcomas are primary intramedullary high-grade malignant tumours in which neoplastic cells produce osteoid. * Low-grade central Low-grade central osteosarcomas

arise from the medullary cavity of bone and are composed of hypo-cellular to moderately cellular fibroblastic stroma with variable amounts of osteoid. * Periosteal Periosteal osteosarcoma

is an intermediate-grade chondroblastic osteosarcoma that occurs on the surface of the metaphysis of long bone. * Parosteal Parosteal osteosarcoma is a low-grade tumour that originates from

the outer surface of the periosteum. * Telangiectatic Telangiectatic osteosarcoma occurs in the metaphyseal portion of the long bones. It is characterized by dilated blood-filled vascular

spaces lined by malignant osteoblasts. * Chondroblastic In chondroblastic osteosarcoma, chondroid matrix is predominant, with minimal amounts of osseous matrix. * Small cell Small cell

osteosarcoma is composed of small cells with variable degrees of osteoid production. * Periosteal surfaces Thick membranes composed of fibrous connective tissue that wraps around all bone

except for the articulating surfaces in joints. * Alternative lengthening of telomeres (ALT). A mechanism used by 10–15% of cancer cells to counteract telomere attrition that accompanies DNA

replication and finite replicative potential. ALT uses homologous recombination to maintain telomere length throughout many cell doublings in the absence of telomerase activity. *

Chromothripsis A genomic phenomenon in which a single catastrophic event results in massive genomic rearrangements and remodelling of a chromosome. * Kataegis Kataegis is defined by patterns

of localized hypermutation colocalized with regions of somatic genome rearrangements. * Quality-adjusted life years This measure takes into account both the quantity (life expectancy) and

the quality of the remaining life years generated by health care interventions. * Chimeric antigen receptors (CARs). These are engineered receptors that consist of an antibody-derived

targeting domain fused with a T cell signalling domain that, when expressed by T cells, confers T cell antigen specificity governed by the targeting domain of the CAR. * Keyhole limpet

haemocyanin (KLH). This is a large, multi-subunit metalloprotein that is found in the haemolymph of the giant keyhole limpet (_Megathura crenulata_), which is a type of gastropod, and is

used extensively as a carrier protein to generate a substantial immune response in the production of antibodies. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS

ARTICLE Kansara, M., Teng, M., Smyth, M. _et al._ Translational biology of osteosarcoma. _Nat Rev Cancer_ 14, 722–735 (2014). https://doi.org/10.1038/nrc3838 Download citation * Published:

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