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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 substantially improve disease outcome.

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Figure 1: Osteoclast, osteoblast and immune cell crosstalk.
Figure 2: Pathways for targeted therapies in osteosarcoma.
Figure 3: Targeting immune modulators in osteosarcoma.

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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).

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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.

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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

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