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Review
. 2022 Jan;179(2):201-217.
doi: 10.1111/bph.15713. Epub 2021 Dec 21.

Osteosarcoma mechanobiology and therapeutic targets

Zunaira Shoaib  1 , Timothy M Fan  2   3 , Joseph M K Irudayaraj  3   4   5
Affiliations
Review

Osteosarcoma mechanobiology and therapeutic targets

Zunaira Shoaib et al. Br J Pharmacol. 2022 Jan.

Abstract

Osteosarcoma is one of the most common primary tumours of the bone, with a 5-year survival rate of less than 20% after the development of metastases. Osteosarcoma is highly predisposed in Paget's disease of the bone, and both have common characteristic skeletal features due to rapid bone remodelling. Osteosarcoma prognosis is location dependent, which further emphasizes the likely contribution of the bone microenvironment in its pathogenesis. Mechanobiology describes the processes involved when mechanical cues from the changing physical microenvironment of the bone are transduced to biological pathways through mechanosensitive cellular components. Mechanobiology-driven therapies have been used to curb tumour progression by direct alteration of the physical microenvironment or inhibition of metastasis-associated mechanosensitive proteins. This review emphasizes the contribution of mechanobiology to the progression of osteosarcoma and sheds light on current mechanobiology-based therapies and potential new targets for improving disease management. Additionally, the many different 3D models currently used to study osteosarcoma mechanobiology are summarized.

Keywords: 3D cell culture; bisphosphonates; bone remodelling; bone sarcoma; mechanobiology; mechanotransduction; osteosarcoma; pharmacology; therapy.

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Figures

FIGURE 1
FIGURE 1
Diagram showing effects of substrate stiffness on cell behaviour. A stiffer substrate has been shown to increase cell spread and invasion; thus, a stiffer ECM and bone microarchitecture might contribute to aggressive cancer behaviour
FIGURE 2
FIGURE 2
Rapid bone remodelling in Paget's disease and osteosarcoma contributes to a deformed, isotropic bone structure that helps in forming a “cancer niche” in the bone, possibly facilitating bone sarcomas as well as homing metastases from secondary non‐bone tumours. The pores in normal mature bone are aligned in one direction to support the body's weight. Immature bone or woven bone with rapid bone resorption and deposition shows disorganized alignment and increased isotropy in porosity and collagen fibres, leading to decreased bone strength. Depending on how osteolytic or osteoblastic the bone remodelling process is, the porosity and stiffness of the bone deviate from the normal, and bone becomes brittle and prone to fracture. Most importantly, highly isotropic bone is a characteristic feature of cancerous bone
FIGURE 3
FIGURE 3
An overview of the crosstalk of molecular pathways with cytoskeletal agents, mechanosensors and external forces. Some of these relationships present exciting new targets for cancer research and therapy and need to be explored more fully in osteosarcoma cells in the context of mechanotransduction. ECM, extracellular matrix; FA, focal adhesions; ONM/INM, outer nuclear membrane/inner nuclear membrane; AC + RELA, acetylated RELA
See this image and copyright information in PMC

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