Abstract
Mechanotransduction is the process in which cells can convert extracellular mechanical stimuli into biochemical changes within a cell. While this a normal process for physiological development and function in many organ systems, tumour cells can exploit this process to promote tumour progression. Here we summarise the current state of knowledge of mechanotransduction in osteosarcoma (OSA), the most common primary bone tumour, referencing both human and canine models and other similar mesenchymal malignancies (e.g., Ewing sarcoma). Specifically, we discuss the mechanical properties of OSA cells, the pathways that these cells utilise to respond to external mechanical cues, and mechanotransduction-targeting strategies tested in OSA so far. We point out gaps in the literature and propose avenues to address them. Understanding how the physical microenvironment influences cell signalling and behaviour will lead to the improved design of strategies to target the mechanical vulnerabilities of OSA cells.
Highlights
The bone is a dynamic tissue that provides structural support to the human body throughout one’s life; as such, it must be able to undergo adaptive processes to maintain structural integrity during various mechanical stimuli, such as walking and running [1]
The increases in pFAK and pERK levels were abrogated with an integrin beta 1 blocking antibody, demonstrating that this integrin is a key mediator of OSA mechanotransduction [93]
This suggest at least two possibilities, (i) that by enhancing phosphorylation these compounds might interfere with the putative dynamic switch between open and close conformation required for optimal metastatic growth, suggested by the previously discussed study with phosphomimetic and phosphodefective mutants [173]; or (ii) that these anti-malarial compounds could exert anti-ezrin activities through other means, perhaps preventing phosphorylation-independent protein–protein interactions or impacting other phosphorylation sites (i.e.,: Tyr354) that have been described for ezrin [184,185]
Summary
The bone is a dynamic tissue that provides structural support to the human body throughout one’s life; as such, it must be able to undergo adaptive processes to maintain structural integrity during various mechanical stimuli, such as walking and running [1]. Roux’s principle postulated that local bone cells regulate the mechanical response, the majority of Wolff’s Law attempted the use of mathematical rules to explain how the trabecular architecture is positioned to withstand mechanical forces. It was highly criticised because of insufficient evidence and its inadequacy in addressing the biological basis of bone organisation [3,4]. The link between biology and mechanical force was not proposed until almost a century later, when Harold Frost postulated the ‘mechanostat theory’ [5] This theory stated that a mechanical threshold needs to be reached in order to activate a bone modelling or remodelling response [5,6]. Not known at the time, Frost’s theory attempted to explain the process we refer to as mechanotransduction
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