Mechanical Stimulation Modulates Osteocyte Regulation of Cancer Cell Phenotype

Abstract

Breast and prostate cancers preferentially metastasise to bone tissue, with metastatic lesions forming in the skeletons of most patients. On arriving in bone tissue, disseminated tumour cells enter a mechanical microenvironment that is substantially different to that of the primary tumour and is largely regulated by bone cells. Osteocytes, the most ubiquitous bone cell type, orchestrate healthy bone remodelling in response to physical exercise. However, the effects of mechanical loading of osteocytes on cancer cell behaviour is still poorly understood. The aim of this study was to characterise the effects of osteocyte mechanical stimulation on the behaviour of breast and prostate cancer cells. To replicate an osteocyte-controlled environment, this study treated breast (MDA-MB-231 and MCF-7) and prostate (PC-3 and LNCaP) cancer cell lines with conditioned media from MLO-Y4 osteocyte-like cells exposed to mechanical stimulation in the form of fluid shear stress. We found that osteocyte paracrine signalling acted to inhibit metastatic breast and prostate tumour growth, characterised by reduced proliferation and invasion and increased migration. In breast cancer cells, these effects were largely reversed by mechanical stimulation of osteocytes. In contrast, conditioned media from mechanically stimulated osteocytes had no effect on prostate cancer cells. To further investigate these interactions, we developed a microfluidic organ-chip model using the Emulate platform. This new organ-chip model enabled analysis of cancer cell migration, proliferation and invasion in the presence of mechanical stimulation of osteocytes by fluid shear stress, resulting in increased invasion of breast and prostate cancer cells. These findings demonstrate the importance of osteocytes and mechanical loading in regulating cancer cell behaviour and the need to incorporate these factors into predictive in vitro models of bone metastasis.

RBM3 suppresses stemness remodeling of prostate cancer in bone microenvironment by modulating N6-methyladenosine on CTNNB1 mRNA

“…It is well accepted that the “stress” faced by cancer cells in the tumor microenvironment is an important driving force that affects tumor progression [ 25 – 28 ]. Similarly, cancer cells metastasized to the bone microenvironment also face various stresses, such as metabolic stress, inflammation, shear stress, and others [ 29 – 32 ]. In this scenario, the response of cancer cells mediated largely by a group of stress-response proteins like RBM3 plays a crucial role in deciding the fate of cancer cells in the tumor microenvironment; that is “to be or not to be”.…”

Bone-on-a-Chip: Biomimetic Models Based on Microfluidic Technologies for Biomedical Applications

“…As summarized in Table , different combinations of cell types have been used in BOCs for various research purposes, such as bone remodeling, bone vascularization, and bone metastasis. Immortalized murine bone cells, including MC3T3-E1, MLO-Y4, and Raw264.7, are widely used in BOCs because of their ease of access and culture, despite having inconsistent clinical results. ,,,, Among primary cells, mesenchymal stem cells (MSCs) are the most widely used to simulate the bone microenvironment in BOCs because of their excellent osteogenic differentiation capacity, good agreement with clinical results, and relative ease to obtain cells from humans and animals. , For vessels, human umbilical vein endothelial cells (HUVECs) ,,,,,, are most commonly used, and some reports have used primary cells isolated from cord blood …”

Cancer-on-a-Chip: Models for Studying Metastasis

“…In metastatic breast and prostate cancers, osteocytes and cancer cells communicate through the mechanical stimulation that is induced by fluidic shear stress. Osteocytes generally inhibit metastatic breast and prostate tumor growth and turn metastatic cancer cells towards a mesenchymal phenotype [59]; however, mechanical stimulation by constant high flow rate 1000 µL/h (shear stress ~0.03 Pa) in comparison to standard flow rate 30 µL/h (shear stress ~3 × 10 −5 Pa) reversed some of these effects. A microfluidic model with oscillatory fluid flow (peak stress of 1 Pa) was developed.…”