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issues, necessitating further research to optimize treatment This self-reinforcing loop of osteolysis–immune crosstalk
strategies. licenses escape from dormancy in the BMME.

2.3. Triggers of dormancy escape and reactivation 2.3.3. ECM remodeling
Dormant tumor cells in the BMME can be reactivated This involves altered biomechanical and biochemical
through specific perturbations, primarily driven by cues. The remodeling of the ECM is another key factor
angiogenic switching, inflammatory stimuli, and ECM for the reactivation of tumor cells from a dormant state.
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remodeling. These mechanisms collectively disrupt BMME MMP/TIMP imbalance—triggered by inflammation
homeostasis to reignite tumor proliferation. or angiogenesis—degrades bone-specific components
(e.g., collagen I and laminin), releasing sequestered growth
2.3.1. Angiogenic switch
factors (e.g., VEGF and TGF-β) that activate proliferative
This involves a shift from anti-angiogenic to pro-angiogenic pathways. Crucially, collagen and fibronectin in the ECM
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signaling. In dormancy, hypoxic stress stabilizes HIFs, can activate the FAK and PI3K/AKT signaling pathways
inducing metabolic adaptation (e.g., glycolytic dependence) through interactions with integrin receptors, promoting
while quiescent endothelial cells secrete thrombospondin-1 cell proliferation and migration.
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(TSP-1) to inhibit angiogenesis. Reactivation occurs In summary, angiogenic switch, inflammatory
when vascular endothelial growth factor (VEGF)/
VEGF receptor (VEGFR) signaling dominates: hypoxia- stimulation, and ECM remodeling are the main triggering
triggered VEGF surges bind VEGFR on endothelial cells, factors for the reactivation of tumor cells from a dormant
synergizing with fibroblast growth factor/platelet-derived state. These mechanisms provide the necessary conditions
growth factor (PDGF) to drive neovascularization. This for the reactivation of tumor cells by changing the oxygen
switches endothelial cells from TSP-1 secretion (>80% supply, cytokines, and composition of the ECM in the
reduction) to TGF-β1/osteopontin expression, increasing microenvironment.
oxygen/nutrient supply and creating a pro-metastatic 3. BMOC technology: Engineering the
niche. Critically, tumor cells actively perturb this balance: BMME for tumor dormancy research
breast cancer-derived IFN-γ suppresses endothelial cell
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tryptophan metabolism to reduce TSP-1, while prostate The engineering of the BMOC platform requires strict
cancer dormancy escape upregulates MMP-9-dependent coordination of biophysical fidelity and reproducibility. This
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factors (e.g., VEGF and IL-8) and downregulates TSP-1. section summarizes key BMOC studies published in recent
Thus, angiogenic switching represents a BMME-specific years and categorizes them from two main perspectives:
perturbation where bidirectional tumor–endothelial cell device characteristics (device applications, research
crosstalk overcomes dormancy constraints. objectives, materials used, manufacturing methods, fluid
mechanisms, and microenvironment materials) and
2.3.2. Inflammatory stimuli device performance (improved research methods provided
This process involves immune cell infiltration and compared to other devices) (Table 1). It comprehensively
osteoclast-mediated osteolysis. Inflammation reactivates analyzes the ECM and fluid characteristics required for
dormant cells by altering BMME signaling landscapes. Key the BMME. It conducts a comprehensive comparison
cytokines—tumor necrosis factor alpha, IL-1β, and IL-6— with traditional in vivo and in vitro systems, highlighting
activate nuclear factor kappa B (NF-κB)/signal transducer the advantages of the BMOC platform in simulating the
and activator of transcription 3 pathways in tumor cells, human bone marrow niche.
promoting proliferation and survival. Concomitant
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immune infiltration (macrophages, neutrophils, and 3.1. Foundational design principles of the BMOC
T cells) amplifies cytokine release (e.g., IL-8 and C–C technique
motif chemokine 5). It degrades ECM through MMP 3.1.1. Biomaterials mimicking the bone marrow niche
upregulation. Critically, in the BMME, tumor cells initiate
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a vicious cycle 54,55 (Figure 3): secretion of parathyroid The BMOC platforms leverage advanced biomaterials
hormone-related protein binds parathyroid hormone/ and fabrication techniques to recapitulate the BMME,
parathyroid hormone-related peptide receptor on offering a dynamic alternative to traditional in vitro and
osteoblasts, triggering receptor activator of nuclear factor in vivo models. Soft lithography enables the fabrication
kappa-B ligand (RANKL) overexpression. This activates of polydimethylsiloxane (PDMS)-based microfluidic
the RANKL–RANK axis to promote osteoclastogenesis. devices, providing gas-permeable substrates for real-
Osteoclasts then release various pro-tumor factors, time imaging and dynamic cell culture. To emulate
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including PDGF, TGF-β, VEGF, BMPs, and Ca , further the ECM, natural polymers like type I collagen and
2+
stimulating tumor growth and disrupting dormancy. sodium alginate are integrated into PDMS frameworks;
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Volume 1 Issue 3 (2025) 5 doi: 10.36922/OR025200017