TABLE 3.
The bio-medical relevance of breast metastasis-on-chip (BCMoC) systems.
| Chip type | Chip role | Chip design | Chip relevance | References |
|---|---|---|---|---|
| Lymph vessel-tumor tissue-blood vessel chip (LTB) | model for BC cells intravasation in lymph vessels, analysis of the intercellular communication in TME and role of inflammatory cytokines, stromal reaction, hypoxia, and nutrient deficiency during lymphatic metastasis | 3-channels: HUVECs (mimic blood vessel wall), HLECs (mimic lymph vessel wall), hydrogel (ECM), injected with CTCs (MCF7, MDA-MB-231, SKBR3) pre-treated with TGF-β1 and IL-6 miRNAs | IL-6 exposure induces EMT and improved tissue invasion; the growth of HUVECs towards lymph vessel channel was observed by VEGF secretion from HLECs with IL-6 treatment | Cho et al. (2021a) |
| Lymph node-on-chip (LNoC) | model for BC metastasis in LN, pharmacological and diagnostic applications | 3D collagen sponge (ECM), 4T1 BC spheroids (CCs), Jurkat cells (T-cells), BSA/TA NPs in the lymph flow | effect of drug carrier size/contrast agent on the penetration and accumulation of particles in spheroids modelling secondary tumor | German et al. (2023) |
| Liver-on-chip (liver-chip) | formation of PMN in liver; role of primary BC-derived EVs in breast cancer liver metastasis | endothelial and cancer compartment (LSECs, primary BC-derived EVs, BC cells (MCF7, MDA-MB-231)) | activation of LSECs; EMT of BC cells; destruction of vascular barriers; upregulation of fibronectin in LSECs by TGFβ1; increased adhesion of CTCs to the liver microenvironment | Kim et al. (2020) |
| Bone-on-chip (BoC) | role of SNS signalling over bone metastatic BC | cancer compartment (bone tropic MDA-MB-231-BoM 1833 spheroids; neuron compartment (SH-SY5Y human sympathetic neurons); bone compartment (human peripheral blood derived osteoclasts seeded on top of a bone matrix) | dynamic interaction between BC cells, neurons, and osteoclasts; increased MMP1 and CTGF; bone tropic BC cells received synergistic inputs from neurons and osteoclasts, resulting in increased levels of pro-inflammatory cytokines | Conceição et al. (2022) |
| formation of BC metastasis niche in bone | co-cultured Murine calvaria pre-osteoblasts (MC3T3-E1), MDA-MB-231GFP BC cells | reorganization of the osteoblastic tissue; creation of large holes in surrounding matrix; long invadopodia from BC cells that protruded through matrix; CCs proliferate and organize into string of cells, parallel with elongated axis of the collagenous matrix | Hao et al. (2018) | |
| investigation of circulating neutrophils and breast CCs interactions during bone colonization | BC metastasis compartment: HUVECsGFP, BMSCs, fibroblasts, MDA-MB-231RFP) vascularized BME (ECsGFP, fibroblasts, BMSCs, O-BMSCs)) neutrophils | development of a perfusable vascularized BC metastasis into BME; CCs damage the microvascular network structure and permeability; metastatic-BME promotes neutrophil extravasation; neutrophils affect CCs viability in metastatic BME | Crippa et al. (2022) | |
| Bone perivascular (BoPV) niche-on-a-chip with interstitial fluid flow | investigation of BC metastatic colonization in bone and drug resistance | hECs &BMSCs were co-cultured with MDA-MB-231 BC cells in 3D naïve bone matrix exposed to variable fluid flow velocities and oxygen gradients | formation of capillary-like structures in the niche; DTCs exhibited a slow-proliferative state and increased drug resistance in the BoPV niche-on-a-chip model | Marturano-Kruik et al. (2018) |
| Brain organoid-on-chip | BC cells derived-exosomes impair the early neurodevelopment of brain by BC metastatic transmission to placenta or fetus | hiPSCs-derived brain organoids, MCF7-derived exosomes | BC-derived exosomes affect the BB, CC, and MF of brain organoids; enhanced stemness of brain organoids under exosomes exposure; changes of forebrain development differentiation in brain organoids; increased stemness biomarker OCT4 and forebrain marker PAX6 for tumor progression and oncogenic features | Cui et al. (2022) |
| Blood-brain-niche-on-chip (BBN) and migration-on-chip | investigation of biological processes involved in breast cancer brain metastasis | flow chamber: MDA-MB-231 (TNBC)/JIMT1 (HER2+)/MDA-MB-231-BR/JIMT1-BR; brain niche chamber: brain microvascular ECs, astrocytes/microglia | astrocytes promote CCs extravasation through BBB; microglia influence CCs to remain in the proximity to the BBB; BBN secretions influence CCs migration and extravasation; cytokine response of the brain niche is influenced by interaction with MDA-MB-231-BR; astrocytic upregulated DKK1 influences CCs migration and extravasation across the BBB; CCs metabolism was rewired when stimulated with BN secretions; DKK1 overexpression led to overexpression of FGF13 and PLCB1 in CCs; extracellular DKK1 modulates CCs migration upon entering the brain niche | Westerhof et al. (2023) |
| Gut microbiome-on-chip (GMoC) | probiotic drug’s dosage screening | microfluidic device including Lactobacillus acidophilus, L. casei, Bifidobacterium bifidum strains and MCF7 BC cells | anti-BC activities of probiotic strains against BC cells | Salehi et al. (2023) |
Abbreviations: BBB, blood-brain barrier; BMSCs, bone marrow-derived mesenchymal stem cells; BSA/TA NPs, bovine serum albumin/tannic acid nanoparticles; CCs, cancer cells; CTCs, circulating tumor cells; CTGF, connective tissue growth factor; DKK1 – Dickkopf Wnt signaling pathway inhibitor 1; DTCs, disseminated tumor cells; ECM, extracellular matrix; ECs, endothelial cells; EMT, epithelial-mesenchymal transition; EVs, extracellular vesicles; FGF-13, fibroblast growth factor 13; GFP, green fluorescent protein; HLECs, human lymphatic endothelial cells; HUVECs, human umbilical vein endothelial cells; IL-6, interleukin 6; LN, lymph node; LSECs, liver sinusoidal endothelial cells; MMP1 – matrix metalloproteinase 1; PLCB1 – phospholipase C beta 1; PMN, premetastatic niche; SNS, sympathetic nervous system; TGF-β1, transforming growth factor beta; TME, tumor microenvironment; TNBC, triple negative breast cancer; VEGF, vascular endothelial growth factor.