Table 1 Summary of the studies utilizing bioengineered models to study tumor dormancy
Type of Cancer | Cancer Cell Lines | Niche cells | Biomaterial | Key Findings | References |
|---|---|---|---|---|---|
Biomaterial based models | |||||
 Breast Cancer and Osteosarcoma | D2.0R, D2A1, MCF-7, MDA-MB-231, 4 T1, K7 M2, K7M2AS1.46 | – | Basement Membrane Matrix | Inhibition of MLCK maintained the dormant phenotype of cancer cells and reduced metastatic outgrowth | Barkan et al., [26] |
 Breast Cancer and Osteosarcoma | D2.0R, D2A1, MCF-7, MDA-MB-231, K7 M2, K7M2AS1.46 | – | Basement Membrane Matrix | Cells can be maintained in dormant state by inhibiting MLCK phosphorylation | Barkan et al., [33] |
 Breast Cancer | D2.0R, D2A1 | – | Basement Membrane Matrix | Collagen-I enriched fibrotic environment revoked dormant phenotype in cancer cells | Barkan et al., [35] |
 Breast Cancer and Osteosarcoma | MDA-MB-231, K7 M2, 4 T1, D2.0R, D2A1 | – | Basement Membrane Matrix | Joint inhibition of SFK and MEK1/2 prevented switch from dormant to proliferative phenotype in cancer cells while simultaneously suppressing their survival | EL Touny et al., [30] |
 Breast Cancer | MDA-MB-231 | HMEC-1 | Hyaluronic acid hydrogel | Hyaluronic acid environment lowers the ERK/p38 ratio in cancer cells in 3D co-culture, which is indicative of a dormant phenotype | Kassim et al., [32] |
 Breast, Prostate and Ovarian Cancer | MCF-7, MDA-MB-231, MDA-MB-468, OVCAR-5, MCF10ADCIS.COM, LnCAP | – | Silica-PEG hydrogel | Physical immobilization of cancer cells in a stiff mechanical environment induces dormancy | Preciado et al., [54] |
 Melanoma, Liver, Lung and Breast Cancer | B16,4 T1, H22, A375, A549, HepG2 | – | Fibrin gel | Nuclear translocation of Cdc42 in a stiff mechanical environment induces dormancy in B16 cells by activating Cdc42-tet2 pathway | Liu et al., [29] |
 Breast Cancer | MDA-MB-231, MCF-7, T4–2 | HUVEC, Lung Fibroblasts, Bone marrow mesenchymal stem cells | Laminin rich ECM | Stable microvascular endothelium induces quiescent phenotype in disseminated tumor cells (DTC) which is mediated by Thrombospondin-1 whereas, sprouting endothelium promote proliferation in DTCs by producing periostin & TGF-β1 | Ghajar et al., [28] |
 Breast Cancer | SUM159, SUM149, MDA-MB-231, MDA-MB-435, BT474, MCF-7, T47D, ZR75–1 | HUVEC, Bone marrow derived mesenchymal cells (HS-5), hFOB, BMSC | Collagen biomatrix | Niche cells HUVEC, HS-5, and hFOB induce quiescence in cancer cells and this phenotype can be reversed by inhibiting p38, ALK5, and RTK | Marlow et al., [27] |
 Breast and Ovarian Cancer | MCF-7, MDA-MB-231, OVCAR-3 | – | Collagen gel | Chemically induced hypoxia through CoCl2 treatment induces dormancy in MCF-7 cells by increasing p38/pERK ratio | Lee et al., [51] |
 Breast, Colon and Pancreatic Cancer | MDA-MB-231, HCT-116,CFPAC-1 | – | Collagen gel | Stiff mechanical environment coaxed the cancer cells towards dormancy which resulted in increased drug resistance | Fang et al., [31] |
 Liver Cancer | Huh7, HepG2 | – | PA gel | Soft environments induced dormancy in cancer cells by downregulating the phosphorylation of FAK, ERK and STAT3 resulting in increased drug resistance and stem-like characteristics | Schrader et al., [53] |
 Prostate Cancer | M12, P69, M12mac25, LNCaP C4–2 | – | pHEMA scaffolds | pHEMA scaffolds suppressed the proliferative phenotype in LNCaP cells in vivo whereas, they promoted the growth of M12mac25 cells by triggering the dormant to proliferative switch | Long et al., [55] |
 Breast Cancer | MDA-MB-231, T47D | – | PCL fibrous scaffold | Cancer cells cultured on PCL scaffolds and treated with carboplatin exhibited a quiescent phenotype | Guiro et al., [56] |
 Bladder, Prostate, Lung, Breast Cancer and Neuroblastoma | T24, UMUC-3, PC3, PC3-PSMA, MCF-7, MDA-MB-231, H1975, SH-SY5Y | NIH3T3 mouse fibroblasts, BJ-5ta human foreskin fibroblasts & WPMY-1 human prostate stromal cells | Amikagel | Bladder cancer cells on ~ 215 kPa Amikagels were growth arrested and resistant to docetaxel | Pavan Grandhi et al., [57] |
 Lung Cancer | A549 | – | Matrigel | Matrigel induced dormancy in A549 cells via inhibition of PI3K/Akt and ERK1/2 pathways. | Keeratichmroen et al., [34] |
 Bladder Cancer | SV-HUC-1, TCCSUP, RT4, J82, 253JP, 253JB-V | – | Matrigel, SIS gel | SIS gel suppressed the growth and malignant phenotype of bladder cancer cells by driving them towards dormancy whereas, Matrigel supported the malignant and invasive phenotype | Hurst et al., [46] |
 Bladder Cancer | SV-HUC-1, TCCSUP, RT4, J82, 253JP, 253JB-V | – | Matrigel, SIS gel | SIS gel suppresses malignant phenotype in cancer cells as indicated by gene expression pattern whereas Matrigel promotes the expression of growth associated genes | Dozmorov et al., [47] |
 Bladder Cancer | J82, JB-V | – | Matrigel, Collagen, SIS gel | Dormant phenotype was observed in J82 or JB-V cells injected with SIS gel in nude mice | Hurst et al., [48] |
 Breast, Bladder, Prostate, Pancreatic, Gastric Cancer and Glioblastoma | MDA-MB-231, MDA-MB-435, MDA-MB-235, 4 T1, J82, PC-3, DU145, U251, AGS, Capan-1 | – | SIS gel | Identified drugs to target dormant cells | Hurst et al., [49] |
Microfluidic based models | |||||
 Breast Cancer | MDA-MB-231 | Human hepatocytes, NPCs | PEG hydrogel | Dormant phenotype was observed in cancer cells co-cultured with hepatic niche on the liver-chip incorporating PEG hydrogel | Clark et al., [61] |
 Breast Cancer | MDA-MB-231, MCF-7 | Human hepatocytes, NPCs | – | A subpopulation of cancer cells underwent dormancy on the liver chip and this was associated with a differential cytokine profile | Wheeler et al., [58] |
 Breast Cancer | MDA-MB-231, MCF-7 | Human mammary epithelial cells, human hepatic stellate cells (LX-1, LX-2, TWNT-1), rat hepatic stellate cells (HSC-T6) human endothelial cells (TMNK-1) | – | IL-8 revoked the hepatocyte induced dormancy in MDA-MB-231 cells | Khazali et al., [59] |
 Breast Cancer | MDA-MB-231 | Human hepatocytes, NPCs | – | Introduction of inflammatory stimuli promoted growth of dormant cancer cells | Clark et al., [60] |
 Lung Cancer | H1975 | Human primary airway and alveolar epithelial cells, Human lung microvascular epithelial cells | – | Breathing motion incorporated in engineered lung chip decreased cancer cell growth leading to a dormant phenotype | Hassel et al., [62] |
Bioreactor based model | |||||
 Breast Cancer | MDA-MB-231, MCF-7, MDA-MB-231BRMS1 | Mouse MC3T3-E1 osteoblasts, Normal Human Osteoblast cells | – | Remodeling cytokines TNFα and IL-1β promoted metastatic outgrowth of dormant MDA-MB-231BRMS1 cells | Sosnoski et al., [63] |