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] |
MLCK Myosin light chain kinase, SFK Src family kinases, MEK Mitogen activated protein kinases, ERK Extracellular-signal regulated kinases, Cdc42 Cell division control protein 42, Tet-2 Tet methylcytosine dioxygenase 2, TGF-β1 Transforming growth factor beta 1, ECM Extracellular matrix, HUVEC Human umbilical vein endothelial cells, FAK Focal adhesion kinase, STAT3 Signal transducer and activator of transcription 3, BMSC Bone marrow stromal cells, RTK Receptor tyrosine kinase, pHEMA poly (2-hydroxyethyl methacrylate), PCL Polycaprolactone, PEG Polyethylene glycol, PA Polyacrylamide, SIS Small intestine submucosa, HMEC Human microvascular endothelial cells, TNFα Tumor necrosis factor alpha, NPCs Nonparenchymal cells, hFOB Human fetal osteoblasts, IL Interleukin, PI3K Phosphoinositide 3-kinase, Akt Protein kinase B