The Three-Dimensional In Vitro Cell Culture Models in the Study of Oral Cancer Immune Microenvironment
Abstract
:Simple Summary
Abstract
1. Introduction
2. Tumor Immune Microenvironment of Oral Cancer
2.1. Interaction between the Immune System and Tumor Cells
2.2. Immune and Non-Immune Markers
2.3. Stromal Cell and Extracellular Matrix (ECM) on Cancer Immunity
3. In Vitro Models in Oral Cancer
3.1. Two-Dimensional Models
3.2. Three-Dimensional Models
3.2.1. Scaffold-Free Strategy
Spheroid
Organoid
3.2.2. Scaffold-Based Strategy
Limitation and Improvement of 3D Model
4. Application of 3D Model in Oral Cancer
4.1. Oral Microbiota Study
4.2. Drug Discovery
4.3. Cell–Cell Interactions
3D Model | Aim | Result | References |
---|---|---|---|
Co-culture of monocytes with spheroids originating Malignant/benign HNC | The connection between the response of this cytokine co-culture and the prediction of outcomes. | The secretion of IL-6 during in vitro co-culture with monocytes and BF 1-spheroids serves as a prognostic indicator for recurrence and overall prognosis, whereas co-culture with monocytes and MF 2-spheroids predicts the likelihood of recurrence. | [227] |
Co-culture of HNC cell line with fibroblasts in spheroid form | Generation of a spheroid model of EGFR-expressing HNC. | The upregulation of chemokine expression by anti-EGFR mAb 3 promotes the infiltration of leukocytes into tumor spheroids. This unique mechanism of action of anti-EGFR mAb could potentially enhance the anti-tumor effects of the antibody in living organisms. | [228] |
Spheroid form of HNC cell line culture with leukocytes from PBMC 4 | The evaluation of utilizing a 3D tumor cell culture model, specifically spheroids, as a suitable representation of micro-metastases. | The utilization of the spheroid model demonstrates the manifestation of pathophysiological traits, intricacy, and heterogeneity of tumor tissue observed in vivo, which significantly impacts the effectiveness of therapeutic interventions. | [229] |
Co culture of HNC spheroids with TAMs | The signaling of CD44, influenced by TAMs, has the potential to facilitate stemness through the PI3K-4EBP1-SOX2 pathway. This effect may occur by regulating the availability of HA 5, which is the primary ligand for CD44. | The results establish a mechanistic connection between CD44 in tumor cells, TAMs, and the properties of CSCs 6 at the interface between tumor and stroma. This connection highlights a crucial area for targeting and discovering drugs. | [231] |
Co-culture of HNC cell line with HDFs | The understanding of how cancer cells, fibroblasts, and the surrounding collagen matrices interact and promote cancer cell invasion in different environments with varying concentrations of collagen. | The presence of HDFs played a crucial role in facilitating the invasion of HNC cells into the surrounding extracellular matrix characterized by high collagen concentration, elevated storage modulus, and narrow pore sizes. | [230] |
Co-culture of HNC cell line with CAFS | Assessing the impact of CAFs on the treatment response and migratory behavior of HNC. | The presence of CAFs resulted in enhanced cell proliferation within the tumor spheroids, which was accompanied by elevated EGFR expression. Notably, spheroids exhibiting heightened EGFR expression displayed an augmented response to cetuximab treatment. | [210] |
HNC spheroids | Role of ERK1/2-Nanog pathway in tumorigenesis in HNC. | HNSCCs sustain a population of CSCs by utilizing the ERK1/2 signaling pathway and Nanog. | [232] |
Oral mucosal Organoids and HNC patient-derived tumoroids | In vitro 3D model for HNC. | Drug screening for both existing and experimental therapeutic treatments for HNC. | [163] |
HNC spheroids | The correlation of CD44 and HIF-1α expression. | By focusing on HIF-1α, the impact of NOTCH1-induced stemness, which controls the reaction to chemotherapy or radiotherapy as well as the malignancy in CD44+ HNSCCs, was reduced. Targeting the signaling of HIF-1α/NOTCH1 could potentially serve as a therapeutic approach for the treatment of HNSCC. | [237] |
Co-culture of OSCC cell line with CAFS | Role of stromal NNMT 7 in TME. | The harmful cancer-promoting effects caused by stromal NNMT were reduced when fibroblasts were treated with inhibitors targeting collagen production, such as losartan, tranilast, and halofuginone. | [238] |
5. Potential Application of 3D Model in Studying TAM Functions in Oral Cancer
6. Conclusions and Future Perspective
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
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Type | Secretory Cell | Markers | References |
---|---|---|---|
Immune Cell | M1 TAMs | CD11c, CD80, HLA-DR 1 | [41,42,43] |
M2 TAMs | CD163, CD11b, CD206, MRC1 2 | [43,44,45,46] | |
DC | S100, CD1a, CD83, CD207, CD208, CD80, CD11c, CD86, HLA-DR CLEC9A 3 | [47,48,49] | |
NK cells | CD57 | [50,51,52] | |
pan T cell | CD3 | [12,53,54] | |
cytotoxic T cell | CD8 | [12,55,56] | |
T helper cell | CD4 | [12,57,58] | |
Pan B cell | CD19, CD20 | [12,59,60] | |
MDSCs | CD33, CD11b | [61,62,63] | |
CAFs | α SMA 4 | [64,65,66] | |
Treg | FOXP3+ CD4+ T cells or CD4+ CD25+ CD127low | [39,67,68] | |
Non-immune cell | endothelial cells | CD34 | [69,70,71] |
Salivary biomarkers | L-phenylalanine Sphinganine Phytosphingosine S-carboxymethyl-L-cysteine | [72,73,74] | |
Genomic biomarkers | ITGA3 5, ITGB4 expression | [75,76,77] | |
Oral cancer cell | CCR7 6 | [78,79,80] | |
Oral cancer cell | MYO1B 7 | [81,82,83] |
Stromal Cells | Mechanism | Function | References |
---|---|---|---|
CAFs | Production of numerous ECM proteins such as HAS2 1 expression by CAFs | Tumor cell invasion by increasing ECM-degrading MMPs 2 and decreasing TIMPs 3 | [95,96] |
high expression of α-SMA in CAFs | OSCC invasion into the bone by increasing expression of RANKL 4 and OPG 5 | [97,98,99,100] | |
High secretion of IL-1α by OSCC upregulated expression of secretory cytokines, including CCL7 6, CXCL1 7, and IL-8 | Tumor cell proliferation | [101,102,103] | |
IGF-1 overexpression in CAF and activation of PI3K-AKT and Hedgehog signaling pathways | Tumor cell proliferation, migration invasion, tumorsphere formation angiogenesis. | [104,105,106] | |
Overexpression of NOTCH-1 in CAFs | Increasing tumor volume angiogenesis in OSCC | [107,108,109] | |
Overexpression of IL-6 in CAFs | Expression of VGEF in CAFs and OSCC angiogenesis in OSCC | [110,111,112] | |
Multiple factors derived from CAFs, such as CXCL12 and MCP-1 attract macrophages to tumors and induce the M2 phenotype | A mediator for T-cell suppression | [113,114] | |
IL-1α secreted from OSCC cells induces the chemokine CCL7 in co-cultured CAF | OSCC invasion and progression | [115,116] | |
TAMs | increased expression of arginase I, IL-10 and TGF-β | Suppressive effect on T cells and invasion and metastasis of OSCC | [117,118] |
PDL-1 and IL-10 production in TAMs | Immune escape of OSCC cells | [119,120] | |
the secretion of EGFs 8 and the management of collagen production by TAMs | OSCC invasion and progression | [121,122] | |
EMT 9 induced by TAMs decreased E-mucin and E-cadherin and increased-vimentin protein in OSCC cells | OSCC invasion and progression | [123,124,125] | |
activated the Hh 10 signaling pathway by TAMs | Angiogenesis in OSCC | [126,127] | |
Activation of TGF-β1/TβRII/Smad3 signaling pathway in TAMs | VEGF secretions in OSCC | [128,129] | |
TAM number modulation by PFKFB3 11 | Angiogenesis in OSCC | [130,131] | |
DCs | activated the TNF-α/NF-κB/CXCR-4 pathway by pDCs 12 | Oral cancer proliferation and invasion | [132,133] |
2D Model | 3D Model | Animal Model | |
---|---|---|---|
Modeling human development and disease | - | + | + |
High costs, high personal, and work effort | - | - | + |
High-throughput screening | + | + | - |
Personalized medicine | - | + | - |
Vascularization and immune system | - | - | + |
Architecture | - | + | + |
3D Models | Drug | Application | Reference |
---|---|---|---|
Spheroid | Cetuximab Cisplatin | To assess the impact of both 2D and 3D culture techniques on gene expression related to cell junctions, cell adhesions, cell cycle, and metabolism. To verify the feasibility and practicality of this novel 3D culture approach for oral cancer research. | [147,202,203,204] |
Cisplatin Doxorubicin Methotrexate | To evaluate the differences in chemoresistance between 2D and 3D culture methods. | [205,206,207] | |
Cisplatin 5-FU 2-Gy Radiation | To assess and compare the efficacy of 2D and 3D methods as platforms for chemotherapy and radiotherapy testing. | [208,209] | |
Cetuximab | To develop a biologically significant in vitro model of HNSCC that accurately replicates the tumor environment by incorporating both tumor cells and CAFs in a 3D culture system. | [210] | |
Organotypic models | Cisplatin Docetaxel ± 5-FU | To evaluate and compare the suitability of 2D and 3D methods as platforms for assessing chemotherapy sensitivity. | [151,211,212] |
Cisplatin ± (carboplatin, cetuximab, radiotherapy) | To assess and compare the effectiveness of 2D and 3D methods as platforms for chemotherapy screening and regenerative purposes. | [163,213] | |
Cetuximab mTOR inhibitor Canertinib Dactolisib PF-04691502 Apitolisib Omipalisib Refametinib binimetinib trametinib pimasertib trametinib | To evaluate and compare the efficacy of 2D and 3D methods as platforms for dual drug screening. | [214,215] | |
Microfluidic platforms | 5-FU Cisplatin ± (Paclitaxel, Cetuximab, Carboplatin) | The use of a dynamic culture method as a platform for chemotherapy screening. | [175,216,217] |
IDO1 inhibitor ± (PDL1 antibody, Nivolumab) | [172,218] |
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Dalir Abdolahinia, E.; Han, X. The Three-Dimensional In Vitro Cell Culture Models in the Study of Oral Cancer Immune Microenvironment. Cancers 2023, 15, 4266. https://doi.org/10.3390/cancers15174266
Dalir Abdolahinia E, Han X. The Three-Dimensional In Vitro Cell Culture Models in the Study of Oral Cancer Immune Microenvironment. Cancers. 2023; 15(17):4266. https://doi.org/10.3390/cancers15174266
Chicago/Turabian StyleDalir Abdolahinia, Elaheh, and Xiaozhe Han. 2023. "The Three-Dimensional In Vitro Cell Culture Models in the Study of Oral Cancer Immune Microenvironment" Cancers 15, no. 17: 4266. https://doi.org/10.3390/cancers15174266