Determining Conditions for Successful Culture of Multi-Cellular 3D Tumour Spheroids to Investigate the Effect of Mesenchymal Stem Cells on Breast Cancer Cell Invasiveness

Brown, Marie-Juliet; Bahsoun, Soukaina; Morris, Mhairi A.; Akam, And Elizabeth C

doi:10.3390/bioengineering6040101

Cited by 15 publications

(11 citation statements)

References 35 publications

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“…Metformin-pretreated CM of all three BM-MSC lines inhibited the migration of both MDA-MB-231 and MDA-MB-436 significantly indicating a high indirect impact of metformin on breast cancer mobility. MSCs have been widely implicated in tumor development and metastases and co-culture of BM-MSCs and MDA-MB-231 cells have been found to dramatically reduce the invasiveness of both cell lines when embedded into a matrix [ 21 ].…”

Section: Resultsmentioning

confidence: 99%

Effects of metformin on human bone-derived mesenchymal stromal cell—breast cancer cell line interactions

et al. 2022

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Metformin is used to treat patients with type 2 diabetes mellitus and was found to lower the incidence of cancer. Bone metastasis is a common impairment associated with advanced breast cancer. The present study investigated the effects of metformin on human bone-derived mesenchymal stromal cells (BM-MSC)—breast cancer cell line interactions. BM-MSCs grown from box chisels were tested for growth-stimulating and migration-controlling activity on four breast cancer cell lines either untreated or after pretreatment with metformin. Growth stimulation was tested in MTT tests and migration in scratch assays. Furthermore, the expression of adipokines of BM-MSCs in response to metformin was assessed using Western blot arrays. Compared to breast cancer cell lines (3.6 ± 1.4% reduction of proliferation), 500 µM metformin significantly inhibited the proliferation of BM-MSC lines (mean 12.3 ± 2.2 reduction). Pretreatment of BM-MSCs with metformin showed variable effects of the resulting conditioned media (CM) on breast cancer cell lines depending on the specific BM-MSC—cancer line combination. Metformin significantly reduced the migration of breast cancer cell lines MDA-MB-231 and MDA-MB-436 in response to CM of drug-pretreated BM-MSCs. Assessment of metformin-induced alterations in the expression of adipokines by BM-MSC CM indicated increased osteogenic signaling and possibly impairment of metastasis. In conclusion, the anticancer activities of metformin are the result of a range of direct and indirect mechanisms that lower tumor proliferation and progression. A lower metformin-induced protumor activity of BM-MSCs in the bone microenvironment seem to contribute to the positive effects of the drug in selected breast cancer patients.

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Section: Resultsmentioning

confidence: 99%

Effects of metformin on human bone-derived mesenchymal stromal cell—breast cancer cell line interactions

et al. 2022

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show abstract

“…Metformin-pretreated CM of all three BM-MSC lines inhibited the migration of both MDA-MB-231 and MDA-MB-436 signi cantly indicating a high indirect impact of metformin on breast cancer mobility. MSCs have been widely implicated in tumor development and metastases and co-culture of BM-MSCs and MDA-MB-231 cells have been found to dramatically reduce the invasiveness of both cell lines when embedded into a matrix [21].…”

Section: Discussionmentioning

confidence: 99%

Effects of Metformin on Human Bone-derived Mesenchymal Stromal Cell – Breast Cancer Cell Line Interactions

Teufelsbauer

Lang

Plangger

et al. 2021

Preprint

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Metformin is used to treat patients with type 2 diabetes mellitus and was found to lower the incidence of cancer. Bone metastasis is a common complication of advanced breast cancer. The present study investigated the effects of metformin on human bone-derived mesenchymal stromal cells (BM-MSC) – breast cancer cell line interactions. BM-MSCs grown from box chisels were tested for growth-stimulating and migration-controlling activity on four breast cancer cell lines either untreated or after pretreatment with metformin. Growth stimulation was tested in MTT tests and migration in scratch assays. Furthermore, the expression of adipokines of BM-MSCs in response to metformin was assessed using Western blot arrays. Compared to breast cancer cell lines (3.6 ± 1.4% reduction of proliferation), 500 µM metformin significantly inhibited the proliferation of BM-MSC lines (12.3 ± 2.2 reduction). Pretreatment of BM-MSCs with metformin showed variable effects of the resulting conditioned media (CM) on breast cancer cell lines depending on the specific BM-MSC –cancer line combination. Metformin significantly impaired the migration of breast cancer cell lines MDA-MB-231 and MDA-MB-436 in response to CM of drug-pretreated BM-MSCs. Assessment of metformin-induced alterations in expression of adipokines by BM-MSC CM indicated increased osteogenic signaling and possibly impairment of metastasis. In conclusion, the anticancer activities of metformin are the result of a range of direct and indirect mechanisms that lower tumor proliferation and progression. A lower metformin-induced protumor activity of BM-MSCs in the bone microenvironment seem to contribute to the positive effects of the drug in selected breast cancer patients.

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“…Serum contains lots of cytokines, collagen, and adhesion factors, which have signi cant effects on the growth and proliferation of cells (Brown, Bahsoun, Morris, & Akam, 2019). As shown in Table S2, the low concentration of FBS was detrimental to the formation of MTSs.…”

Section: Rapid Generation Of High-throughput 3d Mtss Using An Optimized Liquid Overlay Methodsmentioning

confidence: 99%

Multi-Omics Analysis Defines 5-Fluorouracil Drug Resistance in 3D Hela Carcinoma Cell Model

Wang

et al. 2021

Preprint

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Cervical cancer is a serious health problem in women around the globe, with 600 thousand new cases each year. However, the use of clinical drug is seriously dampened by the development of drug resistance, which has been evidenced to be associated with metabolic reprogramming and heterogeneity in tumor cells. Efficient in vitro tumor model is essential to improve the efficiency of drug screening and the accuracy of clinical application. Multicellular tumor spheroids (MTSs) can in a way recapitulates tumor traits in vivo, thereby representing a powerful transitional model between 2D monolayer culture and xenograft. In this study, based on the liquid overlay method, a protocol for rapid generation of the MTSs with uniform size and high reproducibility in a high-throughput manner was established. As expected, the cytotoxicity results showed that there was enhanced 5-FU resistance of HeLa carcinoma cells in 3D MTSs than 2D monolayer culture with a resistance index of 5.72. In the presence of both glucose and glutamine, HeLa carcinoma cells preferentially used glutamine as the bioenergetic substrate to support cell proliferation and maintenance under all conditions, while the ubiquitous by-product ammonium might be only recycled in the 3D MTSs. Furthermore, in order to obtain a holistic view of the molecular mechanisms that drive 5-FU resistance in 3D HeLa carcinoma cells, a multi-omics study was applied to discover hidden biological regularities. It was observed that in the 3D MTSs mitochondrial function-related proteins and the metabolites of the tricarboxylic acid cycle (TCA cycle) were significantly decreased, and the cellular metabolism was shifted towards glycolysis. The differences in the protein synthesis, processing, and transportation between 2D monolayer cultures and 3D MTSs was significant, mainly in the heat shock protein family, with the upregulation of protein folding function in endoplasmic reticulum (ER), which promoted the maintenance of ER homeostasis in the 3D MTSs. In addition, at the transcript and protein level, the expression of extracellular matrix (ECM) proteins (e.g., laminin and collagen) were up-regulated in the 3D MTSs, which enhanced the physical barrier of drug penetration. Summarizing, this study formulates a rapid, scalable and reproducible in vitro model of 3D MTS for drug screening purposes, and the findings establish a critical role of glycolytic metabolism, ER hemostasis and ECM proteins expression profiling in tumor chemoresistance of HeLa carcinoma cells towards 5-FU.

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Determining Conditions for Successful Culture of Multi-Cellular 3D Tumour Spheroids to Investigate the Effect of Mesenchymal Stem Cells on Breast Cancer Cell Invasiveness

Cited by 15 publications

References 35 publications

Effects of metformin on human bone-derived mesenchymal stromal cell—breast cancer cell line interactions

Effects of metformin on human bone-derived mesenchymal stromal cell—breast cancer cell line interactions

Effects of Metformin on Human Bone-derived Mesenchymal Stromal Cell – Breast Cancer Cell Line Interactions

Multi-Omics Analysis Defines 5-Fluorouracil Drug Resistance in 3D Hela Carcinoma Cell Model

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