Induction of ALP and MMP9 activity facilitates invasive behavior in heterogeneous human BMSC and HNSCC 3D spheroids

Wessely, Anja; Waltera, Anna; Reichert, Torsten E.; Stöckl, Sabine; Grässel, Susanne; Bauer, Robert

doi:10.1096/fj.201900925r

Cited by 28 publications

(41 citation statements)

References 55 publications

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“…Similar to our results, they did not observe signi cant effects of hDPSC-derived conditioned medium (CM) on in vitro HNSCC proliferation and therapeutic sensitivity, and in vivo tumour growth, despite the increase in tumour VEGF secretion(45). Con icting results on the impact of other MSC subtypes on in vitro and in vivo HNC cell proliferation, survival, migration, invasion and therapeutic sensitivity have previously been described(46)(47)(48)(49)(50)(51)(52)(53). These effects are mediated in a direct way via differentiation ofMSCs into malignant cells (54, 55), cancer-associated broblasts (CAFs) (56) and vascular-related cells (57, 58), or indirectly by (paracrine) interaction with immune cells (27, 59, 60), cancer stem cells (CSCs) (61-63), endothelial cells (24, 28, 64) and tumour cells (24, 30, 31, 65).…”

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confidence: 89%

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Safety and Homing of Human Dental Pulp Stromal Cells in Head and Neck Cancer

Merckx

Monaco

Lambrichts

et al. 2020

Preprint

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Background: Head and neck cancer (HNC) is one of the most common cancers, associated with a huge mortality and morbidity. In order to improve patient outcomes, more efficient and targeted therapies are essential. Bone marrow-derived mesenchymal stromal cells (BM-MSCs) express tumour homing capacity, which could be exploited to target anti-cancer drug delivery to the tumour region and reduce adverse side-effects. Nevertheless, dental pulp stromal cells (DPSCs), an MSC-like population present in teeth, could offer important clinical benefits because of their easy isolation and superior proliferation compared to BM-MSCs. Therefore, we aimed to elucidate the tumour homing and safe usage of DPSCs to treat HNC. Methods: The in vivo survival as well as the effect of intratumourally administered DPSCs on tumour aggressiveness was tested in a HNC xenograft mouse model by using bioluminescence imaging (BLI), (immuno)histology and qRT-PCR. Furthermore, the in vitro and in vivo tumour homing capacity of DPSCs towards a HNC cell line were evaluated by a transwell migration assay and BLI, respectively. Results: Intratumourally injected DPSCs survived for at least two weeks in the tumour micro-environment and had no significant influence on tumour morphology, growth, angiogenesis and epithelial-to-mesenchymal transition. In addition, DPSCs migrated towards tumour cells in vitro, which could not be confirmed after their in vivo intravenous, intraperitoneal or peritumoural injection under the tested experimental conditions. Conclusions: Our research suggests that intratumourally delivered DPSCs might be used as safe factories for the continuous delivery of anti-cancer drugs in HNC. Nevertheless, further optimization as well as efficacy studies are necessary to understand and improve in vivo tumour homing and determine the optimal experimental set-up of stem cell-based cancer therapies, including dosing and timing.

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supporting

confidence: 89%

“…The number of previous studies on the safe use of DPSCs as HNC therapy is limited to Hanyu et al (52,53). Therefore, further (long-term) in vivo studies are required to assess whether DPSCs also not interfere with other parameters of HNSCC aggressiveness, including metastasis, invasion and therapeutic sensitivity.…”

Section: Discussionmentioning

confidence: 99%

Safety and Homing of Human Dental Pulp Stromal Cells in Head and Neck Cancer

Merckx

Monaco

Lambrichts

et al. 2020

Preprint

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“…Density gradient centrifugation to isolate BMSCs was used according to established protocols. Afterward, cells were expanded (passage/P 1–3) in growth medium (StemMACS MSC Expansion Medium, #130091680, Miltenyi Biotec, Bergisch Gladbach, Germany) supplemented with 0.2% MycoZap TM Plus-PR (#VZA2022, Lonza, Basel, Switzerland) ( Leyh et al, 2014 ; Wessely et al, 2019 ). Human MSC-associated markers CD73 + , CD90 + , CD105 + , CD19 – and CD34 – were verified via flow cytometry.…”

Section: Methodsmentioning

confidence: 99%

Influence of Extracellular Vesicles Isolated From Osteoblasts of Patients With Cox-Arthrosis and/or Osteoporosis on Metabolism and Osteogenic Differentiation of BMSCs

Niedermair

Lukas

et al. 2020

Front. Bioeng. Biotechnol.

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Background: Studies with extracellular vesicles (EVs), including exosomes, isolated from mesenchymal stem cells (MSC) indicate benefits for the treatment of musculoskeletal pathologies as osteoarthritis (OA) and osteoporosis (OP). However, little is known about intercellular effects of EVs derived from pathologically altered cells that might influence the outcome by counteracting effects from “healthy” MSC derived EVs. We hypothesize, that EVs isolated from osteoblasts of patients with hip OA (coxarthrosis/CA), osteoporosis (OP), or a combination of both (CA/OP) might negatively affect metabolism and osteogenic differentiation of bone-marrow derived (B)MSCs.Methods: Osteoblasts, isolated from bone explants of CA, OP, and CA/OP patients, were compared regarding growth, viability, and osteogenic differentiation capacity. Structural features of bone explants were analyzed via μCT. EVs were isolated from supernatant of naïve BMSCs and CA, OP, and CA/OP osteoblasts (osteogenic culture for 35 days). BMSC cultures were stimulated with EVs and subsequently, cell metabolism, osteogenic marker gene expression, and osteogenic differentiation were analyzed.Results: Trabecular bone structure was different between the three groups with lowest number and highest separation in the CA/OP group. Viability and Alizarin red staining increased over culture time in CA/OP osteoblasts whereas growth of osteoblasts was comparable. Alizarin red staining was by trend higher in CA compared to OP osteoblasts after 35 days and ALP activity was higher after 28 and 35 days. Stimulation of BMSC cultures with CA, OP, and CA/OP EVs did not affect proliferation but increased caspase 3/7-activity compared to unstimulated BMSCs. BMSC viability was reduced after stimulation with CA and CA/OP EVs compared to unstimulated BMSCs or stimulation with OP EVs. ALP gene expression and activity were reduced in BMSCs after stimulation with CA, OP, and CA/OP EVs. Stimulation of BMSCs with CA EVs reduced Alizarin Red staining by trend.Conclusion: Stimulation of BMSCs with EVs isolated from CA, OP, and CA/OP osteoblasts had mostly catabolic effects on cell metabolism and osteogenic differentiation irrespective of donor pathology and reflect the impact of tissue microenvironment on cell metabolism. These catabolic effects are important for understanding differences in effects of EVs on target tissues/cells when harnessing them as therapeutic drugs.

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“…Type IV and V collagens are the major substrates for MMP9. A large number of studies have proved that MMP9 plays an important role in tumorigenesis, proliferation, apoptosis, invasion, and angiogenesis as well [54][55][56][57]. Moreover, it has been reported that the expression and activation of MMP9 are regulated by multiple signal pathways, such as STAT3 pathway [58,59], JNK pathway [60,61] and PI3K/AKT pathway [62].…”

Section: Discussionmentioning

confidence: 99%

ISG20 serves as a potential biomarker and drives tumor progression in clear cell renal cell carcinoma

Ruan

Gao

et al. 2020

Aging

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Clear cell renal cell carcinoma (ccRCC) is one of the most common malignancies and lacks reliable biomarkers for diagnosis and prognosis, which results in high incidence and mortality rates of ccRCC. In this study, ISG20, HJURP, and FOXM1 were identified as hub genes via weighted gene co-expression network analysis (WGCNA) and Cox regression analysis. Samples validation showed that only ISG20 was up-regulated in ccRCC. Therefore, ISG20 was selected for further study. High ISG20 expression was associated with poor overall survival and disease-free survival. Furthermore, the expression of ISG20 could effectively differentiate ccRCC from normal tissues and was positively correlated to clinical stages. Functional experiments proved that knockdown of ISG20 expression could obviously inhibit cell growth, migration, and invasion in ccRCC cells. To find the potential mechanisms of ISG20, gene set enrichment analysis (GSEA) was performed and revealed that high expression of ISG20 was significantly involved in metastasis and cell cycle pathways. In addition, we found that ISG20 could regulate the expression of MMP9 and CCND1. In conclusion, these findings suggested that ISG20 promoted cell proliferation and metastasis via regulating MMP9/CCND1 expression and might serve as a potential biomarker and therapeutic target in ccRCC.

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Induction of ALP and MMP9 activity facilitates invasive behavior in heterogeneous human BMSC and HNSCC 3D spheroids

Cited by 28 publications

References 55 publications

Safety and Homing of Human Dental Pulp Stromal Cells in Head and Neck Cancer

Safety and Homing of Human Dental Pulp Stromal Cells in Head and Neck Cancer

Influence of Extracellular Vesicles Isolated From Osteoblasts of Patients With Cox-Arthrosis and/or Osteoporosis on Metabolism and Osteogenic Differentiation of BMSCs

ISG20 serves as a potential biomarker and drives tumor progression in clear cell renal cell carcinoma

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