scholarly journals The Release of Inflammatory Mediators from Acid-Stimulated Mesenchymal Stromal Cells Favours Tumour Invasiveness and Metastasis in Osteosarcoma

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5855
Author(s):  
Sofia Avnet ◽  
Silvia Lemma ◽  
Margherita Cortini ◽  
Gemma Di Pompo ◽  
Francesca Perut ◽  
...  
Keyword(s):  
Inflammatory Mediators ◽  
Stromal Cells ◽  
Lung Metastases ◽  
Bone Tumour ◽  
Disease Free Survival ◽  
Serum Levels ◽  
Tumour Microenvironment ◽  
Indirect Measurement ◽  
Fdg Pet Ct

Osteosarcoma is the most frequent primary malignant bone tumour with an impressive tendency to metastasise. Highly proliferative tumour cells release a remarkable amount of protons into the extracellular space that activates the NF-kB inflammatory pathway in adjacent stromal cells. In this study, we further validated the correlation between tumour glycolysis/acidosis and its role in metastases. In patients, at diagnosis, we found high circulating levels of inflammatory mediators (IL6, IL8 and miR-136-5p-containing extracellular vesicles). IL6 serum levels significantly correlated with disease-free survival and 18F-FDG PET/CT uptake, an indirect measurement of tumour glycolysis and, hence, of acidosis. In vivo subcutaneous and orthotopic models, co-injected with mesenchymal stromal (MSC) and osteosarcoma cells, formed an acidic tumour microenvironment (mean pH 6.86, as assessed by in vivo MRI-CEST pH imaging). In these xenografts, we enlightened the expression of both IL6 and the NF-kB complex subunit in stromal cells infiltrating the tumour acidic area. The co-injection with MSC also significantly increased lung metastases. Finally, by using 3D microfluidic models, we directly showed the promotion of osteosarcoma invasiveness by acidosis via IL6 and MSC. In conclusion, osteosarcoma-associated MSC react to intratumoural acidosis by triggering an inflammatory response that, in turn, promotes tumour invasiveness at the primary site toward metastasis development.

scholarly journals Mesenchymal Stromal Cells for Antineoplastic Drug Loading and Delivery

Medicines ◽  
2017 ◽  
Vol 4 (4) ◽  
pp. 87 ◽  
Author(s):  
Francesco Petrella ◽  
Isabella Rimoldi ◽  
Stefania Rizzo ◽  
Lorenzo Spaggiari
Keyword(s):  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Targeted Delivery ◽  
Drug Loading ◽  
Tumour Microenvironment ◽  
Chemotherapeutic Agents ◽  
Immunomodulatory Activity ◽  
Neoplastic Cells

Mesenchymal stromal cells are a population of undifferentiated multipotent adult cells possessing extensive self-renewal properties and the potential to differentiate into a variety of mesenchymal lineage cells. They express broad anti-inflammatory and immunomodulatory activity on the immune system and after transplantation can interact with the surrounding microenvironment, promoting tissue healing and regeneration. For this reason, mesenchymal stromal cells have been widely used in regenerative medicine, both in preclinical and clinical settings. Another clinical application of mesenchymal stromal cells is the targeted delivery of chemotherapeutic agents to neoplastic cells, maximizing the cytotoxic activity against cancer cells and minimizing collateral damage to non-neoplastic tissues. Mesenchymal stem cells are home to the stroma of several primary and metastatic neoplasms and hence can be used as vectors for targeted delivery of antineoplastic drugs to the tumour microenvironment, thereby reducing systemic toxicity and maximizing antitumour effects. Paclitaxel and gemcitabine are the chemotherapeutic drugs best loaded by mesenchymal stromal cells and delivered to neoplastic cells, whereas other agents, like pemetrexed, are not internalized by mesenchymal stromal cells and therefore are not suitable for advanced antineoplastic therapy. This review focuses on the state of the art of advanced antineoplastic cell therapy and its future perspectives, emphasizing in vitro and in vivo preclinical results and future clinical applications.

scholarly journals Epidermal IL-15Rα acts as an endogenous antagonist of psoriasiform inflammation in mouse and man

2013 ◽  
Vol 210 (10) ◽  
pp. 2105-2117 ◽  
Author(s):  
Grégory Bouchaud ◽  
Samuel Gehrke ◽  
Carsten Krieg ◽  
Antonios Kolios ◽  
Jürg Hafner ◽  
...  
Keyword(s):  
T Cells ◽  
Proinflammatory Cytokines ◽  
Stromal Cells ◽  
Γδ T Cells ◽  
Skin Inflammation ◽  
Serum Levels ◽  
Inflammatory Skin Disease ◽  
Danger Signals

Stromal cells at epithelial surfaces contribute to innate immunity by sensing environmental danger signals and producing proinflammatory cytokines. However, the role of stromal cells in controlling local inflammation is unknown. We show that endogenous soluble IL-15 receptor α (IL-15Rα) derived from epidermal stroma, notably keratinocytes, protects against dendritic cell/IL-15-mediated, T cell-driven skin inflammation in vivo, and is relevant to human psoriasis. Selective lack of IL-15Rα on stromal epidermal cells exacerbated psoriasiform inflammation in animals. Epidermal IL-15Rα was shed by keratinocytes via proteolytic cleavage by matrix metalloproteinases upon stimulation with proinflammatory cytokines to counteract IL-15–induced proliferation of IL-17+ αβ and γδ T cells and production of TNF, IL-23, IL-17, and IL-22 during skin inflammation. Notably, administration of soluble IL-15Rα was able to repress secretion of IL-1β, IL-6, and TNF by keratinocytes, dampen expansion of IL-17+ αβ and γδ T cells in vivo, and prevent psoriasis in two mouse models, including human xenograft AGR mice. Serum levels of soluble IL-15Rα negatively correlated with disease severity, and levels rose upon successful treatment of psoriasis in patients. Thus, stressed epidermal stromal cells use soluble IL-15Rα to dampen chronic inflammatory skin disease.

scholarly journals Transformation-associated alterations in interactions between pre-B cells and fibronectin

Blood ◽  
1990 ◽  
Vol 76 (11) ◽  
pp. 2311-2320 ◽  
Author(s):  
FM Lemoine ◽  
S Dedhar ◽  
GM Lima ◽  
CJ Eaves
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Line ◽  
Cell Lines ◽  
Stromal Cells ◽  
Stromal Cell ◽  
Cell Attachment ◽  
Attachment Site ◽  
Receptor Antibodies

Abstract Marrow stromal elements produce as yet uncharacterized soluble growth factors that can stimulate the proliferation of murine pre-B cells, although close contact between these two cell types appears to ensure a better pre-B cell response. We have now shown that freshly isolated normal pre-B cells (ie, the B220+, surface mu- fraction of adult mouse bone marrow) adhere to fibronectin (FN) via an RGD cell-attachment site, as shown in a serum-free adherence assay, and they lose this functional ability on differentiation in vivo into B cells (ie, the B220+, surface mu+ fraction). Similarly, cells from an immortalized but stromal cell-dependent and nontumorigenic murine pre-B cell line originally derived from a Whitlock-Witte culture were also found to adhere to fibronectin (FN) via an RGD cell-attachment site. Moreover, in the presence of anti-FN receptor antibodies, the ability of this immortalized pre-B cell line to proliferate when co-cultured with a supportive stromal cell line (M2–10B4 cells) was markedly reduced (down to 30% of control). This suggests that pre-B cell attachment to FN on stromal cells may be an important component of the mechanism by which stromal cells stimulate normal pre-B cell proliferation and one that is no longer operative to control their more differentiated progeny. Two differently transformed pre-B cell lines, both of which are autocrine, stromal-independent, tumorigenic in vivo, and partially or completely differentiation-arrested at a very early stage of pre-B cell development, did not bind to FN. In addition, anti-FN receptor antibodies were much less effective in diminishing the ability of these tumorigenic pre-B cells to respond to M2–10B4 cell stimulation, which could still be demonstrated when the tumorigenic pre-B cells were co- cultured with M2–10B4 cells at a sufficiently low cell density. Analysis of cell surface molecules immunoprecipitated from both the nontumorigenic and tumorigenic pre-B cell lines by an anti-FN receptor antibody showed an increase in very late antigen (VLA) alpha chain(s) in both tumorigenic pre-B cell lines and a decrease in the beta 1 chain in one. Interestingly, all of the pre-B cell lines expressed similar amounts of messenger RNA for the beta 1 chain of the FN receptor. These results suggest that alteration of FN receptor expression on pre-B cells may represent a mechanism contributing to the outgrowth of leukemic pre-B cells with an autocrine phenotype and capable of stromal cell-independent, autonomous growth.

Time Series Analysis of Transmesothelial Invasion by Endometrial Stromal and Epithelial Cells Using Three-dimensional Confocal Microscopy

2001 ◽  
Vol 7 (S2) ◽  
pp. 580-581
Author(s):  
CA Witz ◽  
S Cho ◽  
VE Centonze ◽  
IA Montoya-Rodriguez ◽  
RS Schenken
Keyword(s):  
Epithelial Cells ◽  
Stromal Cells ◽  
Time Course ◽  
Three Dimensional ◽  
Collagen Iv ◽  
Mesothelial Cells ◽  
Endometrial Stromal Cells ◽  
Human Collagen ◽  
Endometrial Epithelial Cells

Using human peritoneal explants, we have previously demonstrated that endometrial stromal cells (ESCs) and endometrial epithelial cells (EECs) attach to intact mesothelium. Attachment occurs within one hour and mesothelial invasion occurs within 18 hours (Figure 1). We have also demonstrated that, in vivo, the mesothelium overlies a continuous layer of collagen IV (Col IV).More recently we have used CLSM, to study the mechanism and time course of ESC and EEC attachment and invasion through mesothelial monolayers. in these studies, CellTracker® dyes were used to label cells. Mesothelial cells were labeled with chloromethylbenzoylaminotetramethylrhodamine (CellTracker Orange). Mesothelial cells were then plated on human collagen IV coated, laser etched coverslips. Mesothelial cells were cultured to subconfluence. ESCs and EECs, labeled with chloromethylfluorscein diacetate (CellTracker Green) were plated on the mesothelial monolayers. Cultures were examined at 1, 6, 12 and 24 hours with simultaneous differential interference contrast and CLSM.

scholarly journals Antidiabetic and antiulcerative potential of Garcinia lanceifolia Roxb. bark

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Nilutpal Sharma Bora ◽  
Partha Sarathi Bairy ◽  
Abdus Salam ◽  
Bibhuti Bhusan Kakoti
Keyword(s):  
Body Weight ◽  
Serum Levels ◽  
Northeast India ◽  
Scientific Data ◽  
Antidiabetic Activity ◽  
Histological Evaluation ◽  
Albino Rats ◽  
Antiulcer Activity ◽  
Dose Dependent

Abstract Background Garcinia lanceifolia Roxb. has been used by many ethnic communities of Northeast India to mitigate various disorders like dyspepsia, ulcers, diabetes, etc. However, a robust scientific study on its antidiabetic and antiulcer potential is unavailable till date. The aim of this present study is to scientifically validate if the antidiabetic and antiulcer effects reported by the ethnic tribes of Assam has any scientific value or not. The effects were tested in adult Wistar albino rats using approved animal models for preclinical testing of pharmacological activities. Results The hydroalcoholic extract of the bark of Garcinia lanceifolia Roxb. was prepared and its LD50 was calculated. The LD50 was determined to be greater than 5000 mg/kg body weight. The extract at doses of 250 mg/kg body weight and 500 mg/kg body weight was found to exhibit a very potent dose-dependent antidiabetic activity. The results were backed by a battery of test including analysis of serum levels of blood glucose, lipid profiles, in vivo antioxidant enzymes, and histopathological studies. Evidence of dose-dependent antiulcer activity of the extract was backed by robust scientific data. It was found that HAEGL induced a significant dose-dependent increase in the ulcer index in both alcohol-induced and acetic acid-induced ulcer models, which was evident from the macroscopic observation of the inner lining of the gastric mucosa and the histological evaluation of the extracted stomach. Conclusion The results suggested that the bark of Garcinia lanceifolia (Roxb.) has significant antidiabetic and antiulcer potential. Further studies with respect to the development herbal dosage forms and its safety evaluation are required.

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