Inhibition of Human Malignant Pleural Mesothelioma Growth by Mesenchymal Stromal Cells

Abstract

Background: Malignant Pleural Mesothelioma (MPM) is an aggressive tumor that has a significant incidence related to asbestos exposure with no effective therapy and poor prognosis. The role of mesenchymal stromal cells (MSCs) in cancer is controversial due to their opposite effects on tumor growth and in particular, only a few data are reported on MSCs and MPM. Methods: We investigated the in vitro efficacy of adipose tissue-derived MSCs, their lysates and secretome against different MPM cell lines. After large-scale production of MSCs in a bioreactor, their efficacy was also evaluated on a human MPM xenograft in mice. Results: MSCs, their lysate and secretome inhibited MPM cell proliferation in vitro with S or G0/G1 arrest of the cell cycle, respectively. MSC lysate induced cell death by apoptosis. The efficacy of MSC was confirmed in vivo by a significant inhibition of tumor growth, similar to that produced by systemic administration of paclitaxel. Interestingly, no tumor progression was observed after the last MSC treatment, while tumors started to grow again after stopping chemotherapeutic treatment. Conclusions: These data demonstrated for the first time that MSCs, both through paracrine and cell-to-cell interaction mechanisms, induced a significant inhibition of human mesothelioma growth. Since the prognosis for MPM patients is poor and the options of care are limited to chemotherapy, MSCs could provide a potential new therapeutic approach for this malignancy.

Freeze-Dried Mesenchymal Stem Cell-Secretome Pharmaceuticalization: Optimization of Formulation and Manufacturing Process Robustness

“…Many challenges still need to be faced in the transition of MSC-secretome therapies into the clinic. These include practical problems, such as the need for an adequate number of cells (which may be solved using bioreactors [ 25 ]), the necessity of scalable, reproducible and GMP-compliant manufacturing protocols and the MSC-secretome formulation into a standardized pharmaceutical dosage form (possibly in a steady dry state). In this regard, starting from a method that combines ultrafiltration and freeze-drying to transform MSC-secretome into a pharmaceutical product–the lyosecretome, this work used a multi-level 5 × 2 experimental design to develop a freeze-dried formulation of MSC-secretome by using a mannitol/sucrose binary mixture.…”

A novel approach for large-scale manufacturing of small extracellular vesicles from bone marrow-derived mesenchymal stromal cells using a hollow fiber bioreactor

“…3D systems such as hollow fiber bioreactors are favorable since they represent a more native microenvironment of cells ( Almeria et al, 2022 ) and allow the collection of several liters of CM for large-scale manufacturing of sEVs. MSC expansion with hollow fiber bioreactors such as the Quantum system of Terumo BCT has already been implemented for several cell-based applications ( Nold et al, 2013 ; Rojewski et al, 2013 ; Hanley et al, 2014 ; Lechanteur et al, 2014 ; Barckhausen et al, 2016 ; Haack-Sorensen et al, 2016 ; Lambrechts et al, 2016 ; Haack-Sorensen et al, 2018 ; Mizukami et al, 2018 ; Frank et al, 2019 ; Mennan et al, 2019 ; Lisini et al, 2020 ; Vymetalova et al, 2020 ; Cocce et al, 2021 ; Haberle et al, 2021 ; Mendt et al, 2021 ). However, only few studies investigated the use of hollow fiber bioreactor-based systems for the production of MSC-derived sEVs ( Mendt et al, 2018 ; Cao et al, 2020 ; Yan and Wu, 2020 ; Gobin et al, 2021 ; Bellio et al, 2022 ).…”

Conditioned Medium of Mesenchymal Stromal Cells Loaded with Paclitaxel Is Effective in Preclinical Models of Triple-Negative Breast Cancer (TNBC)

“…The use of MSCs primed with PTX has been suggested as a novel approach to overcome toxicity issues. In principle, PTX-loaded MSCs may exert anti-cancer effects both by direct cell–cell contact and by paracrine action of the released drug [ 21 ]. We previously estimated the kinetics of PTX release and retention by MSCs [ 18 ].…”

“…Detectable PTX activity was evidenced at 2 h after MSC loading, reaching peak concentrations of 1.7–2.0 pg/cell at 144 h [ 18 ]. Indeed, in another study, we used PTX-primed MSCs against human pancreatic adenocarcinoma in transwell co-culture and showed a growth-inhibitory effect on CFPAC-1 cells [ 20 ]; moreover, paracrine effects of MSCs, acting without cell-to-cell contact, were demonstrated by Coccè et al [ 21 ].…”