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Bone marrow-derived mesenchymal stromal cells promote survival and drug resistance in tumor cells.

ABSTRACT: Bone marrow mesenchymal stromal cells (BMMSC) have antitumorigenic activities. Here, we hypothesized that circulating BMMSC are incorporated into tumors and protect tumor cells from therapy-induced apoptosis. Adherent cells harvested from murine bone marrow and expressing phenotypic and functional characteristics of BMMSC were tested for their antitumor activity against murine 4T1 mammary adenocarcinoma and LL/2 Lewis lung carcinoma cells. BMMSC but not NIH3T3 or murine skin fibroblasts stimulated the expansion of 4T1 cells in three-dimensional (3D) cocultures, and conditioned medium (CM) from these cells increased the viability of 4T1 and LL/2 cells in two-dimensional (2D) cultures. 4T1 cells exposed to BMMSC CM exhibited a 2-fold reduction in apoptosis under low serum concentrations (0.5% to 1%). Furthermore, exposure of 4T1 and LL/2 cells to BMMSC CM increased their viability in the presence of paclitaxel or doxorubicin at therapeutic concentrations. This effect was accompanied by reductions in caspase-3 activity and Annexin V expression. When coinjected with 4T1 cells in the mammary fat pad of mice subsequently treated with doxorubicin, BMMSC (and not fibroblasts) also inhibited drug-induced apoptosis in tumor cells by 44%. We demonstrated that BMMSC were attracted by 4T1 and LL/2 cells but not by NIH3T3 cells in vitro and that when injected intravenously in 4T1 tumor-bearing mice, these cells (and not NIH3T3) were specifically detected in tumors within 12 to 18 days in which they preferentially localized at the invasive front. Overall, our data identify BMMSC as an important mediator of tumor cell survival and treatment resistance in primary tumors.

SUBMITTER: Bergfeld SA

PROVIDER: S-EPMC4000239 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Bone marrow-derived mesenchymal stromal cells promote survival and drug resistance in tumor cells.

Bergfeld Scott A SA Blavier Laurence L DeClerck Yves A YA

Molecular cancer therapeutics 20140206 4

Bone marrow mesenchymal stromal cells (BMMSC) have antitumorigenic activities. Here, we hypothesized that circulating BMMSC are incorporated into tumors and protect tumor cells from therapy-induced apoptosis. Adherent cells harvested from murine bone marrow and expressing phenotypic and functional characteristics of BMMSC were tested for their antitumor activity against murine 4T1 mammary adenocarcinoma and LL/2 Lewis lung carcinoma cells. BMMSC but not NIH3T3 or murine skin fibroblasts stimulat ...[more]

PMID: 24502925

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Project description:BACKGROUND:Radiotherapy remains one of the cornerstones to improve the outcome of colorectal cancer (CRC) patients. Radiotherapy of the CRC not only help to destroy cancer cells but also remodel the tumour microenvironment by enhancing tumour-specific tropism of bone marrow-derived mesenchymal stromal cell (BM-MSC) from the peripheral circulation. However, the role of local MSCs and recruited BM-MSC under radiation were not well defined. Indeed, the functions of BM-MSC without irradiation intervention remained controversial in tumour progression: BM-MSC was previously shown to modulate the immune function of major immune cells, resulting in an impaired immunological sensitivity and to induce an increased risk of tumour recurrence. In contrast, it could also secrete various cytokines and possess anticancer effect. METHODS:Three co-cultivation modules, 3D culture modules, and cancer organoids were established. The induction of cytokines secretion in hBM-MSCs after irradiation was analysed by ELISA array and flow cytometry. AutoMac separator was used to separate hBM-MSC and CRC automatically. Cells from the co-cultured group and the control group were then irradiated by UV-C lamp and X-ray. Proliferation assay and viability assay were performed. RESULTS:In this study, we show that BM-MSCs can induce the EMT progression of CRC cells in vitro. When irradiated with low doses of ultraviolet radiation and X-rays, BM-MSCs show an anti-tumour effect by secreting certain cytokine (TNF-?, IFN-?) that lead to the inhibition of proliferation and induction of apoptosis of CRC cells. This was further verified in a 3D culture model of a CRC cell in vitro. Furthermore, irradiation on the co-culture system induced the cleavage of caspase3, and attenuated the phosphorylation of phosphatidylinositol 3-kinase (PI3K)/AKT and extracellular signal-regulated kinase in cancer cells. The signal pathways above might contribute to the cancer cell death. CONCLUSIONS:Taken together, we show that BM-MSC can potentially promote the effect of radiotherapy in CRC.

Project description:BackgroundMesenchymal stromal cells (MSCs) have been extensively used in the clinic due to their exquisite tissue repair capacity. However, they also hold promise in the field of cellular vaccination as they can behave as conditional antigen presenting cells in response to interferon (IFN)-gamma treatment under a specific treatment regimen. This suggests that the immune function of MSCs can be pharmacologically modulated. Given the capacity of the agonist pyrimido-indole derivative UM171a to trigger the expression of various antigen presentation-related genes in human hematopoietic progenitor cells, we explored the potential use of UM171a as a means to pharmacologically instill and/or promote antigen presentation by MSCs.MethodsBesides completing a series of flow-cytometry-based phenotypic analyses, several functional antigen presentation assays were conducted using the SIINFEKL-specific T-cell clone B3Z. Anti-oxidants and electron transport chain inhibitors were also used to decipher UM171a's mode of action in MSCs. Finally, the potency of UM171a-treated MSCs was evaluated in the context of therapeutic vaccination using immunocompetent C57BL/6 mice with pre-established syngeneic EG.7T-cell lymphoma.ResultsTreatment of MSCs with UM171a triggered potent increase in H2-Kb cell surface levels along with the acquisition of antigen cross-presentation abilities. Mechanistically, such effects occurred in response to UM171a-mediated production of mitochondrial-derived reactive oxygen species as their neutralization using anti-oxidants or Antimycin-A mitigated MSCs' ability to cross-present antigens. Processing and presentation of the immunogenic ovalbumin-derived SIINFEKL peptide was caused by de novo expression of the Psmb8 gene in response to UM171a-triggered oxidative stress. When evaluated for their anti-tumoral properties in the context of therapeutic vaccination, UM171a-treated MSC administration to immunocompetent mice with pre-established T-cell lymphoma controlled tumor growth resulting in 40% survival without the need of additional supportive therapy and/or standard-of-care.ConclusionsAltogether, our findings reveal a new immune-related function for UM171a and clearly allude to a direct link between UM171a-mediated ROS induction and antigen cross-presentation by MSCs. The fact that UM171a treatment modulates MSCs to become antigen-presenting cells without the use of IFN-gamma opens-up a new line of investigation to search for additional agents capable of converting immune-suppressive MSCs to a cellular tool easily adaptable to vaccination.

Project description:Purpose:This study is aimed at investigating the phenotype, differentiation potential, immunomodulatory properties, and responsiveness of saphenous vein vessel wall-derived mesenchymal stromal cells (SV-MSCs) to various TLR ligands and proinflammatory cytokines, as well as comparing their features to those of their bone marrow-derived counterparts (BM-MSCs). Methods:SV-MSCs were isolated by enzymatic digestion of the saphenous vein vessel wall. Phenotype analysis was carried out by flow cytometry and microscopy, whereas adipogenic, chondrogenic, and osteogenic differentiation potentials were tested in in vitro assays. For comparative analysis, the expression of different stemness, proliferation, and differentiation-related genes was determined by Affymetrix gene array. To compare the immunomodulatory properties of SV-MSCs and BM-MSCs, mixed lymphocyte reaction was applied. To investigate their responses to various activating stimuli, MSCs were treated with TLR ligands (LPS, PolyI:C) or proinflammatory cytokines (TNF?, IL-1?, IFN?), and the expression of various early innate immune response-related genes was assessed by qPCR, while secretion of selected cytokines and chemokines was measured by ELISA. Results:The isolated SV-MSCs were able to differentiate into bone, fat, and cartilage cells/direction in vitro. SV-MSCs expressed the most important MSC markers (CD29, CD44, CD73, CD90, and CD105) and shared almost identical phenotypic characteristics with BM-MSCs. Their gene expression pattern and activation pathways were close to those of BM-MSCs. SV-MSCs showed better immunosuppressive activity inhibiting phytohemagglutinin-induced T lymphocyte proliferation in vitro than BM-MSCs. Cellular responses to treatments mimicking inflammatory conditions were comparable in the bone marrow- and saphenous vein-derived MSCs. Namely, similar to BM-MSCs, SV-MSCs secreted increased amount of IL-6 and IL-8 after 12- or 24-hour treatment with LPS, PolyI:C, TNF?, or IL-1?, compared to untreated controls. Interestingly, a different CXCL-10/IP-10 secretion pattern could be observed under inflammatory conditions in the two types of MSCs. Conclusion:Based on our results, cells isolated from saphenous vein vessel wall fulfilled the ISCT's (International Society for Cellular Therapy) criteria for multipotent mesenchymal stromal cells, and no significant differences in the phenotype, gene expression pattern, and responsiveness to inflammatory stimuli could be observed between BM-MSCs and SV-MSCs, while the latter cells have more potent immunosuppressive activity in vitro. Further functional assays have to be performed to reveal whether SV-MSCs could be useful for certain regenerative therapeutic applications or tissue engineering purposes.

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Bone marrow-derived mesenchymal stromal cells promote survival and drug resistance in tumor cells.

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Bone marrow-derived mesenchymal stromal cells promote survival and drug resistance in tumor cells.

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