Abstract
BackgroundHuman mesenchymal stromal cells (MSC) hold a promise for future cell-based therapies due to their immunomodulatory properties and/or secretory activity. Nevertheless non-neoplastic tumor compartment could also originate from MSC. We aimed to show whether multipotent MSC derived from human adipose tissue (AT-MSC) could create tumor cell-protective milieu and affect tumor cell behaviour in vitro and in vivo.ResultsHere we have demonstrated tumor-promoting effect of AT-MSC on human melanoma A375 cells. AT-MSC coinjection mediated abrogation of tumor latency and supported subcutaneous xenotransplant growth from very low melanoma cell doses. Tumor incidence was also significantly increased by AT-MSC-derived soluble factors. AT-MSC supported proliferation, suppressed apoptosis and modulated melanoma cell responses to cytotoxic drugs in vitro. Expression and multiplex cytokine assays confirmed synergistic increase in VEGF that contributed to the AT-MSC-mediated support of A375 xenotransplant growth. Production of G-CSF and other factors implicated in formation of supportive proinflammatory tumor cell microenvironment was also confirmed. SDF-1α/CXCR4 signalling contributed to tumor-promoting effect of systemic AT-MSC administration on A375 xenotransplants. However, no support was observed for human glioblastoma cells 8MGBA co-injected along with AT-MSC that did not sustain tumor xenotransplant growth in vivo. Tumor-inhibiting response could be attributed to the synergistic action of multiple cytokines produced by AT-MSC on glioblastoma cells.ConclusionsHerein we provide experimental evidence for MSC-mediated protective effect on melanoma A375 cells under nutrient-limiting and hostile environmental conditions resulting from mutual crosstalk between neoplastic and non-malignant cells. This tumor-favouring effect was not observed for the glioblastoma cells 8MGBA. Collectively, our data further strengthen the need for unravelling mechanisms underlying MSC-mediated modulation of tumor behaviour for possible future MSC clinical use in the context of malignant disease.
Highlights
Human mesenchymal stromal cells (MSC) hold a promise for future cell-based therapies due to their immunomodulatory properties and/or secretory activity
Increased tumor incidence rather than change in tumor growth rate was reported for renal cell carcinoma, colon carcinoma and melanoma cells coinjected with MSC in syngeneic model [17]
In our present study we aimed to examine the influence of human adipose tissue derived mesenchymal stromal cells (AT-MSC) on tumor development
Summary
Human mesenchymal stromal cells (MSC) hold a promise for future cell-based therapies due to their immunomodulatory properties and/or secretory activity. Unmanipulated human MSC were shown to increase the metastatic potential of breast cancer cells rather than significant tumor growth support [15]. Several other studies aimed on modelling of the interplay between tumor cells and non-tumorigenic stromal cells have shown various MSC effects on tumor cell behaviour in vitro and in vivo. MSC strongly inhibited proliferation of malignant cells of hematopoietic origin in vitro, significantly increased BV173 tumor incidence in vivo [16]. Increased tumor incidence rather than change in tumor growth rate was reported for renal cell carcinoma, colon carcinoma and melanoma cells coinjected with MSC in syngeneic model [17]. Zhu et al have shown similar effects of MSC-favoured tumor growth for two colon carcinoma cell lines upon coinjection with bone marrow-derived human MSC on xenogeneic model [18]. Glioma outgrowth was significantly supported by intracranial or subcutaneous tumor cell coimplantation together with human adipose tissue derived MSC [19]
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