Irradiation enhances susceptibility of tumor cells to the antitumor effects of TNF-α activated adipose derived mesenchymal stem cells in breast cancer model

Mohammadpour, Hemn; Pourfathollah, Ali Akbar; Zarif, Mahin Nikougoftar; Shahbazfar, Amir Ali

doi:10.1038/srep28433

Cited by 18 publications

(20 citation statements)

References 46 publications

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“…MSCs are found mainly in the connective tissue or interstitium and have marked self-renewal potential and the ability to differentiate into adipocytes, osteoblasts, and chondrocytes [6, 7]. MSCs have low immunogenicity, immunomodulatory activity, and tropism for sites of injury and inflammation and have a potential for the treatment of various diseases, including cancer [8]. These advantages have encouraged investigations of MSCs as vehicles for the delivery of anti-cancer agents [9].…”

Section: Introductionmentioning

confidence: 99%

RETRACTED ARTICLE: Exosomes from glioma cells induce a tumor-like phenotype in mesenchymal stem cells by activating glycolysis

Cui

Lü

et al. 2019

Stem Cell Res Ther

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Background Exosomes are nanoscale membrane vesicles secreted by both normal and cancer cells, and cancer cell-derived exosomes play an important role in the cross-talk between cancer cells and other cellular components in the tumor microenvironment. Mesenchymal stem cells (MSCs) have tropism for tumors and have been used as tumor-tropic vectors for tumor therapy; however, the safety of such therapeutic use of MSCs is unknown. In this study, we investigated the role of glioma cell-derived exosomes in the tumor-like phenotype transformation of human bone marrow mesenchymal stem cells (hBMSCs) and explored the underlying molecular mechanisms. Methods The effect of exosomes from U251 glioma cells on the growth of hBMSCs was evaluated with the CCK-8 assay, KI67 staining, and a cell cycle distribution assessment. The migration and invasion of hBMSCs were evaluated with a Transwell assay. A proteomics and bioinformatics approach, together with Western blotting and reverse transcriptase-polymerase chain reaction, was used to investigate the effect of U251 cell-derived exosomes on the proteome of hBMSCs. Results U251 cell-derived exosomes induced a tumor-like phenotype in hBMSCs by enhancing their proliferation, migration, and invasion and altering the production of proteins involved in the regulation of the cell cycle. Moreover, U251 cell-derived exosomes promoted the production of the metastasis-related proteins MMP-2 and MMP-9, glioma marker GFAP, and CSC markers (CD133 and Nestin). The ten differentially expressed proteins identified participated in several biological processes and exhibited various molecular functions, mainly related to the inactivation of glycolysis. Western blotting showed that U251 cell-derived exosomes upregulated the levels of Glut-1, HK-2, and PKM-2, leading to the induction of glucose consumption and generation of lactate and ATP. Treatment with 2-deoxy- d -glucose significantly reversed these effects of U251 cell-derived exosomes on hBMSCs. Conclusions Our data demonstrate that glioma cell-derived exosomes activate glycolysis in hBMSCs, resulting in their tumor-like phenotype transformation. This suggests that interfering with the interaction between exosomes and hBMSCs in the tumor microenvironment has potential as a therapeutic approach for glioma. Graphical abstract ᅟ

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Section: Introductionmentioning

confidence: 99%

RETRACTED ARTICLE: Exosomes from glioma cells induce a tumor-like phenotype in mesenchymal stem cells by activating glycolysis

Cui

Lü

et al. 2019

Stem Cell Res Ther

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“…Here, our current study provides novel findings, emphasizing the need for both TNBC:MSC cross-talk and pro-inflammatory signals delivered by TNFα and IL-1β, in order to achieve the most substantial levels of pro-metastatic activities: high levels of pro-metastatic chemokines, CXCL8, CCL2 and CCL5, angiogenesis, and tumor cell migration and invasion. Moreover, our findings suggest that previous studies on TNFα-treated MSCs that induced anti-tumor activities in TNBC tumors (101–104) may have overlooked the actual setting that takes place in vivo , when TNBC cells interact with MSCs in the presence of TNFα stimulation.…”

Section: Discussionmentioning

confidence: 78%

Tumor-Stroma-Inflammation Networks Promote Pro-metastatic Chemokines and Aggressiveness Characteristics in Triple-Negative Breast Cancer

et al. 2019

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The tumor microenvironment (TME) plays key roles in promoting disease progression in the aggressive triple-negative subtype of breast cancer (TNBC; Basal/Basal-like). Here, we took an integrative approach and determined the impact of tumor-stroma-inflammation networks on pro-metastatic phenotypes in TNBC. With the TCGA dataset we found that the pro-inflammatory cytokines tumor necrosis factor α (TNFα) and interleukin 1β (IL-1β), as well as their target pro-metastatic chemokines CXCL8 (IL-8), CCL2 (MCP-1), and CCL5 (RANTES) were expressed at significantly higher levels in basal patients than luminal-A patients. Then, we found that TNFα- or IL-1β-stimulated co-cultures of TNBC cells (MDA-MB-231, MDA-MB-468, BT-549) with mesenchymal stem cells (MSCs) expressed significantly higher levels of CXCL8 compared to non-stimulated co-cultures or each cell type alone, with or without cytokine stimulation. CXCL8 was also up-regulated in TNBC co-cultures with breast cancer-associated fibroblasts (CAFs) derived from patients. CCL2 and CCL5 also reached the highest expression levels in TNFα/IL-1β-stimulated TNBC:MSC/CAF co-cultures. The elevations in CXCL8 and CCL2 expression partly depended on direct physical contacts between the tumor cells and the MSCs/CAFs, whereas CCL5 up-regulation was entirely dependent on cell-to-cell contacts. Supernatants of TNFα-stimulated TNBC:MSC “Contact” co-cultures induced robust endothelial cell migration and sprouting. TNBC cells co-cultured with MSCs and TNFα gained migration-related morphology and potent migratory properties; they also became more invasive when co-cultured with MSCs/CAFs in the presence of TNFα. Using siRNA to CXCL8, we found that CXCL8 was significantly involved in mediating the pro-metastatic activities gained by TNFα-stimulated TNBC:MSC “Contact” co-cultures: angiogenesis, migration-related morphology of the tumor cells, as well as cancer cell migration and invasion. Importantly, TNFα stimulation of TNBC:MSC “Contact” co-cultures in vitro has increased the aggressiveness of the tumor cells in vivo , leading to higher incidence of mice with lung metastases than non-stimulated TNBC:MSC co-cultures. Similar tumor-stromal-inflammation networks established in-culture with luminal-A cells demonstrated less effective or differently-active pro-metastatic functions than those of TNBC cells. Overall, our studies identify novel tumor-stroma-inflammation networks that may promote TNBC aggressiveness by increasing the pro-malignancy potential of the TME and of the tumor cells themselves, and reveal key roles for CXCL8 in mediating these metastasis-promoting activities.

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“…These factors, whose production may upregulate in obesity, may be accomplices in tumor initiation. Similar to interleukin (IL)-6, IL-8, IL-1β, tumor necrosis factor-α (TNF-α), VEGF, chemokine (C-C motif) ligand 2 (CCL2) and CCL5 178, 179. Third, in obese patients, adipose tissue accommodates a higher proportion of preadipocytes, in which figures of macrophages and monocytes synergistic increase 180.…”

Section: Adipose Cellsmentioning

confidence: 99%

Role of tumor microenvironment in tumorigenesis

et al. 2017

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Tumorigenesis is a complex and dynamic process, consisting of three stages: initiation, progression, and metastasis. Tumors are encircled by extracellular matrix (ECM) and stromal cells, and the physiological state of the tumor microenvironment (TME) is closely connected to every step of tumorigenesis. Evidence suggests that the vital components of the TME are fibroblasts and myofibroblasts, neuroendocrine cells, adipose cells, immune and inflammatory cells, the blood and lymphatic vascular networks, and ECM. This manuscript, based on the current studies of the TME, offers a more comprehensive overview of the primary functions of each component of the TME in cancer initiation, progression, and invasion. The manuscript also includes primary therapeutic targeting markers for each player, which may be helpful in treating tumors.

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Irradiation enhances susceptibility of tumor cells to the antitumor effects of TNF-α activated adipose derived mesenchymal stem cells in breast cancer model

Cited by 18 publications

References 46 publications

RETRACTED ARTICLE: Exosomes from glioma cells induce a tumor-like phenotype in mesenchymal stem cells by activating glycolysis

RETRACTED ARTICLE: Exosomes from glioma cells induce a tumor-like phenotype in mesenchymal stem cells by activating glycolysis

Tumor-Stroma-Inflammation Networks Promote Pro-metastatic Chemokines and Aggressiveness Characteristics in Triple-Negative Breast Cancer

Role of tumor microenvironment in tumorigenesis

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