Tumor resident mesenchymal stromal cells endow naïve stromal cells with tumor-promoting properties

Ren, Guosheng; Y, Liu; Zhao, Xin; Zhang, J; Zheng, Betty; Zr, Yuan; Zhang, L; Qu, Xun; Tischfield, Jay A.; Shao, Changshun; Shi, Yufang

doi:10.1038/onc.2013.387

Cited by 43 publications

(28 citation statements)

References 18 publications

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“…This is important because we have reported that chemokines are critically involved in MSC-mediated immunosuppression through recruiting immune cells to the vicinity of MSCs, so that labile NO could effectively inhibit the proliferation and functions of the immune cells (5). We employed microbead-based multiplex assay as previously described (20). Surprisingly, none of the cytokines or chemokines that are induced by IFNγ and TNFα was affected by IFNα, except some upregulation of IL-6 (Figure S3).…”

Section: Resultsmentioning

confidence: 99%

Type I interferons exert anti-tumor effect via reversing immunosuppression mediated by mesenchymal stromal cells

et al. 2016

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Mesenchymal stromal cells (MSCs) are strongly immunosuppressive via producing nitric oxide (NO) and known to migrate into tumor sites to promote tumor growth, but the underlying mechanisms remain largely elusive. Here, we found that IFNα-secreting MSCs showed more dramatic inhibition effect on tumor progression than that of IFNα alone. Interestingly, IFNα-primed MSCs could also effectively suppress tumor growth. Mechanistically, we demonstrated that both IFNα and IFNβ (type I IFNs) reversed the immunosuppressive effect of MSCs on splenocyte proliferation. This effect of type I IFNs was exerted through inhibiting iNOS (inducible nitric oxide synthase) expression in IFNγ and TNFα-stimulated MSCs. Notably, only NO production was inhibited by IFNα; production of other cytokines or chemokines tested was not suppressed. Furthermore, IFNα promoted the switch from Stat1 homodimers to Stat1-Stat2 heterodimers. Studies using the luciferase reporter system and chromatin immunoprecipitation assay revealed that IFNα suppressed iNOS transcription through inhibiting the binding of Stat1 to iNOS promoter. Therefore, the synergistic anti-tumor effects of type I IFNs and MSCs were achieved by inhibiting NO production. This study provides essential information for understanding the mechanisms of MSC-mediated immunosuppression and for the development of better clinical strategies using IFNs and MSCs for cancer immunotherapy.

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Section: Resultsmentioning

confidence: 99%

Type I interferons exert anti-tumor effect via reversing immunosuppression mediated by mesenchymal stromal cells

et al. 2016

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“…3, 4 We, thus determined the percentage of macrophages in tumour sites and monocytes in peripheral blood from mice with established B16-F0 melanoma by melanoma cell alone, or together with BM-MSCs or TE-MSCs. Flow cytometrical analysis revealed that tumours from mice with TE-MSCs administration exhibited significantly more macrophage (CD11b + F4/80 + ) accumulation than that from tumours with BM-MSCs inoculation (Figure 2a).…”

Section: Resultsmentioning

confidence: 99%

“…1, 2 Recent studies demonstrated that tumour resident MSCs had an important role in coordinating the tumour microenvironment. 3, 4, 5 After mobilized and integrated into the tumour stroma upon sensing the cues of a tumour, MSCs acquire a series of properties to promote tumour growth, including producing growth factors, inhibiting anti-tumour immune responses, shaping tumour inflammatory environment and building the niche for tumour cells. 6, 7, 8, 9, 10, 11, 12 Importantly, recent studies revealed that the enhanced tumour promotion ability of tumour-derived MSCs is not intrinsic, rather acquired upon arrival at the tumour microenvironment.…”

Section: Introductionmentioning

confidence: 99%

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Tumour cell-derived exosomes endow mesenchymal stromal cells with tumour-promotion capabilities

Lin

Cao

et al. 2016

Oncogene

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Mesenchymal stromal cells (MSCs) are a major component of the tumour microenvironment. A plethora of elegant studies focusing on tumour-derived MSCs have shown that they, unlike normal MSCs in other tissue, exhibit a strong ability to promote tumour progression. However, the mechanisms underlying the conversion of normal MSCs into tumour-associated MSCs are unknown. We report here a critical role of tumour cell-derived exosomes in endowing bone marrow-derived MSCs (BM-MSCs) with a tumour-favourable phenotype. Tumour cell-derived exosomes affected neither the growth factor production nor the immunosuppressive property of MSCs; rather, they endowed MSCs with a strong ability to promote macrophage infiltration into B16-F0 melanoma or EL-4 lymphoma. Ablation of macrophages by clodronate liposome administration reversed the tumour-promoting effect of MSCs educated by tumour cell-derived exosomes (TE-MSCs) on the tumour growth. By comparing the chemokine profile of BM-MSCs with that of TE-MSCs, we found that TE-MSCs produced a large amount of CCR2 ligands, CCL2 and CCL7, which are responsible for macrophage recruitment. CCR2-specific inhibitor was found to block the tumour-promoting effect of TE-MSCs. Thus, our investigations demonstrated that tumour cell-derived exosomes confer BM-MSCs the ability to enhance tumour growth. Therefore, we uncovered a novel mechanism underlying the conversion of normal MSCs to tumour-associated MSCs.

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“…CCL-2, CCL-7, and CCL-12) to facilitate recruiting macrophages/monocytes toward the tumor sites. 59 Recently, a novel mechanism showed by Lin et al 60 have uncovered that MSCs recruited macrophages to the tumor sites via CCR2 chemotaxis axis and subsequently facilitated tumor growth in melanoma and lymphoma under the help of tumor cell-derived exosomes. Therefore, MSCs and LAM, even the tiny particles such as exosomes, might be the potential therapeutic targets for reducing tumor burden.…”

Section: Role Of the Components In The Lymphoma Microenvironmentmentioning

confidence: 99%

Intimate cross-talk between cancer cells and the tumor microenvironment of B-cell lymphomas: The key role of exosomes

Wang

2017

Tumour Biol.

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B-cell lymphomas are composed of tumor cells and the tumor microenvironment, which is conventionally thought to be composed of a mixture of stromal cells, blood vessels, immune cells, and non-cell components, such as extracellular matrix, cytokines, and chemokines. Exosomes, small endocytically derived vesicles that have been proved to be present in a variety of tumor niches and involved in mediating cell signaling networks, are increasingly regarded as important components of tumor microenvironment. In this review, we first focus on the biogenesis, biodistribution, transportation, and other general characteristics of exosomes and then highlight the vital roles of exosomes in lymphomagenesis and disease progression, particularly from the perspective of immune dysfunction, virus infection, and therapeutic resistance mechanisms.

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Tumor resident mesenchymal stromal cells endow naïve stromal cells with tumor-promoting properties

Cited by 43 publications

References 18 publications

Type I interferons exert anti-tumor effect via reversing immunosuppression mediated by mesenchymal stromal cells

Type I interferons exert anti-tumor effect via reversing immunosuppression mediated by mesenchymal stromal cells

Tumour cell-derived exosomes endow mesenchymal stromal cells with tumour-promotion capabilities

Intimate cross-talk between cancer cells and the tumor microenvironment of B-cell lymphomas: The key role of exosomes

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