Mesenchymal Stem Cell-Based Tumor-Targeted Gene Therapy in Gastrointestinal Cancer

Bao, Qi; Zhao, Yue; Nieß, Hanno; Conrad, Claudius; Schwarz, Bettina; Jauch, Karl Walter; Huss, Ralf; Nelson, Peter J.; Bruns, Christiane

doi:10.1089/scd.2012.0060

Cited by 46 publications

(36 citation statements)

References 81 publications

(105 reference statements)

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“…Interestingly, in most human tumors, IDO is believed to be expressed continuously 40 , which may explain why tryptophan catabolism is elevated in cancer patients. Since a tumor can be considered to be a wound that never heals, tissue damage signals result in continuous recruitment of MSCs into the tumor 4142 . Using our inducible IDO-transfected mouse MSCs in tumor models, we observed that the ongoing inflammatory microenvironment also induces the expression of IDO, leading to its immunomodulatory effect.…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal Stem Cells Use IDO to Regulate Immunity in Tumor Microenvironment

et al. 2014

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Mesenchymal stem cells (MSCs) are present in most, if not all, tissues and are believed to contribute to tissue regeneration and the tissue immune microenvironment. Murine MSCs exert immunosuppressive effects through production of the nitric oxide synthase iNOS, while human MSCs utilize indoleamine 2,3-dioxygenase (IDO). Thus, studies of MSC-mediated immunomodulation in mice may not be informative in the setting of human disease, although this critical difference has been mainly ignored. To address this issue, we established a novel humanized system to model human MSCs, employing murine iNOS−/− MSCs that constitutively or inducibly express an ectopic human IDO gene . In this system, inducible IDO expression is driven by a mouse iNOS promoter that can be activated by inflammatory cytokine stimulation in a similar fashion as the human IDO promoter. These IDO-expressing humanized MSCs (MSC-IDO) were capable of suppressing T lymphocyte proliferation in vitro. In melanoma and lymphoma tumor models, MSC-IDO promoted tumor growth in vivo, an effect that was reversed by the IDO inhibitor 1-methyl-tryptophan. We found that MSC-IDO dramatically reduced both tumor-infiltrating CD8+ T cells and B cells. Our findings offer an important new line of evidence that interventional targeting of IDO activity could be used to restore tumor immunity in humans, by relieving IDO-mediated immune suppression of MSCs in the tumor microenvironment as well as in tumor cells themselves.

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Section: Discussionmentioning

confidence: 99%

Mesenchymal Stem Cells Use IDO to Regulate Immunity in Tumor Microenvironment

et al. 2014

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“…They also exhibit a natural tendency of homing into tumors -ability that is starting to be exploited in anticancer treatment, using these versatile cells as cargo delivery for cytotoxic drugs or gene therapy [109]. This behavior has been also reported in pancreatic cancer, by the use of genetically engineered labeled MSCs that efficiently accumulatewithin the pancreatic tumor, when injected into tumor-bearing mice [110].…”

Section: B Mesenchymal Stem Cells -Dual Facets In Cancermentioning

confidence: 89%

Stem Cells in Pancreatic Cancer

Tănase¹,

Enciu²,

Cruceru³

et al. 2014

Pancreatic Cancer - Insights Into Molecular Mechanisms and Novel Approaches to Early Detection and Treatment

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“…Surgical resection is the main treatment method for lung cancer, but most patients are diagnosed at the advanced disease stage, when relatively ineffective drug therapy is the only feasible treatment [2]. Mesenchymal stem cells (MSCs) are non-hematopoietic progenitor cells that can be obtained from bone marrow aspirates or adipose tissue, and then expanded and genetically modified in vitro, presenting a potential therapeutic strategy for cancer patients [3]. The molecular mechanisms behind the function of MSCs in tumorigenesis and cancer development are not well-defined, but better knowledge of these mechanisms could facilitated improved prognosis and suppressed malignancy.…”

Section: Introductionmentioning

confidence: 99%

Exosomal microRNA-144 from bone marrow-derived mesenchymal stem cells inhibits the progression of non-small cell lung cancer by targeting CCNE1 and CCNE2

Liu

Zhang

et al. 2020

Stem Cell Res Ther

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Background: Mesenchymal stem cells (MSCs) are pluripotent mesenchymal cells present in various adult tissues. MSCs secrete exosomes as regulators of the tumor niche, with involvement in tumorigenesis and metastasis. The regulatory role of microRNAs (miRs or miRNAs) in MSCs via targeting cyclin E1 (CCNE1) or cyclin E2 (CCNE2) has been extensively reported. Since exosomes are considered as protective and enriched sources of shuttle miRNAs, we hypothesized that exosomal transfer of miR-144 from bone marrow-derived MSCs (BMMSCs) would affect the development of non-small cell lung cancer (NSCLC) cells by targeting CCNE1 and CCNE2.Methods: We first quantified the levels of miR-144, CCNE1, and CCNE2 in NSCLC tissues and cell lines and then undertook gain-and loss-of-function studies of miR-144, CCNE1, and CCNE2 to investigate their roles in the biological characteristics of NSCLC in vitro. NSCLC cells (A549) were exposed to exosomes derived from MSCs, and cell proliferation and colony formation rate were determined using in vitro assays. Finally, effects of BMMSC-derived exosomal miR-144 on tumor development were studied in vivo. Results:In NSCLC tissues and cell lines, miR-144 was expressed poorly and CCNE1 and CCNE2 were expressed highly. Artificially elevating miR-144 inhibited cell proliferation, colony formation, and the number of S phasearrested cells in NSCLC by downregulating CCNE1 and CCNE2. Additionally, BMMSC-derived exosomal miR-144 led to restrained NSCLC cell proliferation and colony formation. These inhibitory effects of BMMSC-derived exosomes carrying miR-144 on NSCLC were confirmed by experiments in vivo. Conclusion: Collectively, these findings revealed inhibitory effects of BMMSC-derived exosomal miR-144 on NSCLC progression, which were mediated by downregulation of CCNE1 and CCNE2.

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Mesenchymal Stem Cell-Based Tumor-Targeted Gene Therapy in Gastrointestinal Cancer

Cited by 46 publications

References 81 publications

Mesenchymal Stem Cells Use IDO to Regulate Immunity in Tumor Microenvironment

Mesenchymal Stem Cells Use IDO to Regulate Immunity in Tumor Microenvironment

Stem Cells in Pancreatic Cancer

Exosomal microRNA-144 from bone marrow-derived mesenchymal stem cells inhibits the progression of non-small cell lung cancer by targeting CCNE1 and CCNE2

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