Mesenchymal Stem Cells: Potential Precursors for Tumor Stroma and Targeted-Delivery Vehicles for Anticancer Agents

Studeny, Matus; Marini, Frank C.; Dembinski, Jennifer L.; Zompetta, Claudia; Cabreira-Hansen, Maria da Graça; Bekele, B. Nebiyou; Champlin, Richard E.; Andreeff, Michael

doi:10.1093/jnci/djh299

Cited by 787 publications

(746 citation statements)

References 28 publications

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“…In addition, our in vivo and in vitro data indicate that the mechanism of this effect is through inactivation of constitutively activated Stat3 in breast cancer cells, which in turn improves the breast cancer host's cell-mediated immunity. Our present findings are not only consistent with our previous work [5,7] in xenograft models showing MSC homing to the tumor microenvironment and evidence that IFN-β delivered by MSC inhibits human cancer xenografts but also illuminates some of the molecular mechanisms that convey the observed antitumor effects of IFN-β on breast cancer in vivo and extend our previous work on the efficiency of systemically delivered MSC/IFN-β. These results further support the translation of this novel therapeutic concept into clinical trials, which is under development [3].…”

Section: Discussionsupporting

confidence: 92%

“…1a II-III). This phenomenon is consistent with our previous findings in a both breast cancer and melanoma xenograft models [7]. No specific staining was seen in control mice injected, i.v.…”

Section: Msc/ifn-β Cells Selectively Engraft In Breast Tumorsupporting

confidence: 93%

“…1b right panel). This finding is consistent with our previous data that also showed low levels of IFN-β levels in the serum of MSC-IFN-β injected mice [7]. Co-culture of 4 T1 with MSC/IFN-β/GFP reduces cell invasion 4 T1 cells are strongly invasive in vitro and in vivo [19,20].…”

Section: Msc/ifn-β Cells Selectively Engraft In Breast Tumorsupporting

confidence: 92%

“…It has been reported that IFN-β has an inhibitory effect on cancer cell growth in vitro and in xenograft models [7]. However, other evidence has also shown that IFN-β is a strong immune modulator in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…MSC were first characterized by our group as capable of selectively migrating to tumor sites through chemoattraction by tumor cell produced factors [3][4][5]. and local inflammatory chemokines and cytokines induced by tumor invasion [6,7]. Solid tumor growth and invasion create a microenvironment that induces the secretion of factors that attract MSC to specifically migrate to the tumor sites [8].…”

Section: Introductionmentioning

confidence: 99%

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Mesenchymal Stem Cells Overexpressing IFN-β Inhibit Breast Cancer Growth and Metastases through Stat3 Signaling in a Syngeneic Tumor Model

Ling

Marini

Konopleva

et al. 2010

Cancer Microenvironment

110

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We previously demonstrated that mesenchymal stem/stromal cells (MSC) are recruited to tumors and that IFN-β produced by MSC inhibited tumor growth in xenograft models. Because of a deficient immune system, murine xenograft models cannot fully recapitulate tumor and immune cell interactions during progression. Therefore we investigated the capacity of MSC to migrate to and engraft into primary breast tumor sites and subsequently explore mechanisms of tumor inhibition by MSC-delivered IFN-β in a syngeneic, immunocompetent murine model. Herein we report that 1) systemically administrated MSC migrate to established 4 T1 breast cancer sites and localize among the tumor-stroma border and throughout the tumor mass; 2) high levels of IFN-β secreted by MSC are detectable in the tumor microenvironment but not in circulation; 3) intratumorally produced IFN-β inactivates constitutive phosphorylation of signal transducer activator transcription factor 3 (Stat3), Src, and Akt and down-regulates cMyc and MMP2 expression in 4 T1 cells, and 4) in mice with established breast cancer IFN-β expressing MSC administered systemically resulted in inhibition of primary cancer growth and in dramatic reduction of pulmonary and hepatic metastases. 5) MSC-IFN-β treated, but not control mice, maintained normal levels of splenic mature dendritic (DC), CD8+ T cells and CD4+/Foxp3+ regulatory T-cells (Treg). Our findings suggest that MSC are capable of migrating to tumor sites in an immunocompetent environment, that IFN-β produced by MSC suppresses breast cancer growth through inhibition of Stat3 signaling, and dramatically reduces pulmonary and hepatic metastases.

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Section: Discussionsupporting

confidence: 92%

Section: Msc/ifn-β Cells Selectively Engraft In Breast Tumorsupporting

confidence: 93%

Section: Msc/ifn-β Cells Selectively Engraft In Breast Tumorsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Mesenchymal Stem Cells Overexpressing IFN-β Inhibit Breast Cancer Growth and Metastases through Stat3 Signaling in a Syngeneic Tumor Model

Ling

Marini

Konopleva

et al. 2010

Cancer Microenvironment

110

View full text Add to dashboard Cite

show abstract

Mesenchymal Stem Cells Characteristics, Niches, and Applications for Cell Therapy

Ylöstalo¹,

Bartosh²

2013

Encyclopedia of Molecular Cell Biology and Molecular Medicine

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The Biology of Tumour Stroma

Guyot¹,

Lepreux

Darby

et al. 2007

The Cancer Handbook

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The cooperation between epithelial and mesenchymal cells is essential for embryonic development and certainly plays an important role in pathological phenomena such as wound healing and tumour progression. Many epithelial tumours are characterised by the local accumulation of connective tissue cells and extracellular material; this phenomenon has been called stroma reaction , which shows many similarities in its organisation and evolution with the granulation tissue that develops during tissue repair. One of the cellular components of stroma reaction is the myofibroblast, a modified fibroblast that has become capable of expression of α‐smooth muscle actin, the actin isoform typical of vascular smooth muscle cells, and also capable of synthesis of significant amounts of collagen and other extracellular matrix components. The myofibroblast is a key cell for connective tissue remodelling that takes place during wound healing and fibrosis development. Myofibroblasts are also capable of interaction with epithelial cells and other connective tissue cells and may thus control such phenomena as tumour invasion and angiogenesis. In this chapter, we discuss the mechanisms of myofibroblast evolution during normal and malignant conditions, and the interaction of myofibroblasts with other cells in order to control tumour progression. On this basis, we suggest that the myofibroblast may represent a new and important target for anti‐tumour therapy.

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Mesenchymal Stem Cells: Potential Precursors for Tumor Stroma and Targeted-Delivery Vehicles for Anticancer Agents

Abstract: Injected MSC-IFN-beta cells suppressed the growth of pulmonary metastases, presumably through the local production of IFN-beta in the tumor microenvironment. MSC may be an effective platform for the targeted delivery of therapeutic proteins to cancer sites.

Cited by 787 publications

References 28 publications

Mesenchymal Stem Cells Overexpressing IFN-β Inhibit Breast Cancer Growth and Metastases through Stat3 Signaling in a Syngeneic Tumor Model

Mesenchymal Stem Cells Overexpressing IFN-β Inhibit Breast Cancer Growth and Metastases through Stat3 Signaling in a Syngeneic Tumor Model

Mesenchymal Stem Cells Characteristics, Niches, and Applications for Cell Therapy

The Biology of Tumour Stroma

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