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

Abstract

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.

PML represses lung cancer metastasis by suppressing the nuclear EGFR-mediated transcriptional activation ofMMP2

“…48 It has been proposed that the IFNb-mediated downregulation of MMP2 expression in monocytes contributes to the beneficial effect of IFNb in MS. 49 Treating tumor cells with IFNb decreases MMP2 expression, which suppresses tumor metastasis. 50 De novo protein synthesis is required for optimal interferonmediated inhibition of MMP2 expression. 51 We determined that PML induction was essential for IFNb to repress MMP2 expression in lung cancer cells.…”

Polyethylenimine600-β-cyclodextrin: a promising nanopolymer for nonviral gene delivery of primary mesenchymal stem cells

“…2,3 MSCs also exhibit vital characteristics, including tumor tropism, nonimmunogenicity, convenience of isolation, and efficient ex vivo processing that may be useful in treating cancer. 4 However, safety issues such as mutagenesis, toxicity, and immunogenicity caused by viral vectors in these cases remain an important concern. Hence, the development of a safe and efficient nonviral gene-delivery system has drawn increasing attention.…”

The Microenvironment of Breast Cancer Stem Cells

“…They demonstrate that MSC are recruited to tumors and that IFN-beta inhibits tumor growth. (Ling X 2010). Such a reduction in tumor could also be attributable to decrease CSC content.…”

“…A seminal report by Ling X et al, demonstrate that MSC overexpressing IFN-beta inhibit breast cancer growth and metastasis (Ling et al, 2010). They demonstrate that MSC are recruited to tumors and that IFN-beta inhibits tumor growth.…”