Therapeutic potential of mesenchymal stromal cells in a mouse breast cancer metastasis model
Introduction
Mesenchymal stromal cells (MSC) comprise a population of pluripotent progenitor cells isolated from various tissue sources, primarily from bone marrow (BM). Under appropriate conditions, MSC have been induced to ectodermal, endodermal and mesodermal cell lineages 1., 2., 3., 4., 5.. Because of their ability to differentiate into various functional terminal lineages, MSC have been studied intensively in regenerative medicine. In addition to their in vitro and in vivo differentiation and transdifferentiation capabilities, MSC can engraft in degenerated sites to execute therapeutic functions [6, 7]. MSC are considered to be cellular vehicles for the delivery of therapeutic proteins [8, 9].
Umbilical cord blood (UCB) MSC are stem cells that reside in human UCB. Several studies have found favorable properties of these cells, including progenitor status and immunomodulation [10, 11]. Adipose tissue (AD) MSC can be isolated from mammary fat tissue obtained from women undergoing cosmetic reduction mammoplasty [12]. AD MSC have shown properties comparable to BM-derived MSC [13, 14]. UCB and AD MSC represent an economical and easily acquired resource that is gaining attention for clinical trials.
Carcinomas are the result of a well-orchestrated desmoplasic reaction. This process closely resembles wound healing and recruits a variety of growth factors, cytokines and matrix-remodeling proteins [15]. These factors ensure that the tumor site is a wound that never heals [16] and suggest that, similar to sites of injury, MSC could be recruited by endocrine and paracrine signals released from the tumor site. A variety of stromal cells are recruited during carcinoma formation. As MSC are usually present among stromal cells, the effects of MSC transplantation in tumor patients have been investigated thoroughly. Potent anti-tumor effects have been observed and attributed to direct cell contact, leading to the inhibition of Akt activation within Kaposi's sarcoma cells [17]. Recently, genetically modified BM MSC constitutively producing interferon (IFN)-α have shown therapeutic potential by reducing lung metastasis in melanoma [18]. However, it has also been suggested that BM MSC might enhance the motility, invasion and metastasis of cancer cells [19]. Additionally, the effects of transplantation of MSC during the early stage of carcinogenesis without any apparent clinical changes should be evaluated.
In the present study, to determine the therapeutic potential of human MSC in cancer metastasis, UCB and AD MSC were transplanted into a mouse breast cancer metastasis model. The results indicated that human MSC reduced the metastasis in lung and inhibited the growth of human breast cancer cells by inducing the apoptosis process.
Section snippets
Cell line
The human breast cancer cell line MDA-MB-231 was purchased from ATCC (Manassas, VA, USA). MDA-MB-231 cells were maintained in Dulbecco's modified Eagle's medium (DMEM; Gibco BRL, Grand Island, NY) supplemented with 10% heat-inactivated fetal bovine serum (FBS; Gibco), penicillin (100 U/mL; Gibco) and streptomycin (100 µg/mL; Gibco) at 37°C in a CO2 atmosphere.
Lentiviruses were generated using ViraPowerTM Lentiviral Packaging Mix (Invitrogen, Carlsbad, CA, USA). Lipofectamine 2000 (Invitrogen) was
Human UCB and AD MSC transplantation inhibited tumor growth
We have previously demonstrated the MSC properties of AD MSC [21]. UCB MSC expressed MSC surface antigens (see supplementary Figure 1 in the online version). MDA-MB-231 human breast cancer cells were transduced by Turbo-GFP. High expression levels of GFP were observed on the third day after selection by puromycin (data not shown). Subsequently, 2 × 106 GFP-labeled MDA-MB-231 cells were injected into the left thoracic mammary fat pad. Tumors became visible on day 7 after transplantation. Figure 1B
Discussion
Both types of stem cells investigated in the present study have been reported for cytotherapy, primarily for degenerative diseases [9, 22., 23., 24.. Although the therapeutic effect of BM MSC on cancer is controversial 25., 26., 27., 28., we have demonstrated that MSC isolated from UCB and AD inhibit tumor growth and metastasis. In addition, transplantation of both UCB and AD MSC into an early stage cancer model with no detectable clinical symptoms did not promote tumor growth or metastasis.
The
Acknowledgements
This work was supported by grants from the Seoul R&BD program (10548) and the Korean Science & Engineering Foundation (M10641450002-06N4145-00210) and by the Korea Research Foundation (KRF-2008-005-J02903).
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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