Anti-Angiogenesis Therapy Based on the Bone Marrow- Derived Stromal Cells Genetically Engineered to Express Sflt-1 in Mouse Tumor Model - Genetic Engineering: Recent Developments in Applications - page 218

be derived from circulating BMSCs after lung injury, and a large portion of lung
damage could be repaired by forming entire alveoli. Meantime, these adult stem
cells could be effectively used to deliver therapeutic gene to lung while retaining
the ability to differentiate into lung cells [21]. Darwin J Prockpop demonstrated
that injured tissue create a milieu that enhances homing, proliferation and dif-
ferentiation of BMSCs [7]. It has been found that there are high concentrations
of fibroblast growth factor, transforming growth factor β , platelet-derived growth
factor, and epidermal growth factor in injured tissue and in the microenviron-
ment of tumor, in which these facters are needed in the process of homing, pro-
liferation and differentiation of BMSCs [22,23]. Therefore, we hypothesize that
tissue rebuilding in tumorigenesis, wound healing and fetal development entitles
the microenvironments the capability of attracting the systemically administered
BMSCs.
Suppression of VEGF by sFlt-1 adenoviruses administered systemically was
proved to contribute to inhibition of tumor growth [12]. In our study, we em-
ployed BMSCs as a gene vehicle loaded with sflt-1 recombinant adenovirus for
tumor therapy, and found that the BMSCs expressing sFlt-1 preferentially homed
to and survived in the tumor loci where its strong anti-angiogenesis and anti-me-
tastasis effect has been observed. We also observed that BMSCs expressing IL-12
induced a stronger antitumor effect than administration with IL-12 adenoviruses
alone (data not shown). This vehicle may be useful and effective in tumor gene
therapy for four reasons. Firstly, the BMSCs after ex vivo administration may
survive for hundreds of days, which enable them to offer a relatively long effect
for chronic diseases [24]. Secondly, the capacity of BMSCs homing to tumor
sites and protecting viruses against the immune surveillance would strengthen
the effect of recombinant adenovirus gene therapy, which is unsatisfactory when
systemically administered alone because of nonspecific distribution and serious
hepatotoxicity [11,25]. Thirdly, the lower immunogenicity, which is the result of
low expression of MHC and costimulatory molecules, enables BMSCs advanta-
geous for allogeneic or xenogeneic applications [26]. Last, BMSCs are easy to be
expanded in vitro and to be genetically modified, which means convenience and
cost effectiveness in the future preclinical or clinical applications.
However, in the experiments performed by our lab (data not shown) and oth-
ers, the naive BMSCs seemed to promote growth of tumors. On the other hand,
Aarif reported that mesenchymal stem cells injected intravenously homed to neo-
plasm and potently inhibited tumor growth in Kaposi sarcoma model [27]. The
relationship between the stem cells and the cancer cells may depend on the mi-
croenvironment which is created by these two kinds of cells and others [28-31].
Besides, the possible transformation and the consequent tumorigenesis of BMSCs
themselves remains to be clarified. Jakub and his colleagues reported that bone