Mesenchymal stem cells selectively engraft into tumor stroma and produce potent antitumor proteins in situ

Abstract

3025 Background: The formation of stroma is essential for tumor growth and involves complex interactions between malignant cells and non-tumor stromal cells. We have previously demonstrated that IV injected bone marrow derived mesenchymal stem cells (MSC) integrate into solid tumors as stromal elements (Cancer Res 62:3603, 2002; JNCI 96:1593, 2004). Methods: MSC were labeled by a fiber modified Ad vector expressing firefly luciferase (AdLux-F/RGD), injected into normal or tumor-bearing SCID mice, and biodistributed MSC-Lux were imaged utilizing the Xenogen IVIS system. Results: After IP injection, no hMSC-LUX were detected in normal animals after 7 days, while strong punctate regions of LUX-activity were observed in ovarian tumors. Tumor cells transduced with renilla luciferase constructs co- localized with firefly luciferase MSC. Next, we examined whether hMSC-producing interferon-beta (IFNβ-MSC) could inhibit the growth of metastatic tumors in the lungs of SCID mice. When injected IV (4 doses of 106 MSC/week) into SCID mice with pulmonary metastases of carcinomas or melanomas, tumor growth was significantly inhibited as compared with untreated or vector-control MSC controls (p= 0.007). IV injected IFNb-MSC prolonged the survival of mice bearing metastatic breast carcinomas (p=0.001). In an orthotopic, chemoresistant breast cancer model in syngeneic immunocompetent mice, MSC producing IFN-β completely abrograted tumor growth. Localized low-dose XRT to tumors significantly increased the number of tumor-resident MSC. Conclusions: The data suggest that systemically administered gene-modified MSC selectively engraft into the tumor microenvironment and remain resident as part of the tumor architecture. MSC-expressing IFN-β inhibit the growth of melanomas, gliomas, metastatic breast and ovarian cancers in vivo and prolong the survival of mice bearing established tumors. Clinical trials are in preparation. No significant financial relationships to disclose.