Stromal cells provide structural support for malignant cells, modulate the tumor microenvironment, and influence phenotypic behavior as well as the aggressiveness of the malignancy. In response, the tumor provides growth factors, cytokines, and cellular signals that continually initiate new stromal reactions and recruit new cells into the microenvironment to further support tumor growth. It is not fully understood how stroma influences the neoplastic cells, but there is evidence for involvement of soluble paracrine factors, extracellular matrix formation, and direct cell-to-cell interaction. Therefore, it might be possible to manipulate the tissue stroma cells and thereby interfere with the stroma-tumor interactions for therapeutic benefit. The prerequisite for this approach is that stromal cells be accessible to therapeutic manipulation. We have previously demonstrated that bone marrow-derived mesenchymal stem cells (MSC) integrate into solid tumors as stromal elements and contribute to the development of tumors. Importantly, MSC are precursors of structural and supportive tissues and have been implicated in the repair of damaged tissues and in wound healing. Of interest is that the tumor microenvironment appears to exhibit cytokine profiles and cellular signals similar to those characteristics of wounded or damaged tissues. Given this, we hypothesized that MSC would home to and selectively proliferate in the tumor microenvironment and that gene-modified MSC could be used as cellular vehicles to deliver gene products into tumors. Preliminary data suggests that MSC home to and participate in tumor stroma formation in both subcutaneous and metastatic tumor xenografts in mice. Additionally, once homed to tumor beds, MSC proliferate rapidly and integrate. Migration assays have identified apoptotic cells as a potent attractant of MSC in vitro. Our proposed studies aim at understanding the factors that influence MSC homing and selective proliferation in the tumor microenvironment. Additionally, our goals focus on optimizing the cellular delivery of therapeutic genes into the stroma of metastatic and subcutaneous tumor xenografts.
Specific Aim 1 : To determine the biodistribution and selective proliferation of intravenously administered MSC in the stromal microenvironment, to identify cellular mediators that may enhance the selective proliferation and engraftment of MSC, and determine the phenotype and fate of MSC that have engrafted and proliferated in the tumor microenvironment.
Specific Aim 2 : To investigate the tumor targeting ability and normal distribution of MSC in vivo utilizing noninvasive imaging techniques.
Specific Aim 3 : To determine which of several viral gene delivery systems + MSC results in optimal tumor growth inhibition and cell killing. Additionally, to determine the effect of MSC + vector specifically targeted to breast cancer or metastatic melanoma in vivo, on the growth of tumors in immunocompetent and immunodeficient mice.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA109451-05
Application #
7584056
Study Section
Special Emphasis Panel (ZRG1-DT (01))
Program Officer
Fu, Yali
Project Start
2005-05-18
Project End
2011-02-28
Budget Start
2009-03-01
Budget End
2011-02-28
Support Year
5
Fiscal Year
2009
Total Cost
$183,474
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Dembinski, Jennifer L; Wilson, Shanna M; Spaeth, Erika L et al. (2013) Tumor stroma engraftment of gene-modified mesenchymal stem cells as anti-tumor therapy against ovarian cancer. Cytotherapy 15:20-32
Spaeth, Erika L; Labaff, Adam M; Toole, Bryan P et al. (2013) Mesenchymal CD44 expression contributes to the acquisition of an activated fibroblast phenotype via TWIST activation in the tumor microenvironment. Cancer Res 73:5347-59
Spaeth, Erika L; Booth, Christopher M; Marini, Frank C (2013) Quantitative multispectral analysis following fluorescent tissue transplant for visualization of cell origins, types, and interactions. J Vis Exp :e50385
Klopp, Ann H; Zhang, Yan; Solley, Travis et al. (2012) Omental adipose tissue-derived stromal cells promote vascularization and growth of endometrial tumors. Clin Cancer Res 18:771-82
Spaeth, Erika L; Kidd, Shannon; Marini, Frank C (2012) Tracking inflammation-induced mobilization of mesenchymal stem cells. Methods Mol Biol 904:173-90
Kidd, Shannon; Spaeth, Erika; Watson, Keri et al. (2012) Origins of the tumor microenvironment: quantitative assessment of adipose-derived and bone marrow-derived stroma. PLoS One 7:e30563
Barese, Cecilia N; Krouse, Allen E; Metzger, Mark E et al. (2012) Thymidine kinase suicide gene-mediated ganciclovir ablation of autologous gene-modified rhesus hematopoiesis. Mol Ther 20:1932-43
Spaeth, Erika L; Marini, Frank C (2011) Dissecting mesenchymal stem cell movement: migration assays for tracing and deducing cell migration. Methods Mol Biol 750:241-59
Klopp, Ann H; Gupta, Anshul; Spaeth, Erika et al. (2011) Concise review: Dissecting a discrepancy in the literature: do mesenchymal stem cells support or suppress tumor growth? Stem Cells 29:11-9
Kang, Seok-Gu; Shinojima, Naoki; Hossain, Anwar et al. (2010) Isolation and perivascular localization of mesenchymal stem cells from mouse brain. Neurosurgery 67:711-20

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