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    Mesenchymal Stem Cells as Cellular Delivery Vehicles for Control of Metastatic Breast Cancer

    Scientific Abstract:
    Background: Stroma formation is essential for tumor growth and involves complex interactions between a variety of cell types, including breast epithelium, stromal cells, and vascular endothelium. Stroma provides structural support for malignant cells, modulates the tumor microenvironment, and influences the phenotypic behavior of the malignancy. Stroma are thought to derive from fibroblasts localized at the site of cancer. However, we demonstrate that bone marrow derived mesenchymal stem cells (MSC) can be utilized as precursors of tumor stroma. Using the breast cancer cell lines MDA-MB-231, and 231/ADR (an adriamycin resistance 231) cell line as models, we IV injected MSC into mice bearing metastatic tumors and determined that MSC, once homed into the tumor bed, proliferate, and integrate into the tumor microenvironment. Furthermore, IV injected MSC expressing beta-interferon incorporated into the stroma of metastatic breast tumors and suppressed tumor growth. Objective/Hypothesis: We hypothesize that MSC home to, and selectively proliferate in the stroma of tumor xenografts and their metastases. MSC engineered to express therapeutic gene products such as IFNb will suppress tumor growth in vitro and in vivo. The proposed studies aim at understanding the mechanisms responsible for the MSC/tumor cell interactions in the tumor microenvironment, and to optimize the cellular delivery of therapeutic genes into the stroma of breast tumors. Specific Aims/Study Design: SA#1.0-To determine the mechanisms of MSC/tumor cell interactions in the tumor microenvironment. 1.1 To investigate the biodistribution, engraftment, selective proliferation, and fate of injected MSC in murine xenograft tumor models and in immunocompetent mice bearing 4T1 breast cancer. 1.2 To investigate in vitro and in vivo factors associated with engraftment and proliferation of MSC. 1.3 To investigate and monitor the migration and tropism of MSC using non-invasive imaging techniques, and to determine toxicities associated with MSC and their payloads SA#2.0-To investigate the use of MSC as cellular delivery vehicles for the control of tumor growth in vitro and in vivo in established metastatic and implanted xenograft models. 2.1 Optimized MSC carrying a therapeutic payload will be investigated in established breast xenograft models and immunocompetent mouse models. Potential Outcomes and Benefits of the Research: We expect that the delivery of therapeutic genes via MSC into the tumor microenvironment will provide novel tumor targeting and growth suppression of tumors and their metastases.

    Lay Abstract:
    Title: Mesenchymal Stem Cells as Cellular Delivery Vehicles for Control of Metastatic Breast Cancer. Background: Tumor progression requires the cooperation of the tissue environment, in which the supporting cells called stroma and new blood vessel cells form to make a more hospitable environment for the tumor to grow. These stromal cells provide many cellular factors that the growing tumor utilizes to survive, however the tumor itself adjusts the microenvironment in providing growth factors and cellular signals, which recruit the stromal cells. It is thought that the stroma cells originate from the surrounding tissue. We have demonstrated, however, that bone marrow derived mesenchymal stem cells (MSC) can be used as precursor cells for the growing tumor stroma. MSC are a type of stem cells found primarily in the bone marrow. MSC can differentiate into a number of cell types in response to microenviromental cues, and it is of importance that these stem cells are precursors to structural and supportive tissues and have been implicated in the repair of damaged tissues and wound healing. Therefore, MSC may constitute an ideal cellular vehicle for the delivery of therapeutic soluble proteins into these damaged areas. Of interest to us is that the tumor microenvironment appears to exhibit similar cytokine and cellular signals as those characterized in wound healing or damaged tissues, in fact data suggest that tumors behave as “wounds that do not heal”. Given this, we hypothesized that we could take advantage of the ability of MSC to home to and selectively proliferate in the wounding microenvironment (such as a tumor) and that gene modified MSC could be used as cellular vehicles to deliver gene products into these tumors. We have been investigating the ability of MSC to contribute to the formation of stroma in developing tumors and determined that after IV injection, MSC home to, and selectively proliferate in the stroma of tumors. Additionally, MSC engineered to secrete tumor growth inhibitory cytokines, inhibit the development and progression of these growing tumors both in subcutaneous and metastatic models. Purpose and Rationale for the Study: Our proposed studies endeavor at developing targeted treatment for breast cancer and on optimizing the cellular delivery of therapeutic genes into the stroma of breast tumors. Additionally, our goals aim at understanding basic mechanisms of MSC homing, and selective proliferation in the tumors. We expect to bring this concept into clinical trials for the treatment of women with breast cancer.