? ? We propose to evaluate the ability of bone marrow mesenchymal stem cells (MSCs) to act as vehicles for local delivery of chemopreventives in transgenic mice that develop mammary cancer. Recently, efforts to use adult-derived stem cells to deliver chemotherapeutic agents to tumor sites have shown great promise in primary and metastatic tumor models, and we propose to extend this concept to include the delivery of chemopreventative compounds. It remains untested whether a multiple drug delivery system applied in a prevention setting would inhibit mammary tumor development. We therefore propose to measure the ability of ACE-MSC expressing multiple chemopreventive agents to inhibit cancer progression, both in vitro and in vivo, using a previously characterized mouse model of breast cancer. For this purpose, we will utilize transgenic mice engineered to overexpress the growth factor, TGFa (transforming growth factor alpha), in the mammary gland. For this application we propose to engineer ACE-MSCs to express two anti-proliferative/proapoptotic molecules, interferon beta (IFN?) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). To accomplish the goals of this application we will pursue the following two specific aims: 1) Determine the level of chemopreventive factors expressed from ACE-MSCs that is required to maximally inhibit breast tumor cell growth in vitro and, 2) Determine whether selected ACE-MSCs expressing this pair of anticancer factors can inhibit TGFa tumorigenesis. Goal: Test the ability of engineered ACE-MSCs to inhibit TGFa tumorigenesis. Hypothesis: ACE-MSC engineered to locally deliver interferon (IFNb) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) will inhibit cancer progression in mice overexpressing TGFa.
Aim 1. Verify impairment of cell growth and inducement of apoptosis in vitro in mammary cancer cells co-cultured with ACE-MSC expressing IFNb and TRAIL.
Aim 2. Measure the effect of administering ACE-MSC-IFN-TRAIL-td-Tomato versus ACE-MSC-td-Tomato marker gene control to NRL-TGFa mice on tumor latency, incidence, multiplicity and mammary cell turnover dynamics. ? ? ?
