Engineered MSC as Prodrug Activators in Antitumor Treatment

Introduction
Tumor microenvironment substantially affects tumor progression and tumor cell behavior. Mesenchymal stromal cells (MSCs) as one of its component significantly contribute to complex cross-talk between heterogeneous malignant cells and surrounding stroma. MSCs represent a population of cells with multilineage differentiation capability, which secrete wide array of chemokines and growth factors. The MSCs are defined by their ability to differentiate into osteoblasts, adipocytes and chondrocytes, but they can also differentiate into other cell types; pericytes; cancer stem cell niche cells; and tumor associated fibroblasts in the tumor microenvironment.

Materials/methods
We have engineered the human MSCs to produce pro-drug activating therapeutic cells. We have evaluated antitumor and antimetastatic effect of therapeutic cell in combination with respective prodrug in many different human tumor xenograft models on immunodeficient mice. Tumor cells were xenografted subcutaneously, intraperitoneally or systemically, and the treatment efficiency was tested both in local and systemic setting.

Results and conclusions
The therapeutic regimen CDMSC/ 5FC (cytosine deaminase/5- fluorocytosine) very efficiently controls tumor growth and can achieve long-term curative effect. There are several critical factors which determine the efficiency: intrinsic properties of therapeutic cells, ratio of therapeutic to target cells, intrinsic tumor cell properties, timing of the prodrug administration and initial tumor burden. Engineered MSC have shown therapeutic antitumorigenic potential in several hard-to treat tumor types including metastatic melanoma, triple-negative breast cancer, glioblastoma and metastatic ovarian cancer.