Human stem cells in cancer gene therapy

Adult mesenchymal stem cells (MSC) are present in every human body. They help repair damaged tissue and organs because they renew used cells. But they have also been found in the mass of normal cells that mix together with cancer cells to make up a solid tumor. Normal mesenchymal stem cells recognize tumor as a damaged organ and migrate to it. This fact we used to test the idea whether such stem cells after being modified with suicide gene might be utilized as a “vehicle” for cancer treatment. Mesenchymal cells can be isolated from various sources, including bone marrow and fat tissue. For the isolation of MSC we use fat material left from liposuction. After extracting the stem cells from human fat tissue the cells are expanded in tissue culture for therapeutic reason and recombinant non infectious retrovirus is used to insert the gene cytosine deaminase into the cell. This gene can convert the non toxic 5-fluorocytosine (5-FC) to 5-fluorouracil (5-FU), a potent chemotherapeutic drug inside the stem cells. The local cancer chemotherapy is further increased by highly effective, lethal bystander effect. The advantage of this therapy modality is that there is no toxic side effect of the standard-of-care chemotherapy agent, 5-fluorouracil in normal cells, because the 5-FU production is just at the site of the tumor itself. In our previous experiments on immunodeficient animals engrafted with human colon cancer, we first injected the engineered mesenchymal stem cells, and then 5-FC. We found tumor growth was inhibited and none of the mice exhibited any signs of toxic side effects. This work was recently published (Kucerova L, Altanerova V, Matuskova M, Tyciakova S, Altaner C: Adipose Tissue Derived Human Mesenchymal Stem Cells Mediated Prodrug Cancer Gene Therapy. Cancer Res 2007; 67:6304-6313). We continue in our studies trying to find whether our stem cell based cancer gene therapy is capable to be used not only for treatment of primary tumors but also for small metastases. For these experiments we used human breast cancer cells which are able to induce metastases in nude mice. We also are testing whether this approach is effective against other human tumors. The preliminary experiments are showing that this system is capable to kill other human tumors and surprisingly also tumors, which are resistant to 5-fluorouracil. These results show that such therapy might attack also locally tumor cells not only because of production of toxic 5-fluoruracil from nontoxic 5-fluorocytosine but also by some other tumor killing effect.