Mesenchymal Stem Cells

Curing Cancer with Fat

Glioblastoma (GB) is the most common and devastating primary brain tumor, with a median survival rate of only 14 months despite current best treatment practices. One promising approach to the treatment of GB involves the use of mesenchymal stem cells (MSCs), which have been found to have the unique capability of migrating preferentially to cancer cells. Mesenchymal stem cells are multipotent stem cells, which means that they are able to differentiate into a variety of cell types including osteoblasts (bone cells), chondrocytes (cartilage cells), and adipocytes (fat cells). MSCs are normally found in various sites throughout the body, including bone marrow and adipose tissue. At the Quinones lab, we have been able to successfully harvest and grow human MSCs from adipose tissue. Our goal is to target brain tumors using these cells. In order to be able to find the hAMSCs once we inject them into a living organism, we have modified them to express luciferase, an enzyme that promotes a reaction which results in the emission of light (bioluminescence). In this manner, we have been able to demonstrate in vivo in mice that these luciferase-expressing hAMSCs migrate specifically to glioma cells.

(A)In vivo localization of luciferase-expressing hAMSCs in a mouse harboring intracranial GB, as demonstrated by bioluminescence being emitted from the mouse’s head. (B) Coronal section of brain from (A), confirming that the bioluminescence is indeed being emitted from the mouse’s brain. (C) No hAMSCs are found in a mouse that was not injected with experimental intracranial GB, as expected. (D) Coronal section of brain from (C), demonstrating no significant bioluminescence. Compare these images to the considerable amount of bioluminescence emitted from a brain harboring both GB and hAMSCs (B).

Based on these results demonstrating the specific migration of hAMSCs to gliomas, we at the Quinones lab have explored ways of using hAMSCs as gene delivery vehicles to human GB cells. One of the agents that we are currently using is Bone Morphogenic Protein 4 (BMP4), which has been demonstrated to reduce glioma stem cell growth and to induce differentiation of these cancer-promoting cells. Differentiation of glioma stem cells would potentially decrease or even eliminate their cancerous potential, possibly stopping cancer progression. Studies have shown that BMP4 can result in a decrease in brain tumor size and increased survival in experimental animals. We have genetically modified our hAMSCs to secrete BMP4 and are currently testing its effect on both glioma cells and on hAMSCs. Importantly, we have demonstrated in vitro that BMP4 does not result in the differentiation of hAMSCs, which is critical if hAMSCs are to be used as delivery vehicles for this agent.

(A-C) hAMSCs grown in osteogenic, chondrogenic, and adipogenic differentiation media, respectively. As mentioned previously, hAMSCs are multipotent and are therefore able to differentiate into a variety of cell types. These histology pictures demonstrate that hAMSCs can take on the characteristics of bone cells, cartilage cells, and fat cells when grown under the appropriate conditions. (D) hAMSCs grown in media with BMP4. These cells have maintained their original morphology and show no signs of differentiation. This experiment demonstrates the important principle that BMP4 does not cause differentiation of hAMSCs.

Ongoing experiments are evaluating the effect of BMP4 on the growth and differentiation of glioma cells both in vitro and in vivo.

Our overall goal at the Quinones lab is to demonstrate whether human adipose tissue derived mesenchymal stem cells can be utilized as delivery vehicles and provide a treatment that is safe and effective for patients with primary brain cancer. If successful, this approach to treatment could be clinically translated to other types of cancer.