Mesenchymal Stem Cell-Based Therapy for Treatment of Bone Metastases in Breast Cancer
Abstract
Breast cancer is the most common female malignancy and the second leading cause of cancer-related death among women in the United States. More than 70% of late-stage breast cancer patients suffer from bone metastasis, a fatal complication that is often accompanied by severe bone pain, fracture, and potentially lethal complications such as hypercalcemia. Although current treatment strategies for bone metastases can slow metastatic tumor progression and control associated symptoms, bone metastases remain largely incurable. In this study, we will develop a mesenchymal stem cell (MSC)-based targeted therapy to treat pre-existing bone metastases in mouse models. Such therapeutics are designed based on the ability of MSCs to home towards “tumor wounds.” MSCs are multipotent tissue stem cells that play crucial roles in the process of wound healing, and they naturally home to wound sites. As tumors are effectively wounds that do not heal, it is not surprising that MSCs promptly infiltrate developing tumors. Given their wound-homing behavior, MSCs are being used as vehicles to deliver tumor-killing cytokines, such as IFNalpha and IFNbeta, for tumor-targeting therapy in various cancer models. In spite of their potential usefulness, our recent studies indicate that exogenously implanted MSCs could be rapidly educated by the tumor microenvironment to acquire tumor-promoting abilities when inoculated at middle to late stages of tumor progression. This potentially impairs MSC-delivered therapeutic effects in treating advanced stages of breast cancer. Therefore, considering the dual roles of MSCs as vehicles to deliver tumor-killing factors and promoters of tumor growth, in this study, we will genetically ablate two of the key tumor-promoting genes in bone marrow MSCs in order to improve their effectiveness in treating metastatic breast tumors in the bone. We will first demonstrate the principles of our approach using mouse models of breast cancer to bone metastasis, and then we will adapt this system to using human breast cancer cells and human MSCs in a mouse model that possesses a human immune system. This adaptation to a “humanized” mouse model will allow us to define the interactions between the human MSCs and human immune cells that will support translation of our findings to the patient treatment in the clinic. By improving the effectiveness with which MSCs are able to serve as a vehicle to deliver anti-tumor agents to the sites of bone metastases, our findings will establish an avenue for inhibiting the growth of established breast tumor metastases in the bone. This avenue is anticipated to improve quality of life in bone metastasis patients and holds the potential to reduce mortality in breast cancer patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810013
Entities
People
- Guangwen Ren
Organizations
- Jackson Laboratory
- United States Army