Submitted October 31, 2008
Accepted March 9, 2009
Towards a stem cell gene therapy for breast cancer
ZongYi Li, Ying Liu, Sebastian Tuve, Ye Xun, Xiaolong Fan, Liang Min, Qinghua Feng, Nancy Kiviat, Hans-Peter Kiem, Mary Leonora Disis, and Andre Lieber*
University of Washington, Department of Medicine, Division of Medical Genetics, Seattle, WA, United States
Shanghai Sunway Biotech, Shanghai, China
The Rausing Lab and Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Lund, Sweden
University of Washington, Department of Pathology, Seattle, WA, United States
Fred Hutchinson Cancer Research Center, Seattle, WA, United States
University of Washington, Department of Medicine, Division of Oncology, Seattle, WA, United States
* Corresponding author; email: lieber00{at}u.washington.edu.
Current approaches for treatment of late-stage breast cancer rarely result in a long-term cure. In part this is due to tumor stroma that prevents access of systemically or intratumorally applied therapeutics. We propose a stem cell gene therapy approach for controlled tumor stroma degradation that utilizes the patho-physiological process of recruitment of inflammatory cells into the tumor. This approach involves genetic modification of hematopoietic stem cells (HSCs) and their subsequent transplantation into tumor-bearing mice. We show that inducible, intratumoral expression of relaxin (Rlx) either by transplanting tumor cells that contained the Rlx gene or by transplantation of mouse HSCs transduced with an Rlx-expressing lentivirus vector delays tumor-growth in a mouse model of breast cancer. The antitumor effect of Rlx was mediated through degradation of tumor stroma, which provided increased access of infiltrating anti-tumor immune cells to their target tumor cells. Furthermore, we demonstrated in a human/mouse chimeric model that genetically modified HSCs expressing a transgene can access the tumor site. Our findings are relevant for cancer gene- and immunotherapy.
