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 Blood, 28 May 2009, Vol. 113, No. 22, pp. 5423-5433.
Prepublished online as a Blood First Edition Paper on March 27, 2009; DOI 10.1182/blood-2008-10-187237.

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GENE THERAPY

Toward a stem cell gene therapy for breast cancer

ZongYi Li1, Ying Liu1, Sebastian Tuve1, Ye Xun2, Xiaolong Fan3, Liang Min2, Qinghua Feng4, Nancy Kiviat4, Hans-Peter Kiem5,6, Mary Leonora Disis5, and André Lieber1,4

1 Department of Medicine, Division of Medical Genetics, University of Washington, Seattle; 2 Shanghai Sunway Biotech, Pudong, China; 3 The Rausing Lab and Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Lund, Sweden; Departments of 4 Pathology and 5 Medicine, Division of Oncology, University of Washington, Seattle; and 6 Fred Hutchinson Cancer Research Center, Seattle, WA

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 uses the pathophysiologic 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 antitumor immune cells to their target tumor cells. Furthermore, we have shown 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 therapy and immunotherapy.


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