Abstract
Endostatin is an important endogenous inhibitor of neovascularization that has been widely used in anti-angiogenesis therapy for the treatment of cancer. However, its clinical application is largely hampered by its low efficacy. Human placenta-derived mesenchymal stem cells (hpMSCs) are particularly attractive cells for clinical use in cell-based therapies. In the present study, hpMSCs were isolated and characterized. We then evaluated the tumor targeting properties and antitumor effects of hpMSCs as gene delivery vehicles for ovarian cancer therapy. We efficiently engineered hpMSCs to deliver endostatin via adenoviral transduction mediated by Lipofectamine 2000. The tropism capacity of the engineered hpMSCs toward tumor cells was then confirmed by in vitro migration assays and in vivo by intraperitoneal injection of hpMSCs into nude mice. The hpMSCs expressing the human endostatin gene demonstrated preferential homing to the tumor site and significantly decreased the tumor volume without apparent systemic toxic effects. These observations were associated with significantly decreased blood sprouts and tumor cell proliferation as well as a dramatically increased tumor apoptosis index. These results suggested that hpMSCs are potentially an effective delivery vehicle for therapeutic genes for the treatment of ovarian cancer.
Highlights
Ovarian cancer is one of the most common gynecologic malignancies, and it remains the fourth leading cause of cancerrelated death among women [1]
Multiple lines of evidence have demonstrated that the growth and progression of most solid cancers are angiogenesis dependent and tumor angiogenesis is highly orchestrated by a balance between positive and negative regulators [3,4]
For osteogenic and adipogenic differentiation, Human placenta-derived mesenchymal stem cells (hpMSCs) were cultured at 56104 cells per well of 12-well plates in OsteoDiff or Adipodiff induction medium (Miltenyi Biotec GmBH) for 3 weeks, Alizarin Red S and Oil-Red-O were utilized to visualize calcium deposits and fat droplets separately
Summary
Ovarian cancer is one of the most common gynecologic malignancies, and it remains the fourth leading cause of cancerrelated death among women [1]. Despite the many advances in surgical management, chemotherapy, and radiation therapy over the past decades, the prognosis for patients with advanced ovarian cancer remains poor, with a 5-year survival rate of less than 30% for patients with distant metastases. This low survival rate is primarily due to eventual tumor recurrence and emergence of drug-resistance [2]. The requirement for a frequent dosage regimen and high doses of expensive purified protein hampers its future clinical application To overcome these shortcomings, the application of gene therapy has been explored. New and more effective therapeutic tools are needed that target endostatin expression to the tumor cells
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