Abstract
Pancreatic cancer usually has a poor prognosis, and no gene therapy has yet been developed that is effective to treat it. Since a unique characteristic of bone marrow-derived mesenchymal stem cells (MSCs) is that they migrate to tumor tissues, we wanted to determine whether MSCs could serve as a vehicle of gene therapy for targeting pancreatic cancer. First, we successfully extracted MSCs from SD rats. Next, MSCs were efficiently transduced with NK4, an antagonist of hepatocyte growth factor (HGF) which comprising the N-terminal and the subsequent four kringle domains of HGF, by an adenoviral vector. Then, we confirmed that rat MSCs preferentially migrate to pancreatic cancer cells. Last, MSCs expressing NK4 (NK4-MSCs) strongly inhibited proliferation and migration of the pancreatic cancer cell line SW1990 after co-culture. These results indicate that MSCs can serve as a vehicle of gene therapy for targeting pancreatic cancer.
Highlights
Pancreatic cancer is a very aggressive malignant tumor, and has an extremely poor prognosis [1,2].Since most pancreatic cancers are diagnosed late and often have invaded surrounding tissues, local treatment such as surgery of advanced pancreatic cancer is not a viable option
We introduced the NK4 gene into mesenchymal stem cells (MSCs) by using an adenoviral vector and investigated it affects on the proliferation, apoptosis and migration of pancreatic cancer cells
MSCs were isolated from murine bone marrow cells after passage three or four generations, when they displayed a large and polygonal morphology (Figure 1A)
Summary
Pancreatic cancer is a very aggressive malignant tumor, and has an extremely poor prognosis [1,2].Since most pancreatic cancers are diagnosed late and often have invaded surrounding tissues, local treatment such as surgery of advanced pancreatic cancer is not a viable option. Recent advances in our understanding of the genetics and epigenetics of pancreatic cancer have revealed that alterations in several tumor-related genes, including K-ras, p53, matrix metalloproteinases (MMP), hepatocyte growth factor (HGF), and epidermal growth factor receptor [4,5,6], may underlie the aggressiveness of this neoplasm [7]. Recent advances in studying MSC biology have shown that this cell population exhibits some properties that suggest the feasibility of their use as a cellular vehicle: a relative simple isolation method, the ability to be cultured in vitro and to expand to quantities required for therapy, the ability for ex vivo transduction with viral vectors, plasticity, the potential to differentiate under exogenous stimuli, high metabolic activity, an efficient machinery to express therapeutic proteins and the ability to be delivered systemically or locally [11]
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