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  • br Introduction Pancreatic ductal adenocarcinoma remains one

    2018-11-12


    Introduction Pancreatic ductal adenocarcinoma remains one of the most aggressive and devastating tumor malignancies with an overall 5-year survival rate of less than 5% (Kern et al., 2011). The only potentially curative treatment is the complete surgical resection of the tumor. Nevertheless, even after the complete tumor resection disease progression is often described. Under such circumstances identification of therapies that can target both bulk cancer cells and tumor initiating cells is important in improving pancreatic cancer treatment. Recent work in pancreatic cancer biology has identified a distinct subpopulation of cells termed cancer stem cell (CSC) that may represent an integral part of the development and perpetuation of the tumor. Cells bearing stem cell properties from human adenocarcinoma have been defined by the expression of specific cellular markers, their self-renewal capacity, differentiation ability and in vivo tumorigenicity. In pancreatic cancer the subpopulations of CD44+/CD24+/ESA+ (Bednar and Simeone, 2009; Li et al., 2007, 2009); CD133+ (Hermann et al., 2007; Lonardo et al., 2011) or ALDH1+ (Rasheed et al., 2010) have been identified to fulfill all these criteria. Emerging evidences indicate that pancreatic cancer stem cells are resistant to chemotherapy and radiation suggesting that such cells may be the source of the virtual relapse of pancreatic cancer (Balic et al., 2012). Therapeutic modalities leading to the elimination of CSC are an opportunity for the effective treatment of pancreatic cancer. Oncolytic adenoviruses are very promising anticancer agents. They are engineered to specifically target, replicate in and destroy cancer cells (Aghi and Martuza, 2005; Fillat et al., 2010; Friedman et al., 2012; Short and Curiel, 2009). Oncolytic adenoviruses targeting the abnormal Rb/p16 pathway have been shown to be able to kill lipid metabolism pathway and breast cancer initiating cells (Eriksson et al., 2007; Jiang et al., 2008). Furthermore, oncolytic adenoviruses driven by the tissue-specific promoters multidrug resistance (mdr) and cyclo-oxygenase 2 (Cox-2) have been shown to be active in breast cancer initiating cells (Bauerschmitz et al., 2008). Recent studies in small cell lung cancer identified cells with stem-like properties being positive for uPAR gene expression (Gutova et al., 2007; Qiu et al., 2012). As we have previously shown uPAR-controlled adenoviruses are highly active in pancreatic cancer cell lines and exert strong antitumor and anti-metastatic effects in xenografts (Huch et al., 2009). In the current study we sought to explore the ability of uPAR controlled oncolytic adenoviruses to act against pancreatic CSC (PCSC). We used two primary patient xenograft models to characterize pancreatic cancer stem cells and determined the effects of AduPARE1A on PCSC cells and compared to those of gemcitabine, the most common chemotherapeutic agent used in pancreatic cancer treatment. We found that PCSC are susceptible to adenoviral transduction and are sensitive to adenovirus mediated cell death by AduPARE1A oncolytic adenovirus. In vivo treatment with a single AduPARE1A viral administration triggered significant reduction in tumor progression. In contrast to gemcitabine treatment, AduPARE1A did not increase the PCSC population. Thus, our results show that AduPARE1A lipid metabolism pathway shows efficacy in suppressing pancreatic cancer stem cells and could be a beneficial therapy to treat pancreatic cancer patients.
    Materials and methods
    Results
    Discussion In agreement with previous observations we demonstrate an enrichment in the CD133 population by gemcitabine treatment, but not in the CD24, CD44, and ESA positive-cells, suggesting that cancer stem cell chemoresistance, at least with gemcitabine, might differentially affect the PCSC repertoire (Mueller et al., 2009; Venkatesha et al., 2012). Gemcitabine treatment also increased the number of neoplastic sphere-forming cells and the size of the tumorspheres. To validate the tumorigenic potential of tumorspheres we demonstrate that the tumorspheres injected directly into the mouse pancreatic tail result in tumor formation that histologically resemble the morphology of an early passage patient derived xenograft. These results support that tumorsphere derived from CP15 and CP13 tumors retain the features of tumor initiating cells in the pancreatic niche. All together, these suggest that gemcitabine treatment enriches in neoplastic cells with features of PCSC, in both CP15 and CP13 tumors.