Purpose: Neuropilin (Np)-1 and -2 are coreceptors for vascular endothelial growth factor (VEGF). This study was designed to assess their role in pancreatic ductal adenocarcinoma (PDAC).Experimental Design: We assessed Np-1 and Np-2 expression by real-time quantitative PCR in relation to the expression of VEGF ligands and receptors in pancreatic cancer cell lines and tissues.Results: ASPC-1, CAPAN-1, and PANC-1 pancreatic cancer cells and tumor-derived, laser-captured pancreatic cancer cells exhibited higher Np-1 and Np-2 mRNA levels than VEGF receptor-1, -2, or -3 mRNA levels. Transfection of Np-1 and Np-2 cDNAs in COS-7 cells, and treatment with tunicamycin revealed that both proteins were glycosylated. Both proteins were expressed in pancreatic cancer cell lines, in the PDAC samples, and in acinar cells adjacent to the cancer cells. The normal pancreas was devoid of Np-1 immunoreactivity, whereas Np-2 immunoreactivity was present in the endocrine islets and in some acinar cells, but not in ductal cells.Conclusions: The aberrant localization of Np-1 and Np-2 in the cancer cells in PDAC suggests that in addition to exerting proangiogenic effects, these coreceptors may contribute to novel autocrine-paracrine interactions in this malignancy.
Pancreatic ductal adenocarcinomas ( PDACs ) overexpress various cell -surface tyrosine kinase receptors, including the type I highaffinity fibroblast growth factor receptor ( FGFR -1 ). The purpose of this study was to determine whether FGFR -targeted gene therapy is feasible in this disorder. Accordingly, the effects of a conjugate consisting of fibroblast growth factor ( FGF ) -2 linked to a Fab 0 fragment against the adenovirus knob region were evaluated in human pancreatic cancer cell lines treated with an adenoviral vector containing the herpes simplex virus thymidine kinase ( AdTK ) gene. An adenoviral vector containing the firefly luciferase reporter gene ( AdLuc ) served to assess infection efficiency, and was initially tested in L6 rat myoblasts. In parental L6 cells that express exceedingly low levels of high -affinity FGFRs, transduction with AdLuc was enhanced 7 -to 10 -fold with the FGF2 -Fab 0 conjugate, whereas in L6 cells transfected to express FGFR -1, it was enhanced 39 -to 52 -fold. The pancreatic cancer cell lines expressed variable levels of the four high -affinity FGF receptors, and exhibited 2 -to 34 -fold increases in gene transduction in the presence of the FGF2 -Fab 0 conjugate. In the absence of FGF2 -Fab 0 there was no correlation between surface binding of FGF2 and AdLuc transduction efficiency, whereas in the presence of FGF2 -Fab 0 , enhanced AdLuc transduction efficiency correlated with greater surface binding of FGF2. In the absence of AdTK, all the cell lines were insensitive to ganciclovir, whereas after AdTK transduction, only ASPC -1 and PANC -1 cells were resistant to ganciclovir even in the presence of FGF2 -Fab 0 . Ganciclovir -mediated inhibition was dependent on the conjugate in CAPAN -1 and COLO -357 cells, but was independent of the conjugate in T3M4 and MIA -PaCa -2 cells. Real -time quantitative PCR of laser -captured cancer cells revealed high levels of various FGFR mRNA species in six of seven PDAC tumor samples. These findings indicate that transduction efficiency with FGF2 -Fab 0 in pancreatic cancer cells is independent of native adenoviral transduction efficiency and is greatest in cells that exhibit concomitant expression of various highaffinity FGFRs. In view of the overexpression of high -affinity FGFRs in the cancer cells in PDAC, our findings also suggest that the combined use of AdTK, ganciclovir, and FGF2 -Fab 0 may ultimately be a promising therapeutic approach in a subgroup of patients with PDAC.
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