Gene therapy for pancreatic carcinoma: Local and distant antitumor effectsafter somatostatin receptor sst2 gene transfer

Human pancreatic adenocarcinomas lose the ability to express sst2, the soma tostatin receptor, which mediates the antiproliferative effect of somatosta tin. Reintroducing sst2 into human pancreatic cancer cells by stable expres sion evokes an autocrine negative feedback loop leading to a constitutive a ctivation of the sst2 gene and an inhibition of cell proliferation and tumo rigenicity. Irt vivo studies have been conducted in athymic mice to investi gate the antitumor bystander effects resulting from the transfer of the sst 2 gene into human pancreatic cancer cell line BxPC-3. In mixing experiments , a local bystander effect was observed: mixed tumors containing a ratio of sst2-expressing cells to control cells of 25:75, 50:50, and 75:25 grew wit h a time delay of 31, 44, and 50 days, respectively, when compared with con trol tumors derived from control cells. Tumors containing 100% sst2-express ing cells remained quiescent for up to 80 days. A significant increase in a poptosis and a decrease in the Ki67 index were detected in mixed and sst2 t umor when compared with control tumors. In combined experiments, mice were separately xenografted with control cells on one flank and with sst2-expres sing cells on the other flank. A distant antitumor effect was induced: grow th of control tumors was delayed by 33 days, the Ki67 index decreased signi ficantly, and apoptosis increased when compared with control tumors that gr ew alone. The distant bystander effect may be explained in part by a signif icant increase in serum somatostatin-like immunoreactivity levels resulting from the autocrine feedback loop produced by sst2-expressing cells and ind ucing an upregulation of the type 1 somatostatin receptor, sstl, which also mediates the antiproliferative effect of somatostatin. In conclusion, the local and distant antitumor bystander effects obtained in this experimental model suggest that sst2 gene transfer may represent a new therapy for panc reatic cancer.