Gene Therapy for Pancreatic Carcinoma: Local and Distant Antitumor Effects after Somatostatin Receptor sst2 Gene Transfer

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Abstract
Human pancreatic adenocarcinomas lose the ability to express sst2, the somatostatin receptor, which mediates the antiproliferative effect of somatostatin. Reintroducing sst2 into human pancreatic cancer cells by stable expression evokes an autocrine negative feedback loop leading to a constitutive activation of the sst2 gene and an inhibition of cell proliferation and tumorigenicity. In vivo studies have been conducted in athymic mice to investigate the antitumor bystander effects resulting from the transfer of the sst2 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 with a time delay of 31, 44, and 50 days, respectively, when compared with control tumors derived from control cells. Tumors containing 100% sst2-expressing cells remained quiescent for up to 80 days. A significant increase in apoptosis and a decrease in the Ki67 index were detected in mixed and sst2 tumor when compared with control tumors. In combined experiments, mice were separately xenografted with control cells on one flank and with sst2-expressing cells on the other flank. A distant antitumor effect was induced: growth of control tumors was delayed by 33 days, the Ki67 index decreased significantly, and apoptosis increased when compared with control tumors that grew alone. The distant bystander effect may be explained in part by a significant increase in serum somatostatin-like immunoreactivity levels resulting from the autocrine feedback loop produced by sst2-expressing cells and inducing an upregulation of the type 1 somatostatin receptor, sst1, 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 pancreatic cancer.