Inhibition of growth and metastatic progression of pancreatic carcinoma in hamster after somatostatin receptor subtype 2 (sst2) gene expression and administration of cytotoxic somatostatin analog AN-238

Abstract

The sst2 somatostatin receptor mediates the antiproliferative effects of somatostatin analogs. The present study demonstrates that stable expression of sst2 in the hamster pancreatic cancer cells PC-1 and PC-1.0 activates an autocrine negative loop leading to an in vitro inhibition of cell proliferation. In vivo studies conducted in Syrian golden hamsters after orthotopic implantation of PC-1.0 cells showed that both tumor growth and metastatic progression of allografts containing 100% of sst2-expressing cells were significantly inhibited for up to 20 days after implantation, as compared with control allografts that did not express sst2. A local antitumor bystander effect was observed after induction of mixed tumors containing a 1:3 ratio of sst2-expressing cells to control cells. Tumor volume and incidence of metastases of mixed tumors were significantly reduced at day 13 post implantation. This effect decreased with time as at day 20, growth of mixed tumors was similar to that of control tumors. After administration of the cytotoxic somatostatin conjugate AN-238 on day 13, antitumor bystander effect observed in mixed tumors was significantly extended to day 20. We also observed that in vitro invasiveness of sst2-expressing PC-1.0 cells was significantly reduced. Tyrosine dephosphorylation of E-cadherin may participate in restoring the E-cadherin function, reducing in turn pancreatic cancer cell motility and invasiveness. This dephosphorylation depends on the tyrosine phosphatase src homology 2-containing tyrosine phosphatase 1 (SHP-1) positively coupled to sst2 receptor. The inhibitory effect of sst2 gene expression on pancreatic cancer growth and invasion combined with chemotherapy with targeted cytotoxic somatostatin analog administration provides a rationale for a therapeutic approach to gene therapy based on in vivo sst2 gene transfer.bystander effect ͉ tumor invasion ͉ targeted chemotherapeutic agent ͉ experimental gene therapy ͉ E-cadherin S omatostatin is a widely distributed peptide that negatively regulates a number of cellular processes, including growth of multiple epithelial cell types (1). Somatostatin and its stable analog suppress the growth of various cancer cells, including neuroendocrine tumors that express somatostatin receptors (2, 3). The evidence indicates that direct antiproliferative effects of somatostatin and its analogs are mediated by specific cell surface receptors. Five subtypes of somatostatin receptors have been cloned from human, mouse, and rat (4). We found that, among them, the subtypes sst1, sst2, and sst5 mediate the antiproliferative effect of stable somatostatin analogues in vitro (5). We demonstrated that somatostatin subtype 2 (sst2) receptor mediated this antiproliferative effect through the association and stimulation of the tyrosine phosphatase src homology 2-containing tyrosine phosphatase 1 (SHP-1) activity (5, 6) and the subsequent arrest of cells in G 0 ͞G 1 phase of cell cycle in response to an up-regulation of CDKI p27 KIP1 expression and an increase in hypopho...

Somatostatin receptor subtype 2 sensitizes human pancreatic cancer cells to death ligand-induced apoptosis

“…Molecular mechanisms involved in the antiproliferative and antitumorigenic action of sst2 depend on an sst2-dependent induction of somatostatin expression, which in turn constitutively activates the sst2 receptor. In addition to the BxPC-3 cell model, this sst2-somatostatin autocrine loop was also demonstrated in human Capan-1 or hamster PC1-0 pancreatic cancer cells, and in murine fibroblastic NIH 3T3 cells (9,10). In the athymic mouse model, sst2-dependent tumor growth inhibition was associated with decreased Ki67 proliferative index and an induction of apoptosis in the sst2-expressing tumors (8).…”

“…We previously demonstrated that SHP-1 is a critical effector of sst2-mediated inhibition of cell proliferation and tumorigenicity (10,16). SHP-1 has been also shown to be a critical component for induction of apoptosis by somatostatin in MCF-7 breast carcinoma cells, or by angiotensin II through the AT2 receptor (17,19).…”

The new truncated somatostatin receptor variant sst5TMD4 is associated to poor prognosis in breast cancer and increases malignancy in MCF-7 cells

“…Indeed, sst2 is considered a good prognosis factor due to its association with low proliferative and invasive breast cancers (Orlando et al, 2004). Moreover, sst2 expression loss in certain cancer cells results in the elimination of an autocrine inhibitory feedback loop, which leads to phenotypic and functional alterations (Benali et al, 2000;Leu et al, 2008), including epithelial-to-mesenchymal transition, and increased cell proliferation (Leu et al, 2008) and metastasis (Benali et al, 2000).…”

Antitumor effects of somatostatin

“…Somatostatin is a potent anti-migrative and anti-invasive agent for various tumor cells including pancreatic cancer, neuroblastoma and glioma cells (Benali et al, 2000;Cattaneo et al, 2006;Pola et al, 2003). However, the molecular mechanisms involve in these effects are also cell type specific and depend on sst expression pattern, on sst effector coupling as well as on signalling cascade involved in target cells.…”

“…The synthesis and secretion of the natural ligand somatostatin-14 by sst 2 -transfected cells was responsible for an autocrine/paracrine inhibitory loop. Furthermore, in experimental pancreatic cancer models, sst 2 re-expression caused a dramatic inhibition of primary tumor growth and inhibited metastatic progression (Benali et al, 2000). Preclinical studies conducted in pancreatic adenocarcinoma animal models demonstrated that intratumoral sst2 gene transfer (using polyethylenimine synthetic vector) caused inhibition of intratumoral production of somatostatin that was critical for the sst2 antitumoral effect.…”