Benali N, Cordelier P, Calise D, Pages P, Rochaix P, Nagy A, Esteve J P, Pour P M, Schally A V, Vaysse N, Susini C, Buscail L
Institut National de la Santé et de la Recherche Médicale U531, Institut Louis Bugnard, Institut Federatif de Recherche-31, Centre Hospitalier Universitaire Rangueil, 31403 Toulouse, France.
Proc Natl Acad Sci U S A. 2000 Aug 1;97(16):9180-5. doi: 10.1073/pnas.130196697.
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.
生长抑素2型（sst2）受体介导生长抑素类似物的抗增殖作用。本研究表明，在仓鼠胰腺癌细胞PC-1和PC-1.0中稳定表达sst2可激活自分泌负反馈回路，从而在体外抑制细胞增殖。在用PC-1.0细胞原位植入叙利亚金仓鼠后进行的体内研究表明，与不表达sst2的对照同种异体移植物相比，植入后长达20天，含有100%表达sst2细胞的同种异体移植物的肿瘤生长和转移进程均受到显著抑制。在诱导含有表达sst2细胞与对照细胞比例为1:3的混合肿瘤后，观察到局部抗肿瘤旁观者效应。植入后第13天，混合肿瘤的肿瘤体积和转移发生率显著降低。随着时间推移，这种效应逐渐减弱，因为在第20天时，混合肿瘤的生长与对照肿瘤相似。在第13天给予细胞毒性生长抑素偶联物AN-238后，混合肿瘤中观察到的抗肿瘤旁观者效应显著延长至第20天。我们还观察到，表达sst2的PC-1.0细胞的体外侵袭性显著降低。E-钙黏蛋白的酪氨酸去磷酸化可能参与恢复E-钙黏蛋白功能，进而降低胰腺癌细胞的运动性和侵袭性。这种去磷酸化依赖于与sst2受体正向偶联的含src同源2结构域的酪氨酸磷酸酶1（SHP-1）。sst2基因表达对胰腺癌生长和侵袭的抑制作用，结合靶向细胞毒性生长抑素类似物给药的化疗，为基于体内sst2基因转移的基因治疗方法提供了理论依据。
