[Elderly people and new technologies: friends or enemies?] / Les personnes âgées en Ehpad et les nouvelles technologies.

Faced with the ageing of the French population, it is essential to envisage new technologies to improve the living conditions of elderly people and enable them to communicate more effectively. A study sought to understand the views of senior citizens and the caregivers who look after them regarding these new tools, their appropriation, the support required and their uses. This analysis highlights areas to reflect upon and improve in terms of the services which need to be provided to overcome the reticence of certain users.

Targeting the PI3K/mTOR pathway in murine endocrine cell lines: in vitro and in vivo effects on tumor cell growth.

The mammalian target of rapamycin (mTOR) inhibitors, such as rapalogues, are a promising new tool for the treatment of metastatic gastroenteropancreatic endocrine tumors. However, their mechanisms of action remain to be established. We used two murine intestinal endocrine tumoral cell lines, STC-1 and GLUTag, to evaluate the antitumor effects of rapamycin in vitro and in vivo in a preclinical model of liver endocrine metastases. In vitro, rapamycin inhibited the proliferation of cells in the basal state and after stimulation by insulin-like growth factor-1. Simultaneously, p70S6 kinase and 4EBP1 phosphorylation was inhibited. In vivo, rapamycin substantially inhibited the intrahepatic growth of STC-1 cells, irrespectively of the timing of its administration and even when the treatment was administered after cell intrahepatic engraftment. In addition, treated animals had significantly prolonged survival (mean survival time: 47.7 days in treated animals versus 31.8 days in controls) and better clinical status. Rapamycin treatment was associated with a significant decrease in mitotic index and in intratumoral vascular density within STC-1 tumors. Furthermore, the antitumoral effect obtained after treatment with a combination of rapamycin and phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 was more significant than with rapamycin alone in both cell lines. Our results suggest that the antitumor efficacy of rapamycin in neuroendocrine tumors results from a combination of antiproliferative and antiangiogenic effects. Interestingly, a more potent antitumor efficiency could be obtained by simultaneously targeting several levels of the PI3K/mTOR pathway.

Effects of somatostatin and octreotide on the interactions between neoplastic gastroenteropancreatic endocrine cells and endothelial cells: a comparison between in vitro and in vivo properties.

BACKGROUND/AIMS: Experimental studies in vitro suggest that somatostatin and some of its analogues used in clinical practice, such as octreotide, may have potent antiangiogenic properties. However, the clinical transposition of these data is difficult. METHODS: To address this issue, we designed a comparative study of the effects of somatostatin and octreotide on the interactions between neoplastic endocrine cells and endothelial cells in several in vitro and in vivo experimental models, including primary cultures of human umbilical vein endothelial cells (HUVEC), indirect cocultures between HUVEC and the somatostatin-producing endocrine cell line STC-1, and an animal model of intrahepatic dissemination of STC-1 cells. RESULTS: 10(-8)M octreotide markedly inhibited both basal and VEGF-stimulated HUVEC proliferation, had no effect on endothelial cell migration, but inhibited endothelial tubule formation. HUVEC cocultured with the somatostatin- and VEGF-producing STC-1 cells presented a markedly decreased proliferation, a slightly increased motility and an increased capacity of tubule formation; in this system, the inhibition of endothelial cell proliferation was abolished by neutralizing anti-somatostatin but was restored in the presence of anti-VEGF antibodies. This suggests that somatostatin is able to antagonize the effects of VEGF on endothelial cell proliferation but not on endothelial cell sprouting. Finally, no significant effect of octreotide on tumor growth and intratumoral microvascular density was detected in an experimental model of intrahepatic dissemination of STC-1 cells. CONCLUSION: The in vitro antiangiogenic effects of somatostatin and its analogues are likely to be efficiently counterbalanced in the tumor microenvironment by the concomitant release of proangiogenic factors like VEGF.

VEGF secretion by neuroendocrine tumor cells is inhibited by octreotide and by inhibitors of the PI3K/AKT/mTOR pathway.

Gastroenteropancreatic (GEP) endocrine tumors are hypervascular tumors able to synthesize and secrete high amounts of VEGF. We aimed to study the regulation of VEGF production in GEP endocrine tumors and to test whether some of the drugs currently used in their treatment, such as somatostatin analogues and mTOR inhibitors, may interfere with VEGF secretion. We therefore analyzed the effects of the somatostatin analogue octreotide, the mTOR inhibitor rapamycin, the PI3K inhibitor LY294002, the MEK1 inhibitor PD98059 and the p38 inhibitor SB203850 on VEGF secretion, assessed by ELISA and Western blotting, in three murine endocrine cell lines, STC-1, INS-r3 and INS-r9. Octreotide and rapamycin induced a significant decrease in VEGF production by all three cell lines; LY294002 significantly inhibited VEGF production by STC-1 and INS-r3 only. We detected no effect of PD98059 whereas SB203850 significantly inhibited VEGF secretion in INS-r3 and INS-r9 cells only. By Western blotting analysis, we observed decreased intracellular levels of VEGF and HIF-1alpha under octreotide, rapamycin and LY294002. For rapamycin and LY294002, this effect was likely mediated by the inhibition of the mTOR/HIF-1/VEGF pathway. In addition to its well-known anti-secretory effects, octreotide may also act through the inhibition of the PI3K/Akt pathway, as suggested by the decrease in Akt phosphorylation detected in all three cell lines. In conclusion, our study points out to the complex regulation of VEGF synthesis and secretion in neoplastic GEP endocrine cells and suggests that the inhibition of VEGF production by octreotide and rapamycin may contribute to their therapeutic effects.

Angiogenesis and tumor progression in neuroendocrine digestive tumors.

BACKGROUND: Clinical observations suggest that in neuroendocrine digestive tumors a high intratumoral microvascular density is associated with good prognosis. We used an experimental orthotopic xenograft model to analyze the relations between angiogenic activity and tumor progression in this tumor subset. MATERIAL AND METHODS: We compared 2 endocrine cell lines: STC-1, a low vascular endothelial growth factor (VEGF)-producing cell line, and INS-r3, a high VEGF-producing cell line. Tumor cells were grafted in the adventitial layer of the caecal wall of nude mice, sacrificed after 8 wk. RESULTS: At 8 wk, "primary" tumors were present in all animals. STC-1 derived tumors were morphologically moderately differentiated, with high proliferative and apoptotic activities; in contrast, INS-r3 derived tumors were well differentiated, with low proliferative and apoptotic activities. VEGF was expressed in <50% grafted STC-1 cells but in >90% of grafted INS-r3 cells. Microvascular density was significantly higher in INS-r3 derived tumors than in STC-1 derived tumors. All STC-1 derived tumors (n = 8) have invaded the mucosa, in contrast to none of the INS-r3 derived tumors (n = 8); liver metastases were detected in 7/8 animals bearing STC-1 derived tumors and in 0/8 animals with INS-r3 derived tumors, despite the presence of lymph node metastases. CONCLUSIONS: Our experimental data concur with clinical findings to suggest that in well differentiated digestive neuroendocrine tumors angiogenesis is disconnected from tumor progression: the development of a highly vascular tumor microenvironment is correlated with VEGF secretion but is not associated with invasive and metastatic properties; it must therefore be regarded as an indirect marker of differentiation.

The role of angiogenesis in endocrine liver metastases: an experimental study.

Liver metastases are a major adverse event during the evolution of digestive endocrine tumors. However, little is known about their natural history and the determinants of their growth. In particular, whereas liver endocrine metastases, like their primary counterparts, are hypervascular, the role of tumor-associated angiogenesis has been little explored. We therefore designed an experimental model to study the intrahepatic growth of tumor endocrine cells; murine enteroendocrine STC-1 cells were injected into the spleen of nude mice to obtain their hepatic dissemination through the portal vein. Three stages of intrahepatic tumor growth were identified. Engraftment stage, until day 4 after intrasplenic injection of STC-1 cells, was avascular. Early growth, until day 17, resulted in small, infralobular nodules. Late growth, after day 17, was characterized by the development of large nodules associated with peritumoral vessels and containing abnormal intratumoral vessels. To test the effects of potentially anti-angiogenic agents on tumor growth, we then used STC-1 cells stably transfected with the endostatin-coding sequence. Intrahepatic tumor volume showed no significant change at days 4 and 8, but a dramatic decrease at day 28 (9.7 +/- 1.7% of liver tissue versus 25.2 +/- 2.4% in controls), because of a markedly lower number of large nodules (11 +/- 1.8% versus 42 +/- 5.8%) likely to result from an increased apoptotic index (39.4 +/- 5.6% versus 18.3 +/- 3.4). Our results suggest that active angiogenesis is not necessary for the engraftment and early growth of endocrine cells metastatic to the liver but is required at a later stage of progression.