In VitroInfluences between Pancreatic Adenocarcinoma Cells and Pancreatic Islets

Wang, Feng; Larsson, Jörgen; Adrian, Thomas E.; Gasslander, Thomas; Permert, Johan

doi:10.1006/jsre.1998.5393

Cited by 36 publications

(27 citation statements)

References 28 publications

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“…To the best of our knowledge, the present study is the first to investigate the effect of intra-pancreatic insulin on pancreatic cancer cells in vivo. The results are consistent with those of previous in vitro studies, which have demonstrated the stimulatory effects of insulin on pancreatic cancer cells (14,15). Thus, antagonizing the activity of intra-pancreatic insulin may contribute to the inhibition of pancreatic cancer.…”

Section: Discussionsupporting

confidence: 92%

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Insulin and hypoxia-inducible factor-1 cooperate in pancreatic cancer cells to increase cell viability

Zhang

Cui

et al. 2015

Oncology Letters

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Abstract. The aim of the present study was to investigate whether interstitial insulin and cancer-induced hypoxia-inducible factor-1 (HIF-1) cooperate in pancreatic cancer cells. A population of 45 nude mice were divided into one intact control group and six pancreatic tumor-carrier groups. Pancreatic tumors were generated using HIF-1-positive wild-type MiaPaCa2 (wt-MiaPaCa2) pancreatic cancer cells in three groups of carriers and MiaPaCa2 cells transfected with small interfering RNA against HIF-1α (si-MiaPaCa2 cells) in the other three carrier groups. To vary the intrapancreatic insulin levels, tumor-carrying mice were subjected to one of the following conditions: i) Untreated, ii) single injection of the β-cell toxin streptozotosin prior to cancer cell transplantation and iii) daily injection of insulin following cancer cell transplantation. After 12 weeks, tumor viability was assessed by histological analysis. Western blotting of the tumor grafts was performed to determine the protein expression levels of insulin receptor (IR) and two downstream proteins, hexokinase-II (HK-II) and vascular endothelial growth factor (VEGF). Histologically, the greatest viability was observed in wt-MiaPaCa2 tumors with carriers that remained untreated. These tumors also exhibited greater IR expression than their si-MiaPaCa2 counterparts, indicating that HIF-1 is necessary for basal expression of IR. However, IR expression was increased in wt-MiaPaCa2 and si-MiaPaCa2 tumors when the carriers were treated with exogenous insulin. This indicates that the insulin-induced IR expression was independent of HIF-1. Notably, the insulin-induced IR expression was associated with increased HK-II and VEGF expression in wt-MiaPaCa2 tumors but not si-MiaPaC2 tumors. Therefore, the present study proposes that insulin and HIF-1 may cooperate to increase pancreatic cancer cell viability. Furthermore, the HIF-1 signaling pathway is required for insulin-induced HK-II and VEGF expression, as well as basal IR expression levels in pancreatic cancer cells.

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Section: Discussionsupporting

confidence: 92%

“…When pancreatic cancer occurs, intrapancreatic insulin activates insulin receptors (IRs) expressed on cancer cells, and induces cell growth, migration and angiogenesis (12)(13)(14)(15). Notably, IR activation and HIF-1α expression have the same effect on pancreatic cancer cell growth, migration and angiogenesis.…”

Section: Introductionmentioning

confidence: 99%

Insulin and hypoxia-inducible factor-1 cooperate in pancreatic cancer cells to increase cell viability

Zhang

Cui

et al. 2015

Oncology Letters

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“…Furthermore, a high glycemic load (based on dietary intake) was associated with elevated pancreatic cancer risk in the NHS (28), suggesting that diet can similarly influence pancreatic carcinogenesis. Although some data support a direct role for insulin in pancreatic carcinogenesis, mainly through its growthpromoting properties (29,30), it is not known whether insulin per se is the underlying factor that explains the higher rates of pancreatic cancer risk among diabetics and obese individuals. Other studies suggest that peripheral insulin resistance and islet cell proliferation, but not insulin itself, play an important role in exocrine pancreatic cancer (11).…”

Section: Discussionmentioning

confidence: 99%

Prediagnostic Plasma C-Peptide and Pancreatic Cancer Risk in Men and Women

Michaud

Wolpin

Giovannucci

et al. 2007

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background: Hyperinsulinemia and insulin resistance have been proposed as underlying mechanisms for the increase in pancreatic cancer among long-standing diabetics and obese individuals. An association between serum insulin levels and pancreatic cancer risk was reported in a recent study, but the population was composed of heavy smokers and their findings may not be generalizable to nonsmokers. Methods: Pancreatic cancer cases and matched controls were obtained from four large-scale prospective cohorts to examine the association between prediagnostic plasma levels of C-peptide and insulin and pancreatic cancer. One hundred ninety-seven pancreatic cancer cases were diagnosed during a maximum of 20 years of follow-up, after excluding cases diagnosed within 2 years of blood collection or with baseline diabetes. We estimated OR and confidence intervals (CI) using conditional logistic regression with adjustment for pancreatic cancer risk factors.

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“…Experimental studies have demonstrated that insulin may have growth-promoting effects on pancreatic ductal adenocarcinoma cells (Fisher et al, 1996;Wang et al, 1998;Ding et al, 2000) and that peripheral insulin resistance promotes pancreatic ductal carcinogenesis (Bell et al, 1988;Schneider et al, 2001). Additionally, treatment with metformin, an oral hypoglycemic agent that leads to decreases in peripheral insulin resistance and pancreatic insulin production, may prevent the development of malignant lesions (Schneider et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Circulating insulin-like growth factor axis and the risk of pancreatic cancer in four prospective cohorts

et al. 2007

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Insulin-like growth factor (IGF)-I induces growth in pancreatic cancer cells and blockade of the IGF-I receptor has antitumour activity. The association of plasma IGF-I and IGF binding protein-3 (IGFBP-3) with pancreatic cancer risk has been investigated in two small studies, with conflicting results. We conducted a nested case -control study within four large, prospective cohorts to investigate whether prediagnostic plasma levels of IGF-I, IGF-II, and IGFBP-3 were associated with pancreatic cancer risk. Plasma levels in 212 cases and 635 matched controls were compared by conditional logistic regression, with adjustment for other known pancreatic cancer risk factors. No association was observed between plasma levels of IGF-I, IGF-II, or IGFBP-3 and incident diagnosis of pancreatic cancer. Relative risks for the highest vs the lowest quartile of IGF-I, IGF-II, and IGFBP-3 were 0.94 (95% confidence interval (CI), 0.60 -1.48), 0.96 (95% CI, 0.61 -1.52), and 1.21 (95% CI, 0.75 -1.92), respectively. The relative risk for the molar ratio of IGF-I and IGFBP-3, a surrogate measure for free IGF-I, was 0.84 (95% CI, 0.54 -1.31). Additionally, no association was noted in stratified analyses or when requiring longer follow-up. In four prospective cohorts, we found no association between the risk of pancreatic cancer and prediagnostic plasma levels of IGF-I, IGF-II, or IGFBP-3.

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In VitroInfluences between Pancreatic Adenocarcinoma Cells and Pancreatic Islets

Cited by 36 publications

References 28 publications

Insulin and hypoxia-inducible factor-1 cooperate in pancreatic cancer cells to increase cell viability

Insulin and hypoxia-inducible factor-1 cooperate in pancreatic cancer cells to increase cell viability

Prediagnostic Plasma C-Peptide and Pancreatic Cancer Risk in Men and Women

Circulating insulin-like growth factor axis and the risk of pancreatic cancer in four prospective cohorts

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