Serum and tissue level of insulin‐like growth factor‐I (IGF‐I) and IGF‐I binding proteins as an index of pancreatitis and pancreatic cancer

Karna, Ewa; Surażyński, Arkadiusz; Orłowski, Kazimierz A.; Łaszkiewicz, Joanna; Puchałski, Z; Nawrat, Piotr; Pałka, Jerzy

doi:10.1046/j.1365-2613.2002.00237.x

Cited by 70 publications

(49 citation statements)

References 31 publications

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“…In pancreatic cancer, a frequent overexpression of IGF-IR and its ligands has been reported [28,29]. IGF-IR can potently contribute not only to the development of tumors but also to the resistance to therapy [30,31].…”

Section: Discussionmentioning

confidence: 99%

Characterization of human pancreatic orthotopic tumor xenografts suitable for drug screening

et al. 2011

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Background Efforts to identify novel therapeutic options for human pancreatic ductal adenocarcinoma (PDAC) have failed to result in a clear improvement in patient survival to date. Pancreatic cancer requires efficient therapies that must be designed and assayed in preclinical models with improved predictor ability. Among the available preclinical models, the orthotopic approach fits with this expectation, but its use is still occasional. Methods An in vivo platform of 11 orthotopic tumor xenografts has been generated by direct implantation of fresh surgical material. In addition, a frozen tumorgraft bank has been created, ensuring future model recovery and tumor tissue availability.Results Tissue microarray studies allow showing a high degree of original histology preservation and maintenance of protein expression patterns through passages. The models display stable growth kinetics and characteristic metastatic behavior. Moreover, the molecular diversity may facilitate the identification of tumor subtypes and comparison of drug responses that complement or confirm information obtained with other preclinical models. Conclusions This panel represents a useful preclinical tool for testing new agents and treatment protocols and for further exploration of the biological basis of drug responses.

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Section: Discussionmentioning

confidence: 99%

Characterization of human pancreatic orthotopic tumor xenografts suitable for drug screening

et al. 2011

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“…Panc1, MiaPaCa2, and Colo357 cells express high levels of the IGF-IR and show enhanced proliferation following IGF-I treatment (7,8). We examined the ability of klotho to inhibit activation of the IGF-I pathway in these cells.…”

Section: Klotho Inhibits Activation Of the Igf-i Pathways In Pancreatmentioning

confidence: 99%

“…The IGF-I pathway promotes tumorigenesis of various malignancies, and excessive activation of the IGF-I receptor (IGF-IR) is associated with malignant transformation, increased tumor aggressiveness, and protection from apoptosis (3,5,6). IGF-I and IGF-IR are often overexpressed in human pancreatic tumors and cell lines, and inhibition of the IGF-I pathway suppresses tumorgenicity and increases sensitivity of pancreatic tumors to radiation and chemotherapy (7,8). Targeted therapies directed against the IGF-IR are currently being tested for the treatment of pancreatic cancer in clinical trials (http:// clinicaltrials.gov/).…”

Section: Introductionmentioning

confidence: 99%

KL1 Internal Repeat Mediates Klotho Tumor Suppressor Activities and Inhibits bFGF and IGF-I Signaling in Pancreatic Cancer

Abramovitz

Rubinek

Ligumsky

et al. 2011

Clinical Cancer Research

126

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Purpose: Klotho is a transmembrane protein which can be shed, act as a circulating hormone and modulate the insulin-like growth factor (IGF)-I and the fibroblast growth factor (FGF) pathways. We have recently identified klotho as a tumor suppressor in breast cancer. Klotho is expressed in the normal pancreas and both the IGF-I and FGF pathways are involved in pancreatic cancer development. We, therefore, undertook to study the expression and activity of klotho in pancreatic cancer.Experimental Design: Klotho expression was studied using immunohistochemistry and quantitative RT-PCR. Effects of klotho on cell growth were assessed in the pancreatic cancer cells Panc1, MiaPaCa2, and Colo357, using colony and MTT assays and xenograft models. Signaling pathway activity was measured by Western blotting.Results: Klotho expression is downregulated in pancreatic adenocarcinoma. Overexpression of klotho, or treatment with soluble klotho, reduced growth of pancreatic cancer cells in vitro and in vivo, and inhibited activation of the IGF-I and the bFGF pathways. KL1 is a klotho subdomain formed by cleavage or alternative splicing. Compared with the full-length protein, KL1 showed similar growth inhibitory activity but did not promote FGF23 signaling. Thus, its administration to mice showed favorable safety profile.Conclusions: These studies indicate klotho as a potential tumor suppressor in pancreatic cancer, and suggest, for the first time, that klotho tumor suppressive activities are mediated through its KL1 domain. These results suggest the use of klotho or KL1 as potential strategy for the development of novel therapeutic interventions for pancreatic cancer. Clin Cancer Res; 17(13); 4254-66. Ó2011 AACR.

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“…Both IGF-I and IGF-I receptor (IGF-IR) are overexpressed in human pancreatic tumors as well as in pancreatic cancer cell lines (13,14). Blockade of the IGF-IR by a dominant negative inhibitor suppresses tumorigenicity both in vitro and in vivo and increases sensitivity of pancreatic tumors to radiation and chemotherapy-induced apoptosis.…”

mentioning

confidence: 99%

Insulin-like Growth Factor-I Receptor Mediates the Prosurvival Effect of Fibronectin

Edderkaoui

Hong

Lee

et al. 2007

Journal of Biological Chemistry

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We recently showed that extracellular matrix (ECM) proteins, which are abundant in desmoplastic pancreatic tumor, are as potent as growth factors in inhibiting apoptosis in pancreatic cancer (PaCa) cells. Here we show that fibronectin, a major ECM component, engages insulin-like growth factor-I receptor (IGF-IR) to inhibit PaCa cell death. We found that fibronectin-induced protection from apoptosis is fully mediated by IGF-IR and is independent of IGF-I. Pharmacologic and molecular inhibitions of IGF-IR stimulated apoptosis and prevented the prosurvival effect of fibronectin in PaCa cells. Our data indicate that fibronectin protects from apoptosis through trans-activation of IGF-IR. We showed that fibronectin stimulated complex formation between its receptor ␤3 integrin and protein-tyrosine phosphatase SHP-2. This process of complex formation, in turn, pre- Pancreatic cancer is the fourth most common cause of death in western countries with almost the same rate of incidence and mortality per year (1, 2). The disease is very resistant to radioand/or chemotherapies. One reason for that is the resistance of pancreatic cancer (PaCa) 2 cells to apoptosis (3).Pancreatic adenocarcinoma is a fibrotic tumor, which is characterized by a high level of extracellular matrix (ECM) proteins. ECM mediates adhesion and invasiveness of cancer cells. Cell survival also depends on adequate connections with ECM proteins through specific integrin receptors. We recently showed that ECM proteins are key mediators of PaCa cell survival (4, 5) and that detachment from ECM stimulates PaCa cell death. The mechanisms through which ECM proteins protect PaCa cells from death are not fully understood.Fibronectin is a major ECM protein of pancreatic adenocarcinoma; its receptors, ␤3 and ␤1 integrins, are up-regulated in pancreatic cancer cells (6). Fibronectin stimulates invasion and adhesion and markedly increases survival of pancreatic cancer cells (7,8).The importance of fibronectin and other extracellular matrix proteins in pancreatic cancer is underscored by several findings. Pancreatic adenocarcinoma is one of the most lethal of human cancers with a 5-year survival rate of less than 5% (9). This cancer has a characteristic of marked desmoplasia, which is a remarkable increase in extracellular matrix that infiltrates and envelopes the cancer (10). Importantly there is at least one report that demonstrates that greater amounts of intratumor extracellular matrix in pancreatic cancer patients are correlated with more aggressive disease and more rapid death (11). Finally recent studies in animal models of pancreatic cancer show that tumors grow more rapidly when the fibroblastic cells of the cancer called stellate cells are included in inocula with cancer cells (12). The addition of the stellate cells results in the experimental tumors taking on the characteristics of the human cancer with the extracellular matrix infiltrating and enveloping the cancer cells.In addition, another powerful mediator of PaCa cell survival is insulin-like growth fa...

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Serum and tissue level of insulin‐like growth factor‐I (IGF‐I) and IGF‐I binding proteins as an index of pancreatitis and pancreatic cancer

Cited by 70 publications

References 31 publications

Characterization of human pancreatic orthotopic tumor xenografts suitable for drug screening

Characterization of human pancreatic orthotopic tumor xenografts suitable for drug screening

KL1 Internal Repeat Mediates Klotho Tumor Suppressor Activities and Inhibits bFGF and IGF-I Signaling in Pancreatic Cancer

Insulin-like Growth Factor-I Receptor Mediates the Prosurvival Effect of Fibronectin

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