scholarly journals Role of Tumor and Stroma-Derived IGF/IGFBPs in Pancreatic Cancer

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1228
Author(s):  
Divya Thomas ◽  
Prakash Radhakrishnan
Keyword(s):  
Pancreatic Cancer ◽  
Research Evidence ◽  
Current Evidence ◽  
Igf Binding Proteins ◽  
Considerable Research ◽  
Signaling Axis ◽  
Igf Binding ◽  
Novel Therapeutic ◽  
Made In

Pancreatic cancer (PC) is the utmost stroma-rich cancer, which is accompanied by fibrotic reactions that stimulate interactions between tumor cells and stroma to promote tumor progression. Considerable research evidence denotes that insulin-like growth factor (IGF)/IGF binding proteins (IGFBP) signaling axis facilitate tumor growth, metastasis, drug resistance, and thereby facilitate PC into an advanced stage. The six members of IGFBPs were initially considered as passive carriers of free IGFs; however, current evidence revealed their functions beyond the endocrine role in IGF transport. Though numerous efforts have been made in blocking IGF/IGFBPs, the targeted therapies remain unsuccessful due to the complexity of tumor-stromal interactions in the pancreas. In this review, we explore the emerging evidence of the various roles of the tumor as well as stroma derived IGF/IGFBPs and highlight as a novel therapeutic target against PC progression.

scholarly journals Use of Thiols in the Treatment of COVID-19: Current Evidence

Lung ◽  
2021 ◽  
Author(s):  
Mario Cazzola ◽  
Paola Rogliani ◽  
Sundeep Santosh Salvi ◽  
Josuel Ora ◽  
Maria Gabriella Matera
Keyword(s):  
Oxidative Stress ◽  
Influenza Virus Infection ◽  
Current Evidence ◽  
Low Molecular Weight ◽  
Oxygen Species ◽  
Cytokine Storm ◽  
Antioxidant Defences ◽  
Antioxidant Molecule ◽  
Novel Therapeutic

AbstractThere is a possible role for oxidative stress, a state characterized by an altered balance between the production of free radicals or reactive oxygen species (ROS) and antioxidant defences, in coronavirus disease 2019 (COVID-19), the genesis of which is quite complex. Excessive oxidative stress could be responsible for the alveolar damage, thrombosis, and red blood cell dysregulation observed in COVID-19. Apparently, deficiency of glutathione (GSH), a low-molecular-weight thiol that is the most important non-enzymatic antioxidant molecule and has the potential to keep the cytokine storm in check, is a plausible explanation for the severe manifestations and death in COVID-19 patients. Thiol drugs, which are considered mucolytic, also possess potent antioxidant and anti-inflammatory properties. They exhibit antibacterial activity against a variety of medically important bacteria and may be an effective strategy against influenza virus infection. The importance of oxidative stress during COVID-19 and the various pharmacological characteristics of thiol-based drugs suggest a possible role of thiols in the treatment of COVID-19. Oral and intravenous GSH, as well as GSH precursors such as N-acetylcysteine (NAC), or drugs containing the thiol moiety (erdosteine) may represent a novel therapeutic approach to block NF-kB and address the cytokine storm syndrome and respiratory distress observed in COVID-19 pneumonia patients

scholarly journals The role of GLI-SOX2 signaling axis for gemcitabine resistance in pancreatic cancer

Oncogene ◽  
2018 ◽  
Vol 38 (10) ◽  
pp. 1764-1777 ◽  
Author(s):  
Yanfei Jia ◽  
Dongsheng Gu ◽  
Jun Wan ◽  
Beiqin Yu ◽  
Xiaoli Zhang ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Gemcitabine Resistance ◽  
Signaling Axis

The role of radiotherapy in locally advanced pancreatic cancer

2021 ◽  
pp. 20210044
Author(s):  
Florence Huguet ◽  
Victoire Dabout ◽  
Eleonor Rivin del Campo ◽  
Sébastien Gaujoux ◽  
Jean Baptiste Bachet
Keyword(s):  
Pancreatic Cancer ◽  
Radiation Therapy ◽  
Technical Progress ◽  
Vascular Invasion ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Metastatic Tumour ◽  
Borderline Resectable ◽  
Made In

At diagnosis, about 15% of patients with pancreatic cancer present with a resectable tumour, 50% have a metastatic tumour, and 35% a locally advanced tumour, non-metastatic but unresectable due to vascular invasion, or borderline resectable. Despite the technical progress made in the field of radiation therapy and the improvement of the efficacy of chemotherapy, the prognosis of these patients remains very poor. Recently, the role of radiation therapy in the management of pancreatic cancer has been much debated. This review aims to evaluate the role of radiation therapy for patients with locally advanced tumours.

scholarly journals Role of Dimerized C16orf74 in Aggressive Pancreatic Cancer: A Novel Therapeutic Target

2019 ◽  
Vol 19 (1) ◽  
pp. 187-198 ◽  
Author(s):  
Toshihiro Kushibiki ◽  
Toru Nakamura ◽  
Masumi Tsuda ◽  
Takahiro Tsuchikawa ◽  
Koji Hontani ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Therapeutic Target ◽  
Novel Therapeutic

scholarly journals The critical role and potential target of the autotaxin/lysophosphatidate axis in pancreatic cancer

Tumor Biology ◽  
2017 ◽  
Vol 39 (3) ◽  
pp. 101042831769454 ◽  
Author(s):  
Ming Quan ◽  
Jiu-jie Cui ◽  
Xiao Feng ◽  
Qian Huang
Keyword(s):  
Pancreatic Cancer ◽  
Current Knowledge ◽  
Critical Role ◽  
Treatment Resistance ◽  
G Protein Coupled Receptors ◽  
Signaling Axis ◽  
Tumorigenesis And Progression ◽  
Pathologic Processes ◽  
G Protein Coupled

Autotaxin, an ecto-lysophospholipase D encoded by the human ENNP2 gene, is expressed in multiple tissues, and participates in numerous critical physiologic and pathologic processes including inflammation, pain, obesity, embryo development, and cancer via the generation of the bioactive lipid lysophosphatidate. Overwhelming evidences indicate that the autotaxin/lysophosphatidate signaling axis serves key roles in the numerous processes central to tumorigenesis and progression, including proliferation, survival, migration, invasion, metastasis, cancer stem cell, tumor microenvironment, and treatment resistance by interacting with a series of at least six G-protein-coupled receptors (LPAR1–6). This review provides an overview of the autotaxin/lysophosphatidate axis and collates current knowledge regarding its specific role in pancreatic cancer. With a deeper understanding of the critical role of the autotaxin/lysophosphatidate axis in pancreatic cancer, targeting autotaxin or lysophosphatidate receptor may be a potential and promising strategy for cancer therapy.

scholarly journals IGF-I stimulates chemotaxis of human neuroblasts. Involvement of type 1 IGF receptor, IGF binding proteins, phosphatidylinositol-3 kinase pathway and plasmin system

2000 ◽  
Vol 165 (1) ◽  
pp. 123-131 ◽  
Author(s):  
A Puglianiello ◽  
D Germani ◽  
P Rossi ◽  
S Cianfarani
Keyword(s):  
Cell Migration ◽  
Cell Motility ◽  
Igf Binding Proteins ◽  
Neuroblast Migration ◽  
Igf I ◽  
Igf Binding ◽  
Igf Receptor ◽  
Kinase Pathway

SH-SY5Y human neuroblastoma cells express IGF receptors, IGFs and IGF binding proteins (IGFBPs), and provide a model for studying the role of the IGF system in human neuronal development. We investigated the effect of IGF-I and des(1-3)IGF-I on the motility of SH-SY5Y cells by a cell migration assay based on the assessment of the number of cells which migrated across 8 microm pore size membranes and around an agarose drop. IGF-I and des(1-3)IGF-I stimulated neuroblast chemotaxis in a dose-dependent manner. Treatment of cells with these agents for 24 h resulted in a significant increase (IGF-I by 70% and des(1-3)IGF-I by 90%; P<0. 0001) in cell motility relative to control conditions. Addition of monoclonal antibody against type 1 IGF receptor (alpha-IR3), significantly (P<0.05) reduced the cell motility induced by IGF-I (by 30%) and des(1-3)IGF-I (by 70%). Wortmannin, a specific inhibitor of phosphatidylinositol (PI)-3 kinase intracellular signalling, also reduced the IGF-stimulated cell migration (by over 40%, P<0.01), indicating a key role of the PI-3 kinase pathway in mediating the IGF effect on neuroblast migration. Finally, cell treatment with plasminogen (PLG) markedly enhanced neuroblast migration (by over 200%, P<0.01), whereas incubation with the PLG inhibitor 4-(2-aminoethyl)-benzenesulphonyl fluoride reduced cell motility (by 80%, P<0.01), thus suggesting an involvement of PLG-dependent IGFBP proteolysis in the regulation of neuroblast motility. In conclusion, IGF-I is a potent stimulator of neuroblast migration through the activation of type 1 IGF receptor and the PI-3 kinase intracellular pathway. IGFBPs and the plasmin system seem to play a role in cell motility, although the nature and the extent of their involvement has yet to be elucidated.

scholarly journals The Role of IGF-Binding Proteins in Mediating the Effects of Recombinant Human IGF-I on Insulin Requirements in Type 1 Diabetes Mellitus

2001 ◽  
Vol 86 (8) ◽  
pp. 3686-3691 ◽  
Author(s):  
E. C. Crowne ◽  
J. S. Samra ◽  
T. Cheetham ◽  
C. L. Acerini ◽  
A. Watts ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Binding Protein ◽  
Igf Binding Proteins ◽  
Insulin Requirements ◽  
Free Insulin ◽  
Igf I ◽  
Igf Binding ◽  
Igf Binding Protein

To determine the role of IGF-binding proteins in mediating the direct effects of recombinant human IGF-I on insulin requirements in type 1(insulin-dependent) diabetes mellitus, overnight changes in IGF-I, IGF-II, and IGF-binding protein-1, -2, and -3, collected under euglycemic conditions, were compared in nine subjects after double blind, randomized, sc administration of recombinant human IGF-I (40μ g/kg) or placebo at 1800 h. On both nights a somatostatin analog infusion (300 ng/kg·h) suppressed endogenous GH production, and three timed discrete GH pulses (total, 0.029 IU/kg·night) ensured identical GH levels. After recombinant human IGF-I administration, IGF-I levels and the IGF-I/IGF-binding protein-3 ratio increased [mean ± sem:IGF-I, 401 ± 22 ng/ml; placebo, 256 ± 20 ng/ml (P = 0.0002); IGF-I, 0.108 ± 0.006; placebo, 0.074 ± 0.004 (P = 0.0003), respectively], and insulin requirements decreased (IGF-I, 0.12 ± 0.03; placebo, 0.23 ± 0.03 U/kg·min; P = 0.008). The normal within-individual inverse relationships between insulin and IGF-binding protein-1 levels were observed (lag time 2 h: r =− 0.34; P &lt; 0.01). Yet despite reduced free insulin levels (8.5 ± 1.5; placebo, 12.2 ± 1.2 mU/liter; P = 0.03), IGF-binding protein-1 levels were reduced after recombinant human IGF-I administration (53.7 ± 6.8; placebo, 82.2 ± 11.8 ng/ml; P = 0.008). The largest reductions in free insulin levels after recombinant human IGF-I and thus putative improvement in insulin sensitivity occurred in subjects with the smallest increase in the plasma IGF-I/IGF-binding protein-3 ratio (r = 0.7; P = 0.03). Taken together, these data are consistent with the hypothesis that transcapillary movement of IGF-I (perhaps mediated by IGF-binding protein-1), out of the circulation facilitates altered insulin sensitivity. These data have important implications for risk-benefit assessment of recombinant human IGF-I therapy in type 1 diabetes mellitus.

scholarly journals 40 YEARS OF IGF1: Role of IGF-binding proteins in regulating IGF responses to changes in metabolism

2018 ◽  
Vol 61 (1) ◽  
pp. T139-T169 ◽  
Author(s):  
David R Clemmons
Keyword(s):  
Binding Protein ◽  
Surface Proteins ◽  
Type I ◽  
Cellular Functions ◽  
Igf Binding Proteins ◽  
Distinct Cell ◽  
Type I Igf Receptor ◽  
Igf Binding ◽  
Igf Binding Protein

The IGF-binding protein family contains six members that share significant structural homology. Their principal function is to regulate the actions of IGF1 and IGF2. These proteins are present in plasma and extracellular fluids and regulate access of both IGF1 and II to the type I IGF receptor. Additionally, they have functions that are independent of their ability to bind IGFs. Each protein is regulated independently of IGF1 and IGF2, and this provides an important mechanism by which other hormones and physiologic variables can regulate IGF actions indirectly. Several members of the family are sensitive to changes in intermediary metabolism. Specifically the presence of obesity/insulin resistance can significantly alter the expression of these proteins. Similarly changes in nutrition or catabolism can alter their synthesis and degradation. Multiple hormones such as glucocorticoids, androgens, estrogen and insulin regulate IGFBP synthesis and bioavailability. In addition to their ability to regulate IGF access to receptors these proteins can bind to distinct cell surface proteins or proteins in extracellular matrix and several cellular functions are influenced by these interactions. IGFBPs can be transported intracellularly and interact with nuclear proteins to alter cellular physiology. In pathophysiologic states, there is significant dysregulation between the changes in IGFBP synthesis and bioavailability and changes in IGF1 and IGF2. These discordant changes can lead to marked alterations in IGF action. Although binding protein physiology and pathophysiology are complex, experimental results have provided an important avenue for understanding how IGF actions are regulated in a variety of physiologic and pathophysiologic conditions.

scholarly journals Nutritional regulation of IGF-II, but not IGF-I, is age dependent in sheep

1999 ◽  
Vol 163 (3) ◽  
pp. 395-402 ◽  
Author(s):  
JM Oldham ◽  
JA Martyn ◽  
KM Hua ◽  
NA MacDonald ◽  
SC Hodgkinson ◽  
...  
Keyword(s):  
Plasma Levels ◽  
Plasma Concentrations ◽  
Age Groups ◽  
Nutritional Regulation ◽  
Igf Binding Proteins ◽  
Ewe Lambs ◽  
Igf I ◽  
Age Dependent ◽  
Igf Binding

In post-natal animals, plasma concentrations of IGF-I are tightly regulated by nutritional status. The current study reports that plasma levels of IGF-II in sheep are also regulated by nutrition, but whether plasma IGF-II is increased, decreased or remains the same, depends on the age of the animal. Ewe lambs, ranging in age from 2 days to 2 years, were fed or fasted for lengths of time between 24 and 72 h. Blood samples were taken at intervals of 24 h throughout the treatment period and immediately before slaughter. Plasma concentrations of IGF-I increased with advancing age in fed animals (P<0.001) and were reduced by fasting in all age groups (P<0.001). Plasma concentrations of IGF-II also increased as animals matured (P<0.001), but did not show an overall effect of the fasting treatment. An interaction between age and nutrition (P<0.001) resulted from a decrease in plasma IGF-II in response to fasting in neonatal animals (P<0.01) and, conversely, increased levels of plasma IGF-II in fasted mature animals (P<0.01 or P<0.001). Fasted sheep of peripubertal age showed no change in plasma levels of IGF-II. The nutritional sensitivity of serum IGF-binding proteins (BPs) also changed with age. The 29 kDa BP, which we presume to be BP1, was elevated by fasting in young animals and reduced slightly in older animals. BP2 was increased to a similar magnitude by fasting at all ages. BP3 was depressed by fasting in young animals and showed little change in adults. In contrast, a 24 kDa BP, which is probably BP4, showed little change in young animals and was reduced substantially in older sheep. In conclusion, the response of plasma IGF-II to fasting suggests that this peptide has functions in mediating nutritional stress which depend on the age of the animal, and also that the role of IGF-II may differ from that of IGF-I in adults.

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