scholarly journals IGF-I Regulates Pheochromocytoma Cell Proliferation and Survival In Vitro and In Vivo

Endocrinology ◽  
2012 ◽  
Vol 153 (8) ◽  
pp. 3724-3734 ◽  
Author(s):  
María Celia Fernández ◽  
Marcela Venara ◽  
Susana Nowicki ◽  
Héctor E. Chemes ◽  
Marta Barontini ◽  
...  
Keyword(s):  
Critical Role ◽  
Tumor Development ◽  
Receptor Expression ◽  
Vascular Density ◽  
Receptor System ◽  
Igf I ◽  
Tumor Phenotype ◽  
The Impact

IGFs are involved in malignant transformation and growth of several tissues, including the adrenal medulla. The present study was designed to evaluate the impact of IGF-I on pheochromocytoma development. We used a murine pheochromocytoma (MPC) cell line (MPC4/30) and an animal model with a reduction of 75% in circulating IGF-I levels [liver-IGF-I-deficient (LID) mice] to perform studies in vitro and in vivo. We found that, in culture, IGF-I stimulation increases proliferation, migration, and anchorage-independent growth, whereas it inhibits apoptosis of MPC cells. When injected to control and to LID mice, MPC cells grow and form tumors with features of pheochromocytoma. Six weeks after cell inoculation, all control mice developed sc tumors. In contrast, in 73% of LID mice, tumor development was delayed to 7–12 wk, and the remaining 27% did not develop tumors up to 12 wk after inoculation. LID mice harboring MPC cells and treated with recombinant human IGF-I (LID+) developed tumors as controls. Tumors developed in control, LID, and LID+ mice had similar histology and were similarly positive for IGF-I receptor expression. The apoptotic index was higher in tumors from LID mice compared with those from control mice, whereas vascular density was decreased. In summary, our work demonstrates that IGF-I has a critical role in maintaining tumor phenotype and survival of already transformed pheochromocytoma cells and is required for the initial establishment of these tumors, providing encouragement to carry on research studies to address the IGF-I/IGF-I receptor system as a target of therapeutic strategies for pheochromocytoma treatment in the future.

scholarly journals Dual oxidase 1 limits the IFNγ-associated antitumor effect of macrophages

2020 ◽  
Vol 8 (1) ◽  
pp. e000622
Author(s):  
Lydia Meziani ◽  
Marine Gerbé de Thoré ◽  
Pauline Hamon ◽  
Sophie Bockel ◽  
Ruy Andrade Louzada ◽  
...  
Keyword(s):  
Antitumor Effect ◽  
Therapeutic Strategy ◽  
Critical Role ◽  
Tumor Development ◽  
Intratumoral Injection ◽  
Histocompatibility Complex ◽  
Dual Oxidase

BackgroundMacrophages play pivotal roles in tumor progression and the response to anticancer therapies, including radiotherapy (RT). Dual oxidase (DUOX) 1 is a transmembrane enzyme that plays a critical role in oxidant generation.MethodsSince we found DUOX1 expression in macrophages from human lung samples exposed to ionizing radiation, we aimed to assess the involvement of DUOX1 in macrophage activation and the role of these macrophages in tumor development.ResultsUsing Duox1−/− mice, we demonstrated that the lack of DUOX1 in proinflammatory macrophages improved the antitumor effect of these cells. Furthermore, intratumoral injection of Duox1−/− proinflammatory macrophages significantly enhanced the antitumor effect of RT. Mechanistically, DUOX1 deficiency increased the production of proinflammatory cytokines (IFNγ, CXCL9, CCL3 and TNFα) by activated macrophages in vitro and the expression of major histocompatibility complex class II in the membranes of macrophages. We also demonstrated that DUOX1 was involved in the phagocytotic function of macrophages in vitro and in vivo. The antitumor effect of Duox1−/− macrophages was associated with a significant increase in IFNγ production by both lymphoid and myeloid immune cells.ConclusionsOur data indicate that DUOX1 is a new target for macrophage reprogramming and suggest that DUOX1 inhibition in macrophages combined with RT is a new therapeutic strategy for the management of cancers.

scholarly journals MicroRNA-28-5p Regulates Liver Cancer Stem Cell Expansion via IGF-1 Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-16 ◽  
Author(s):  
Qing Xia ◽  
Tao Han ◽  
Pinghua Yang ◽  
Ruoyu Wang ◽  
Hengyu Li ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Liver Cancer ◽  
Critical Role ◽  
Self Renewal ◽  
Sorafenib Treatment ◽  
The Impact

Background. MicroRNAs (miRNAs) play a critical role in the regulation of cancer stem cells (CSCs). However, the role of miRNAs in liver CSCs has not been fully elucidated. Methods. Real-time PCR was used to detect the expression of miR-miR-28-5p in liver cancer stem cells (CSCs). The impact of miR-28-5p on liver CSC expansion was investigated both in vivo and in vitro. The correlation between miR-28-5p expression and sorafenib benefits in HCC was further evaluated in patient-derived xenografts (PDXs). Results. Our data showed that miR-28-5p was downregulated in sorted EpCAM- and CD24-positive liver CSCs. Biofunctional investigations revealed that knockdown miR-28-5p promoted liver CSC self-renewal and tumorigenesis. Consistently, miR-28-5p overexpression inhibited liver CSC’s self-renewal and tumorigenesis. Mechanistically, we found that insulin-like growth factor-1 (IGF-1) was a direct target of miR-28-5p in liver CSCs, and the effects of miR-28-5p on liver CSC’s self-renewal and tumorigenesis were dependent on IGF-1. The correlation between miR-28-5p and IGF-1 was confirmed in human HCC tissues. Furthermore, the miR-28-5p knockdown HCC cells were more sensitive to sorafenib treatment. Analysis of patient-derived xenografts (PDXs) further demonstrated that the miR-28-5p may predict sorafenib benefits in HCC patients. Conclusion. Our findings revealed the crucial role of the miR-28-5p in liver CSC expansion and sorafenib response, rendering miR-28-5p an optimal therapeutic target for HCC.

scholarly journals The Rapid Decrease in Astrocyte-Associated Dystroglycan Expression by Focal Cerebral Ischemia is Protease-Dependent

2007 ◽  
Vol 28 (4) ◽  
pp. 812-823 ◽  
Author(s):  
Richard Milner ◽  
Stephanie Hung ◽  
Xiaoyun Wang ◽  
Maria Spatz ◽  
Gregory J del Zoppo
Keyword(s):  
Cerebral Ischemia ◽  
Basal Lamina ◽  
Focal Cerebral Ischemia ◽  
Glucose Deprivation ◽  
Artery Occlusion ◽  
Receptor Expression ◽  
Cerebral Microvessels ◽  
The Impact

During focal cerebral ischemia, the detachment of astrocytes from the microvascular basal lamina is not completely explained by known integrin receptor expression changes. Here, the impact of experimental ischemia (oxygen—glucose deprivation (OGD)) on dystroglycan expression by murine endothelial cells and astrocytes grown on vascular matrix laminin, perlecan, or collagen and the impact of middle cerebral artery occlusion on αβ-dystroglycan within cerebral microvessels of the nonhuman primate were examined. Dystroglycan was expressed on all cerebral microvessels in cortical gray and white matter, and the striatum. Astrocyte adhesion to basal lamina proteins was managed in part by α-dystroglycan, while ischemia significantly reduced expression of dystroglycan both in vivo and in vitro. Furthermore, dystroglycan and integrin α6β4 expressions on astrocyte end-feet decreased in parallel both in vivo and in vitro. The rapid loss of astrocyte dystroglycan during OGD appears protease-dependent, involving an matrix metalloproteinase-like activity. This may explain the rapid detachment of astrocytes from the microvascular basal lamina during ischemic injury, which could contribute to significant changes in microvascular integrity.

scholarly journals Can Hypoxic Conditioning Improve Bone Metabolism? A Systematic Review

2019 ◽  
Vol 16 (10) ◽  
pp. 1799 ◽  
Author(s):  
Marta Camacho-Cardenosa ◽  
Alba Camacho-Cardenosa ◽  
Rafael Timón ◽  
Guillermo Olcina ◽  
Pablo Tomas-Carus ◽  
...  
Keyword(s):  
Bone Metabolism ◽  
Critical Role ◽  
Hypoxia Inducible Factor ◽  
Experimental Studies ◽  
Hormonal Responses ◽  
Hypoxia Exposure ◽  
Ambient Oxygen ◽  
The Impact

Among other functions, hypoxia-inducible factor plays a critical role in bone–vascular coupling and bone formation. Studies have suggested that hypoxic conditioning could be a potential nonpharmacological strategy for treating skeletal diseases. However, there is no clear consensus regarding the bone metabolism response to hypoxia. Therefore, this review aims to examine the impact of different modes of hypoxia conditioning on bone metabolism. The PubMed and Web of Science databases were searched for experimental studies written in English that investigated the effects of modification of ambient oxygen on bone remodelling parameters of healthy organisms. Thirty-nine studies analysed the effect of sustained or cyclic hypoxia exposure on genetic and protein expression and mineralisation capacity of different cell models; three studies carried out in animal models implemented sustained or cyclic hypoxia; ten studies examined the effect of sustained, intermittent or cyclic hypoxia on bone health and hormonal responses in humans. Different modes of hypoxic conditioning may have different impacts on bone metabolism both in vivo and in vitro. Additional research is necessary to establish the optimal cyclical dose of oxygen concentration and exposure time.

scholarly journals Aging predisposes to acute inflammatory induced pathology after tumor immunotherapy

2013 ◽  
Vol 210 (11) ◽  
pp. 2223-2237 ◽  
Author(s):  
Myriam N. Bouchlaka ◽  
Gail D. Sckisel ◽  
Mingyi Chen ◽  
Annie Mirsoian ◽  
Anthony E. Zamora ◽  
...  
Keyword(s):  
Critical Role ◽  
The Elderly ◽  
Mouse Tumor ◽  
Aged Mice ◽  
Liver Histopathology ◽  
Multiple Organs ◽  
The Impact ◽  
Young Mice

Cancer commonly occurs in the elderly and immunotherapy (IT) is being increasingly applied to this population. However, the majority of preclinical mouse tumor models assessing potential efficacy and toxicities of therapeutics use young mice. We assessed the impact of age on responses to systemic immune stimulation. In contrast to young mice, systemic cancer IT regimens or LPS given to aged mice resulted in rapid and lethal toxicities affecting multiple organs correlating with heightened proinflammatory cytokines systemically and within the parenchymal tissues. This inflammatory response and increased morbidity with age was independent of T cells or NK cells. However, prior in vivo depletion of macrophages in aged mice resulted in lesser cytokine levels, increased survival, and decreased liver histopathology. Furthermore, macrophages from aged mice and normal human elderly volunteers displayed heightened TNF and IL-6 production upon in vitro stimulation. Treatment of both TNF knockout mice and in vivo TNF blockade in aged mice resulted in significant increases in survival and lessened pathology. Importantly, TNF blockade in tumor-bearing, aged mice receiving IT displayed significant anti-tumor effects. These data demonstrate the critical role of macrophages in the age-associated hyper-inflammatory cytokine responses to systemic immunostimulation and underscore the importance of performing preclinical assessments in aged mice.

scholarly journals Targeting the Urotensin II/UT G Protein-Coupled Receptor to Counteract Angiogenesis and Mesenchymal Hypoxia/Necrosis in Glioblastoma

2021 ◽  
Vol 9 ◽  
Author(s):  
Vadim Le Joncour ◽  
Pierre-Olivier Guichet ◽  
Kleouforo-Paul Dembélé ◽  
Alexandre Mutel ◽  
Daniele Campisi ◽  
...  
Keyword(s):  
G Protein ◽  
Nude Mice ◽  
Tumor Development ◽  
Integrin Αvβ3 ◽  
Vascular Density ◽  
Urotensin Ii ◽  
Potential Ligand ◽  
G Protein Coupled

Glioblastomas (GBMs) are the most common primary brain tumors characterized by strong invasiveness and angiogenesis. GBM cells and microenvironment secrete angiogenic factors and also express chemoattractant G protein-coupled receptors (GPCRs) to their advantage. We investigated the role of the vasoactive peptide urotensin II (UII) and its receptor UT on GBM angiogenesis and tested potential ligand/therapeutic options based on this system. On glioma patient samples, the expression of UII and UT increased with the grade with marked expression in the vascular and peri-necrotic mesenchymal hypoxic areas being correlated with vascular density. In vitro human UII stimulated human endothelial HUV-EC-C and hCMEC/D3 cell motility and tubulogenesis. In mouse-transplanted Matrigel sponges, mouse (mUII) and human UII markedly stimulated invasion by macrophages, endothelial, and smooth muscle cells. In U87 GBM xenografts expressing UII and UT in the glial and vascular compartments, UII accelerated tumor development, favored hypoxia and necrosis associated with increased proliferation (Ki67), and induced metalloproteinase (MMP)-2 and -9 expression in Nude mice. UII also promoted a “tortuous” vascular collagen-IV expressing network and integrin expression mainly in the vascular compartment. GBM angiogenesis and integrin αvβ3 were confirmed by in vivo99mTc-RGD tracer imaging and tumoral capture in the non-necrotic area of U87 xenografts in Nude mice. Peptide analogs of UII and UT antagonist were also tested as potential tumor repressor. Urotensin II-related peptide URP inhibited angiogenesis in vitro and failed to attract vascular and inflammatory components in Matrigel in vivo. Interestingly, the UT antagonist/biased ligand urantide and the non-peptide UT antagonist palosuran prevented UII-induced tubulogenesis in vitro and significantly delayed tumor growth in vivo. Urantide drastically prevented endogenous and UII-induced GBM angiogenesis, MMP, and integrin activations, associated with GBM tumoral growth. These findings show that UII induces GBM aggressiveness with necrosis and angiogenesis through integrin activation, a mesenchymal behavior that can be targeted by UT biased ligands/antagonists.

scholarly journals The Impact of Carboxylesterases in Drug Metabolism and Pharmacokinetics

2019 ◽  
Vol 20 (2) ◽  
pp. 91-102 ◽  
Author(s):  
Li Di
Keyword(s):  
Tissue Distribution ◽  
Critical Role ◽  
Individual Variability ◽  
Human Pharmacokinetics ◽  
Metabolizing Enzymes ◽  
Soft Drugs ◽  
Hydrolysis Of Esters ◽  
The Impact

Background:Carboxylesterases (CES) play a critical role in catalyzing hydrolysis of esters, amides, carbamates and thioesters, as well as bioconverting prodrugs and soft drugs. The unique tissue distribution of CES enzymes provides great opportunities to design prodrugs or soft drugs for tissue targeting. Marked species differences in CES tissue distribution and catalytic activity are particularly challenging in human translation.Methods:Review and summarization of CES fundamentals and applications in drug discovery and development.Results:Human CES1 is one of the most highly expressed drug metabolizing enzymes in the liver, while human intestine only expresses CES2. CES enzymes have moderate to high inter-individual variability and exhibit low to no expression in the fetus, but increase substantially during the first few months of life. The CES genes are highly polymorphic and some CES genetic variants show significant influence on metabolism and clinical outcome of certain drugs. Monkeys appear to be more predictive of human pharmacokinetics for CES substrates than other species. Low risk of clinical drug-drug interaction is anticipated for CES, although they should not be overlooked, particularly interaction with alcohols. CES enzymes are moderately inducible through a number of transcription factors and can be repressed by inflammatory cytokines.Conclusion:Although significant advances have been made in our understanding of CESs, in vitro - in vivo extrapolation of clearance is still in its infancy and further exploration is needed. In vitro and in vivo tools are continuously being developed to characterize CES substrates and inhibitors.

Effects of ALK1Fc treatment on prostate cancer cells interacting with bone and bone cells in bone metastasis models.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e16576-e16576
Author(s):  
Marianna Kruithof-de Julio ◽  
Letizia Astrologo ◽  
Eugenio Zoni ◽  
Sofia Karkampouna ◽  
Peter C Gray ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Metastasis ◽  
Cancer Cells ◽  
Bone Cells ◽  
Critical Role ◽  
Prostate Cancer Cells ◽  
Primary Prostate Cancer ◽  
The Impact

e16576 Background: Prostate cancer is the second most common cancer in men worldwide. Lethality is normally associated with the consequences of metastasis rather than the primary tumor. In particular, bone is the most frequent site of metastasis and once prostate tumor cells are engrafted in the skeleton, curative therapy is no longer possible. Bone morphogenetic proteins (BMPs) play a critical role in bone physiology and pathology. However, little is known about the role of BMP9 and its signaling receptors, ALK1 and ALK2, in prostate cancer and bone metastasis. In this context, we investigate the impact of BMP9 on primary prostate cancer and derived bone metastasis. Methods: The human ALK1 extracellular domain (ECD) binds BMP9 and BMP10 with high affinity. In order to study the effect of BMP9 in vitro and in vivo we use a soluble chimeric protein, consisting of ALK1 ECD fused to human Fc (ALK1Fc), for preventing the activation of endogenous signaling. ALK1Fc sequesters BMP9 and BMP10, preserving the activation of ALK1 through other ligands. Results: We show that ALK1Fc reduces BMP9-mediated signaling and decreases proliferation of highly metastatic and tumor initiating human prostate cancer cells in vitro. In line with these observations, we demonstrate that ALK1Fc reduces tumor growth in vivo in an orthotopic transplantation model. The propensity of the primary prostate cancer to metastasize to the bone is also investigated. In particular, we report how the ALK1Fc influences the prostate cancer cells in vitro and in vivo when these are probed in different bone settings (co-culture with bone cells and intraosseous transplantation in mice). Conclusions: Our study provides the first demonstration that ALK1Fc inhibits prostate cancer cells growth identifying BMP9 as a putative therapeutic target and ALK1Fc as a potential therapy. All together, these findings justify the ongoing clinical development of drugs blocking ALK1 and ALK2 receptor activity.

scholarly journals RhoH is critical for cell-microenvironment interactions in chronic lymphocytic leukemia in mice and humans

Blood ◽  
2012 ◽  
Vol 119 (20) ◽  
pp. 4708-4718 ◽  
Author(s):  
Anja Troeger ◽  
Amy J. Johnson ◽  
Jenna Wood ◽  
William G. Blum ◽  
Leslie A. Andritsos ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Critical Role ◽  
Disease Onset ◽  
Lymphocytic Leukemia ◽  
Cell Contact ◽  
Cell Microenvironment ◽  
The Impact ◽  
Cell Cell

Abstract Trafficking of B-cell chronic lymphocytic leukemia (CLL) cells to the bone marrow and interaction with supporting stromal cells mediates important survival and proliferation signals. Previous studies have demonstrated that deletion of Rhoh led to a delayed disease onset in a murine model of CLL. Here we assessed the impact of RhoH on homing, migration, and cell-contact dependent interactions of CLL cells. Rhoh−/− CLL cells exhibited reduced marrow homing and subsequent engraftment. In vitro migration toward the chemokines CXCL12 and CXCL13 and cell-cell interactions between Rhoh−/− CLL cells and the supporting microenvironment was reduced. In the absence of RhoH the distribution of phosphorylated focal adhesion kinase, a protein known to coordinate activation of the Rho GTPases RhoA and Rac, appeared less polarized in chemokine-stimulated Rhoh−/− CLL cells, and activation and localization of RhoA and Rac was dysregulated leading to defective integrin function. These findings in the Rhoh−/− CLL cells were subsequently demonstrated to closely resemble changes in GTPase activation observed in human CLL samples after in vitro and in vivo treatment with lenalidomide, an agent with known influence on microenvironment protection, and suggest that RhoH plays a critical role in prosurvival CLL cell-cell and cell-microenvironment interactions with this agent.

scholarly journals SREBP-1c/MicroRNA 33b Genomic Loci Control Adipocyte Differentiation

2016 ◽  
Vol 36 (7) ◽  
pp. 1180-1193 ◽  
Author(s):  
Nathan L. Price ◽  
Brandon Holtrup ◽  
Stephanie L. Kwei ◽  
Martin Wabitsch ◽  
Matthew Rodeheffer ◽  
...  
Keyword(s):  
Lipid Droplet ◽  
Target Genes ◽  
Adipocyte Differentiation ◽  
Regulatory Element ◽  
Critical Role ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
The Impact

White adipose tissue (WAT) is essential for maintaining metabolic function, especially during obesity. The intronic microRNAs miR-33a and miR-33b, located within the genes encoding sterol regulatory element-binding protein 2 (SREBP-2) and SREBP-1, respectively, are transcribed in concert with their host genes and function alongside them to regulate cholesterol, fatty acid, and glucose metabolism. SREBP-1 is highly expressed in mature WAT and plays a critical role in promotingin vitroadipocyte differentiation. It is unknown whether miR-33b is induced during or involved in adipogenesis. This is in part due to loss of miR-33b in rodents, precludingin vivoassessment of the impact of miR-33b using standard mouse models. This work demonstrates that miR-33b is highly induced upon differentiation of human preadipocytes, along withSREBP-1. We further report that miR-33b is an important regulator of adipogenesis, as inhibition of miR-33b enhanced lipid droplet accumulation. Conversely, overexpression of miR-33b impaired preadipocyte proliferation and reduced lipid droplet formation and the induction of peroxisome proliferator-activated receptor γ (PPARγ) target genes during differentiation. These effects may be mediated by targeting of HMGA2, cyclin-dependent kinase 6 (CDK6), and other predicted miR-33b targets. Together, these findings demonstrate a novel role of miR-33b in the regulation of adipocyte differentiation, with important implications for the development of obesity and metabolic disease.

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