scholarly journals Endothelial Glycocalyx-Mediated Intercellular Interactions: Mechanisms and Implications for Atherosclerosis and Cancer Metastasis

2020 ◽  
Author(s):  
Solomon A. Mensah ◽  
Alina A. Nersesyan ◽  
Eno E. Ebong
Keyword(s):  
Cancer Metastasis ◽  
Vascular System ◽  
Lucifer Yellow ◽  
Critical Role ◽  
Endothelial Glycocalyx ◽  
Dye Transfer ◽  
Intercellular Interaction ◽  
Intercellular Interactions ◽  
The Impact

Abstract Purpose The endothelial glycocalyx (GCX) plays a critical role in the health of the vascular system. Degradation of the GCX has been implicated in the onset of diseases like atherosclerosis and cancer because it disrupts endothelial cell (EC) function that is meant to protect from atherosclerosis and cancer. Examples of such EC function include interendothelial cell communication via gap junctions and receptor-mediated interactions between endothelial and tumor cells. This review focuses on GCX-dependent regulation of these intercellular interactions in healthy and diseased states. The ultimate goal is to build new knowledge that can be applied to developing GCX regeneration strategies that can control intercellular interaction in order to combat the progression of diseases such as atherosclerosis and cancer. Methods In vitro and in vivo studies were conducted to determine the baseline expression of GCX in physiologically relevant conditions. Chemical and mechanical GCX degradation approaches were employed to degrade the GCX. The impact of intact versus degraded GCX on intercellular interactions was assessed using cytochemistry, histochemistry, a Lucifer yellow dye transfer assay, and confocal, intravital, and scanning electron microscopy techniques. Results Relevant to atherosclerosis, we found that GCX stability determines the expression and functionality of Cx43 in gap junction-mediated EC-to-EC communication. Relevant to cancer metastasis, we found that destabilizing the GCX through either disturbed flow-induced or enzyme induced GCX degradation results in increased E-selectin receptor-mediated EC-tumor cell interactions. Conclusion Our findings lay a foundation for future endothelial GCX-targeted therapy, to control intercellular interactions and limit the progression of atherosclerosis and cancer.

scholarly journals The Therapeutic Potential of Tackling Tumor-Induced Dendritic Cell Dysfunction in Colorectal Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Beatriz Subtil ◽  
Alessandra Cambi ◽  
Daniele V. F. Tauriello ◽  
I. Jolanda M. de Vries
Keyword(s):  
Colorectal Cancer ◽  
Cancer Metastasis ◽  
Therapeutic Potential ◽  
Current Knowledge ◽  
Critical Role ◽  
Locally Advanced ◽  
Standard Of Care ◽  
Future Research ◽  
The Impact

Colorectal cancer (CRC) is the third most diagnosed malignancy and the second leading cause of cancer-related deaths worldwide. Locally advanced and metastatic disease exhibit resistance to therapy and are prone to recurrence. Despite significant advances in standard of care and targeted (immuno)therapies, the treatment effects in metastatic CRC patients have been modest. Untreatable cancer metastasis accounts for poor prognosis and most CRC deaths. The generation of a strong immunosuppressive tumor microenvironment (TME) by CRC constitutes a major hurdle for tumor clearance by the immune system. Dendritic cells (DCs), often impaired in the TME, play a critical role in the initiation and amplification of anti-tumor immune responses. Evidence suggests that tumor-mediated DC dysfunction is decisive for tumor growth and metastasis initiation, as well as for the success of immunotherapies. Unravelling and understanding the complex crosstalk between CRC and DCs holds promise for identifying key mechanisms involved in tumor progression and spread that can be exploited for therapy. The main goal of this review is to provide an overview of the current knowledge on the impact of CRC-driven immunosuppression on DCs phenotype and functionality, and its significance for disease progression, patient prognosis, and treatment response. Moreover, present knowledge gaps will be highlighted as promising opportunities to further understand and therapeutically target DC dysfunction in CRC. Given the complexity and heterogeneity of CRC, future research will benefit from the use of patient-derived material and the development of in vitro organoid-based co-culture systems to model and study DCs within the CRC TME.

scholarly journals NLRP7 Promotes Choriocarcinoma Growth and Progression through the Establishment of an Immunosuppressive Microenvironment

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2999
Author(s):  
Deborah Reynaud ◽  
Roland Abi Nahed ◽  
Nicolas Lemaitre ◽  
Pierre-Adrien Bolze ◽  
Wael Traboulsi ◽  
...  
Keyword(s):  
Immune Response ◽  
Tumor Cells ◽  
Major Gene ◽  
Critical Role ◽  
Orthotopic Model ◽  
Independent Manner ◽  
Maternal Immune Response ◽  
The Impact

The inflammatory gene NLRP7 is the major gene responsible for recurrent complete hydatidiform moles (CHM), an abnormal pregnancy that can develop into gestational choriocarcinoma (CC). However, the role of NLRP7 in the development and immune tolerance of CC has not been investigated. Three approaches were employed to define the role of NLRP7 in CC development: (i) a clinical study that analyzed human placenta and sera collected from women with normal pregnancies, CHM or CC; (ii) an in vitro study that investigated the impact of NLRP7 knockdown on tumor growth and organization; and (iii) an in vivo study that used two CC mouse models, including an orthotopic model. NLRP7 and circulating inflammatory cytokines were upregulated in tumor cells and in CHM and CC. In tumor cells, NLRP7 functions in an inflammasome-independent manner and promoted their proliferation and 3D organization. Gravid mice placentas injected with CC cells invalidated for NLRP7, exhibited higher maternal immune response, developed smaller tumors, and displayed less metastases. Our data characterized the critical role of NLRP7 in CC and provided evidence of its contribution to the development of an immunosuppressive maternal microenvironment that not only downregulates the maternal immune response but also fosters the growth and progression of CC.

Gap junction expression and cell proliferation in differentiating cultures of Cx43 KO mouse hepatocytes

2001 ◽  
Vol 281 (4) ◽  
pp. G1004-G1013 ◽  
Author(s):  
Takashi Kojima ◽  
Alfredo Fort ◽  
Mingyuan Tao ◽  
Masao Yamamoto ◽  
David C. Spray
Keyword(s):  
Lucifer Yellow ◽  
Primary Cultures ◽  
Mrna Levels ◽  
Wild Type ◽  
Dye Transfer ◽  
Gap Junctional Communication ◽  
Junctional Communication ◽  
Junctional Conductance ◽  
Mouse Hepatocytes

Primary cultures of adult mouse hepatocytes are shown here to reexpress differentiated hepatocyte features following treatment with 2% DMSO and 10−7 M glucagon. To examine the roles of gap junctional communication during hepatocyte growth and differentiation, we have compared treated and untreated hepatocytes from connexin (Cx)32-deficient [Cx32 knockout (KO)] and wild-type mice. In untreated cultures, DNA replication of Cx32 KO hepatocytes was markedly higher than of wild types. Although Cx26 mRNA levels remained high at all time points in wild-type and Cx32 KO hepatocytes, Cx32 mRNA and protein in wild-type hepatocytes underwent a marked decline, which recovered in 10-day treated cultures. Increased levels of Cx26 protein and junctional conductance were observed in Cx32 KO hepatocytes at 96 h in culture, a time when cell growth rate was high. Treatment with DMSO/glucagon highly reinduced Cx26 expression in Cx32 KO hepatocytes, and such treatment reinduced expression of both Cx32 and Cx26 expression in wild types. Dye transfer was not observed following Lucifer yellow injection into DMSO/glucagon-treated Cx32 KO hepatocytes, whereas the spread was extensive in wild types. Nevertheless, high junctional conductance values were observed in treated cells from both genotypes. These studies provide a method by which the differentiated phenotype can be obtained in cultured mouse hepatocytes and provide in vitro evidence that expression of gap junctions formed of Cx32 are involved in the regulation of growth of mouse hepatocytes.

scholarly journals Acid Challenge on Push-Out Bond Strength of Three Different Tricalcium Silicate Cements: An In-vitro Study

2021 ◽  
pp. 72-79
Author(s):  
Mattapudi Basavaiah Babu ◽  
T. B. V. G. Raju ◽  
N. Mahendra Varma ◽  
Gowtam Dev Dondapati ◽  
Srivalli Podili ◽  
...  
Keyword(s):  
Bond Strength ◽  
Critical Role ◽  
Compressive Load ◽  
Clinical Importance ◽  
Filling Material ◽  
Significant Difference ◽  
The Impact ◽  
Push Out ◽  
Acid Challenge

Aim: To evaluate the impact of environmental pH on intra-radicular dentin push-out bond strengths of MTA, MTA HP, and Biodentine. Materials and Methodology: Freshly extracted human mandibular single-rooted premolars or maxillary anterior incisors that were either intact or contained only small carious lesions were selected.120 mid root dentins is horizontally divided into 1.0 mm thick slices and divided into 3 MTA, MTA HP, BIODENTINE groups. The compressive load is applied at a speed of 0.5 mm/min by exerting a downward pressure on the outer surface of MTA using a 1.00 mm diameter cylindrical stainless-steel plunger. Maximum load to MTA was reported in newtons at the time of dislodgement and converted to megapascals. The 1-way analysis of variance test was used to compare the push-out bond strength of the groups with the same storage time (4 or 34 days), followed by the pair-wise comparison of the Tukey post hoc test. The Student's t-test was used to evaluate 3-group means. At P = .005, the degree of significance was set. Thus the clinical importance of the present study states that considering several factors like microhardness, composition by products, particle sizes and the environmental pH plays a critical role in selection of root end filling material. Results: There was significant difference between groups (P = .001) after 4 days of PBS and Acid condition, where Bio dentine had significantly the highest bond strength. Conclusion: The strength of MTA HP, BIODENTINE, MTA materials at dentine interface increases over 30 days in the storage of PBS solution at pH 7.4, after an initial acid challenge by acetic acid of pH 5.4, which decreases initial bond strength.

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 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 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 S100A4 promotes colorectal carcinoma growth by enhancing aerobic glycolysis

2020 ◽  
Author(s):  
Guiyang Wu ◽  
Chongshan Wu ◽  
Fubo Ye ◽  
Xiongwen Zhu ◽  
Zaiping Chen
Keyword(s):  
Cancer Cell ◽  
Proportional Hazards Model ◽  
Aerobic Glycolysis ◽  
Critical Role ◽  
Cox Proportional Hazards ◽  
Cox Proportional Hazards Model ◽  
Altered Expression ◽  
S100a4 Expression ◽  
The Impact

Abstract Background Glucose metabolism transformation plays critical role in cancer cell malignancies maintenance. Aberrant cancer cell metabolism is considered to be the hallmark of cancer. S100A4 has been identified as an oncogene in a variety of cancers. However, its role in the cancer cell glucose reprogramming has been seldom reported. The aim of this study was to examine the role of S100A4 in aerobic glycolysis in colorectal cancer (CRC). Methods We investigated S100A4 expression in 224 cases of primary CRC and matched normal colonic tissue specimens, and explored the underlying mechanisms of altered S100A4 expression as well as the impact of this altered expression on CRC growth and glycolysis using in vitro and animal models of CRC. Results S100A4 was more highly expressed in CRC tissues than in the adjacent normal tissues (59.4% vs 17.4%, P <0.05). Higher S100A4 expression was associated with advanced node stage ( P =0.018) and larger tumor size ( P =0.035). A Cox proportional hazards model suggested that S100A4 expression was an independent prognostic factor for both OS (HR: 3.967, 95%CI: 1.919-8.200, P <0.001) and DFS (HR: 4.350, 95%CI: 2.264-8.358, P <0.001) in CRC after surgery. Experimentally, silencing S100A4 expression significantly decreased the growth and glycolysis rate of CRC both in vitro and in vivo . Mechanically, S100A4 could affect the hypoxia-inducible factor (HIF)-1α activity as demonstrated by the HIF-1α response element–luciferase activity in CRC cells. Conclusions These results disclose a novel role for S100A4 in reprogramming the metabolic process in CRC by affecting the HIF-1α activity and provide potential prognostic predictors for CRC.

scholarly journals Orai3 Regulates Pancreatic Cancer Metastasis by Encoding a Functional Store Operated Calcium Entry Channel

2021 ◽  
Author(s):  
Samriddhi Arora ◽  
Jyoti Tanwar ◽  
Nutan Sharma ◽  
Suman Saurav ◽  
Rajender K. Motiani
Keyword(s):  
Pancreatic Cancer ◽  
Survival Time ◽  
Cell Lines ◽  
Cancer Progression ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Critical Role ◽  
Mesenchymal Transition

Pancreatic cancer (PC) is one of the most lethal forms of cancers with 5-year mean survival rate of less than 10%. Most of the PC associated deaths are due to metastasis to secondary sites. Calcium (Ca2+) signaling plays a critical role in regulating hallmarks of cancer progression including cell proliferation, migration and apoptotic resistance. Store operated Ca2+ entry (SOCE) mediated by Orai1/2/3 channels is a highly regulated and ubiquitous pathway responsible for Ca2+ influx into non-excitable cells. In this study, we performed extensive bioinformatic analysis of publicly available datasets and observed that Orai3 expression is inversely associated with the mean survival time of PC patients. Orai3 expression analysis in a battery of PC cell lines corroborated its differential expression profile. We then carried out thorough Ca2+ imaging experiments in 6 PC cell lines and found that Orai3 forms a functional SOCE in PC cells. Our in vitro functional assays show that Orai3 regulates PC cell cycle progression, apoptosis and migration. Most importantly, our in vivo xenograft studies demonstrate a critical role of Orai3 in PC tumor growth and secondary metastasis. Mechanistically, Orai3 controls G1 phase progression, matrix metalloproteinase expression and epithelial-mesenchymal transition in PC cells. Taken together, this study for the first time reports that Orai3 drives aggressive phenotypes of PC cells i.e. migration in vitro and metastasis in vivo. Considering that Orai3 expression is inversely associated with the PC patients survival time, it appears to be a highly attractive therapeutic target.

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